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Degeneration of the Cerebellum in Huntington's Disease (HD): Possible Relevance for the Clinical Picture and Potential Gateway to Pathological Mechanisms of the Disease Process
Brain Pathology
Abstract
Huntington's disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo- and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad-based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo-like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD.
... However, the striatum is far from the only region showing pathology in the form of neuronal loss and astrogliosis. Other affected brain regions include the cerebral cortex, hippocampus, thalamic nuclei, brainstem nuclei, and the cerebellum and widespread pathology and reduced volumes can be observed in several regions in early and mid-stage HD 39,[44][45][46] . ...
... The cerebellum in HD While the basal ganglia are the primary site of pathology in HD, there is evidence for early involvement of the cerebellum, although in general, cerebellar pathology is more variable compared to other brain regions 45,50,51 . Intriguingly, it appears the presence and extent of cerebellar pathology in HD patients are not correlated with striatal degeneration or CAG repeat length 45,51 . ...
... The cerebellum in HD While the basal ganglia are the primary site of pathology in HD, there is evidence for early involvement of the cerebellum, although in general, cerebellar pathology is more variable compared to other brain regions 45,50,51 . Intriguingly, it appears the presence and extent of cerebellar pathology in HD patients are not correlated with striatal degeneration or CAG repeat length 45,51 . Cerebellar pathology in HD is predominantly defined by a loss of GABAergic Purkinje cells, the primary output cells of the cerebellum, and general atrophy, while glutamatergic neurons in the granular layer appear comparatively spared 45,51-54 . ...
... The structural imaging studies of HD generally considered the striatum and the cortex as the primary location of pathology, and the cerebellum also showed considerable atrophy in HD (31) and played an important role in HD (31)(32)(33). The degeneration of the cerebellum in HD is correlated with disrupted fine motor skills, postural instability, impaired rapid alternating movements, etc (31). ...
... The structural imaging studies of HD generally considered the striatum and the cortex as the primary location of pathology, and the cerebellum also showed considerable atrophy in HD (31) and played an important role in HD (31)(32)(33). The degeneration of the cerebellum in HD is correlated with disrupted fine motor skills, postural instability, impaired rapid alternating movements, etc (31). ...
... The structural imaging studies of HD generally considered the striatum and the cortex as the primary location of pathology, and the cerebellum also showed considerable atrophy in HD (31) and played an important role in HD (31)(32)(33). The degeneration of the cerebellum in HD is correlated with disrupted fine motor skills, postural instability, impaired rapid alternating movements, etc (31). Our results also showed that the resting-state intrinsic activity of the right cerebellum increased in HD patients, possibly suggesting that increased neural activity was required to counterbalance the structural atrophy of the cerebellum. ...
Introduction
Functional neuroimaging could provide abundant information of underling pathophysiological mechanisms of the clinical triad including motor, cognitive and psychiatric impairment in Huntington's Disease (HD).
Methods
We performed a voxel-based meta-analysis using anisotropic effect size-signed differential mapping (AES-SDM) method.
Results
6 studies (78 symptomatic HD, 102 premanifest HD and 131 healthy controls) were included in total. Altered resting-state brain activity was primarily detected in the bilateral medial part of superior frontal gyrus, bilateral anterior cingulate/paracingulate gyrus, left insula, left striatum, right cortico-spinal projections area, right inferior temporal gyrus area, right thalamus, right cerebellum and right gyrus rectus area. Premanifest and symptomatic HD patients showed different alterative pattern in the subgroup analyses.
Discussion
The robust and consistent abnormalities in the specific brain regions identified in the current study could help to understand the pathophysiology of HD and explore reliable neuroimaging biomarkers for monitoring disease progression, or even predicting the onset of premanifest HD patients.
... The cerebellum plays a role in functions commonly affected in HD patients, such as impairment of dexterity, postural instability, or ataxia-like symptoms. Indeed, the presence of neuropathology in the cerebellum has been described in HD patients and mouse models and 11:17 is predominantly characterized by Purkinje cell loss, while the granular layer is relatively spared [2][3][4][5]. Neuroimaging showed degeneration of cerebellar gray matter in anterior and posterior lobules of the cerebellum in patients with mild motor symptoms [6]. Similarly, significant loss of Purkinje neurons was found in patients with motor phenotypes specifically, corroborating the involvement of the cerebellum in HD symptoms and a correlation of HD phenotype with cerebellar pathology [4]. ...
... Despite the importance of cerebellar disturbances in HD, the mechanisms behind them remain largely unclear. For example, the occurrence and degree of cerebellar pathology do not strictly correlate with CAG repeat length or the degree of striatal degeneration [2,4,9], which begs the question of what other mechanisms drive cerebellar degeneration in HD. Previous studies of mouse and human samples reported gene expression changes in the cerebellum, though delayed in severity compared to the striatum [10][11][12]. ...
... This result was unexpected, as granule cells are typically considered resistant in HD. Instead, compromised function and loss of Purkinje cells is the cerebellar phenotype most described in HD patients and mouse models [2,3,5]. Functional analysis of DEGs in cerebellar vGluT2 + neurons revealed vesicular fusion and exocytosis as predominantly enriched biological processes, suggesting neurotransmitter release and synaptic signaling may be affected. ...
Although Huntington’s disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting primarily of granule cells, commonly considered disease resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected in these neurons. Furthermore, increased expression of cyclin D1 ( Ccnd1 ) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.
... [3] Many publications have provided neuropathological evidence demonstrating its marked atrophy, and image studies have shown significant gray matter (GM) loss in the striatum even in asymptomatic patients suggesting that striatal involvement is an early event of the neurodegenerative process in HD. [4,5] Striatal degeneration might justify most of the progressive symptoms in HD. [6] However, there is emerging evidence of the possible involvement of extrastriatal regions, such as the cerebellum, that might contribute significantly to the explanation of symptoms presented in HD such as impaired gait imbalance, rapid alternating movements, oculomotor changes, and dysarthria. [7][8][9][10] The cerebellum is also implicated in cognitive and psychiatric disturbances [11][12][13][14][15] and may possibly be associated with cognitive function decline and with the development of behavioral changes in HD. [10,16] The cerebellum is located dorsal to the brainstem and is connected to it by three pairs of cerebellar peduncles. It receives input from many areas of the neuro-axis and influences motor performance through connections with the dorsal thalamus and, in the last instance, the motor cortices. ...
... Injury of the hemispheric portion of the cerebellum and globose, emboliform, and/or dentate nucleus leads to difficulty in initiating movements, dysmetria, dysdiadochokinesia, dysarthria, and ataxia (Table 1). [9,17] Thus, the cerebellum has functional connectivity with cortical and subcortical motor structures, playing a crucial role in a cluster of functions ranging from motor control, movement initiation, coordination, modulation of posture and balance, to higher cognitive abilities and behavior. Although all these described functions that are related to the cerebellum may be impaired in HD, the association of cerebellar degeneration in HD is still controversial. ...
... Recent studies have highlighted the signs of cerebellar dysfunction in HD, involving both motor symptoms as psychiatric and cognitive changes, potentially implying that the cerebellum might be more central in HD degeneration than previously established. [9,10,16] In this way, the aim of this article was to systematically review all the current literature to elucidate the cerebellar relationship with HD symptoms. ...
Huntington’s disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.
... The cerebellum plays roles in motor coordination and control, attention, and many other processes [88][89][90]. Earliest reports of HD neuropathology did not note any cerebellar pathology [77], however recent studies have varied in their assessment of cerebellar atrophy, volume loss, and degeneration [3, 36,91]. Vonsattel and others reported that the cerebellum displayed normal neuronal density but was atrophied in late stage HD brains [36,92]. ...
... However, other studies were reporting the density of Purkinje cells were reduced by half [3]. A systematic study using serial sections of the cerebellum in HD brains showed widespread loss of Purkinje cells and degeneration of neurons in the deep cerebellar nuclei present at early stages of HD [91]. Interestingly, when HD patients are separated by symptom predominance, those with predominant motor symptoms had significant loss of Purkinje cells whereas those with predominant mood symptoms did not show any loss of Purkinje cells in the neocerebellum [93]. ...
Huntington’s disease (HD) is a devastating neurodegenerative disease that results in motor, cognitive, and psychiatric impairments. HD results from an autosomal dominant polyglutamine expansion in the huntingtin (HTT) gene that results in a misfolded and aggregated protein. The disease is uniformly fatal and demonstrates characteristic neuropathological changes. While the striatum is preferentially affected, the cortex and many other brain regions are involved in pathogenesis and show progressive changes throughout the disease.
... We also found that lower GM volumes in the cerebellum were associated with lower scores in the psychological wellbeing and the relationship with the environment domain in HD patients. Atrophy of the cerebellum starts in early stages of HD and involves multiple neurodegenerative features [42,46]. Given that cerebellar atrophy is associated with classical HD symptoms (i.e., ataxia, delay in the initiation and termination of movements, hypotonia, dysarthria, and impaired Content courtesy of Springer Nature, terms of use apply. ...
... fine movements) [46], it is to be expected that awareness of these difficulties could lead to negative self-feelings and lower self-esteem, affecting the QoL in the psychological wellbeing domain. Furthermore, because of the progression of motor symptoms, available external resources become scarce, and home environments may have to be greatly accommodated, also negatively affecting the evaluation of the environment. ...
Purpose
Following a case–control design, as a primary objective, this study aimed to explore the relationship between quality of life (QoL) scores and gray matter (GM) volumes in patients with Huntington’s disease (HD). As a secondary objective, we assessed the relationship between QoL scores and other important behavioral, clinical and demographical variables in patients with HD and HD patients’ caregivers.
Methods
We recruited 75 participants (25 HD patients, 25 caregivers, and 25 controls) and assessed their QoL using the World Health Organization Quality of Life scale-Brief Version (WHOQOL-BREF). Participants were also assessed with general cognitive functioning tests and clinical scales. In addition, we acquired MRI scans from all participants.
Results
Our results showed that patients exhibited significantly lower scores in all four QoL domains (physical health, psychological wellbeing, social relationships, and relationship with the environment) compared to caregivers and controls. Caregivers showed lower scores than controls in the physical health and the environmental domains. In HD patients, lower scores in QoL domains were associated with lower GM volumes, mainly in the precuneus and the cerebellum. Moreover, in HD patients, physical disability and GM volume reduction were significant predictors of QoL decrease in all domains. For caregivers, years of formal education was the most important predictor of QoL.
Conclusions
HD patients exhibit greater GM volume loss as well as lower QoL scores compared to caregivers and controls. However, caregivers displayed lower scores in QoL scores than controls, with years of education being a significant predictor. Our results reflect a first attempt to investigate the relationships among QoL, GM volumes, and other important factors in an HD and HD caregiver sample.
... In Huntington disease (HD), the cardinal pathologic features are the worsening, topographic, degeneration of the neostriatum (caudate nucleus, putamen, and nucleus accumbens), in which the medium spiny neuron is the most vulnerable cell type, and the appearance of huntingtin inclusions due to abnormal polyglutamine (polyQ) expansion of the huntingtin protein (HTT) [13,63,64]. Although the brunt of neurodegeneration in HD is concentrated in the neostriatum, morphometric studies of extra-striatal brain regions, such as the frontal neocortex, white matter, thalamus and brainstem, collectively emphasize widespread degeneration in the HD brain [10,22,23,38,[49][50][51][52]. Yet despite the well-described neurodegenerative changes that occur in the HD brain, data on the neuroanatomic distributions of pathologic inclusions are lacking. ...
... Yet despite the well-described neurodegenerative changes that occur in the HD brain, data on the neuroanatomic distributions of pathologic inclusions are lacking. Furthermore, how these proteins relate to striatal neurodegeneration remain uncertain [49][50][51][52]. If aggregated HTT and its oligomers are toxic, then the distribution of these inclusions may be clinically significant and their removal would be therapeutically relevant [2,3,13,16,18,41,59,66]. ...
Huntington disease is characterized by progressive neurodegeneration, especially of the striatum, and the presence of polyglutamine huntingtin (HTT) inclusions. Although HTT inclusions are most abundant in the neocortex, their neocortical distribution and density in relation to the extent of CAG repeat expansion in the HTT gene and striatal pathologic grade have yet to be formally established. We immunohistochemically studied 65 brains with a pathologic diagnosis of Huntington disease to investigate the cortical distributions and densities of HTT inclusions within the calcarine (BA17), precuneus (BA7), motor (BA4) and prefrontal (BA9) cortices; in 39 of these brains, a p62 immunostain was used for comparison. HTT inclusions predominate in the infragranular cortical layers (layers V-VI) and layer III, however, the densities of HTT inclusions across the human cerebral cortex are not uniform but are instead regionally contingent. The density of HTT and p62 inclusions (intranuclear and extranuclear) in layers V-VI increases caudally to rostrally (BA17 < BA7 < BA4 < BA9) with the median burden of HTT inclusions being 38-fold greater in the prefrontal cortex (BA9) than in the calcarine cortex (BA17). Conversely, intranuclear HTT inclusions prevail in the calcarine cortex irrespective of HTT CAG length. Neocortical HTT inclusion density correlates with CAG repeat expansion, but not with the neuropathologic grade of striatal degeneration (Vonsattel grade) or with the duration of clinical disease since motor onset. Extrapolation of these findings suggest that HTT inclusions are at a regionally-contingent, CAG-dependent, density during the advanced stages of HD. The distribution and density of HTT inclusions in HD therefore does not provide a measure of pathologic disease stage but rather infers the degree of pathogenic HTT expansion.
... Although SCA2 primarily affects cerebellum, HD is primarily characterized by atrophy of striatum and cerebral cortex. 69 However, recent evidence indicates that cerebellum is also affected in HD 70,71 and, in fact, appears to degenerate early 72 and independently from the striatal atrophy. 72 This suggests that similar mechanism of pathogenesis may contribute to cerebellar pathology in both SCA2 and HD. ...
... 69 However, recent evidence indicates that cerebellum is also affected in HD 70,71 and, in fact, appears to degenerate early 72 and independently from the striatal atrophy. 72 This suggests that similar mechanism of pathogenesis may contribute to cerebellar pathology in both SCA2 and HD. Whether and to which degree mutant RNA-triggered mechanisms contribute to this pathology remain to be further determined. ...
Background:
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin-2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis.
Objective:
Here, we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis.
Methods:
The toxic effect of expATXN2 transcripts on SK-N-MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if ribosomal RNA (rRNA) processing is disrupted in SCA2 and Huntington's disease (HD) human brain tissue.
Results:
expATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin β-like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue.
Conclusion:
These findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role of expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
... Huntington's disease (HD) is a rare, hereditary, neurodegenerative disorder presenting as a mutation in the huntingtin gene (HTT) on chromosome 4p16.3. 1 The HTT gene contains a trinucleotide cytosine-adenine-guanine (CAG) repeat sequence, which, in healthy individuals, is below 36 repeats. Expansion above this number leads to the patient developing symptoms, usually in midlife, although the precise age of onset depends on the length of the CAG repeat expansion (longer repeats are associated with earlier onset of the disease) and other genetic factors that are currently only partially understood. 2 Clinically, HD is characterized by motor deficits (including chorea, bradykinesia, dystonia, rigidity, dysarthria, and dysphagia), cognitive deficits, behavioral co-morbidities, and eye movement abnormalities. ...
... Expansion above this number leads to the patient developing symptoms, usually in midlife, although the precise age of onset depends on the length of the CAG repeat expansion (longer repeats are associated with earlier onset of the disease) and other genetic factors that are currently only partially understood. 2 Clinically, HD is characterized by motor deficits (including chorea, bradykinesia, dystonia, rigidity, dysarthria, and dysphagia), cognitive deficits, behavioral co-morbidities, and eye movement abnormalities. 1,[3][4][5][6][7][8] The pathophysiology of HD is strikingly selective, with atrophy affecting the striatum (caudate and putamen), especially in the early disease stages 9 and the external segment of the globus pallidus. Later on as neurodegeneration becomes more widespread, the brainstem, 1,10-12 thalamus, 13,14 and multiple cortical regions [15][16][17] are also affected. ...
Huntington's disease (HD), a genetically determined neurodegenerative disease, is positively correlated with eye movement abnormalities in decision making. The antisaccade conflict paradigm has been widely used to study response inhibition in eye movements, and reliable performance deficits in HD subjects have been observed, including a greater number and timing of direction errors. We recorded the error rates and response latencies of early HD patients and healthy age-matched controls performing the mirror antisaccade task. HD participants displayed slower and more variable antisaccade latencies and increased error rates relative to healthy controls. A competitive accumulator-to-threshold neural model was then employed to quantitatively simulate the controls' and patients' reaction latencies and error rates and uncover the mechanisms giving rise to the observed HD antisaccade deficits. Our simulations showed that (1) a more gradual and noisy rate of accumulation of evidence by HD patients is responsible for the observed prolonged and more variable antisaccade latencies in early HD; (2) the confidence level of early HD patients making a decision is unaffected by the disease; and (3) the antisaccade performance of healthy controls and early HD patients is the end product of a neural lateral competition (inhibition) between a correct and an erroneous decision process, and not the end product of a third top-down stop signal suppressing the erroneous decision process as many have speculated.
... Finally, our observation that in cerebellum the mHTT CAG tract is unstable selectively in Purkinje cells is consistent with somatic expansion of the CAG tract being a prerequisite of mHTT toxicity since these neurons have been shown to be vulnerable in HD 32,59,60 . ...
Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington's disease (HD). However, the relationships between CAG expansions, death of specific cell types, and molecular events associated with these processes are not established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise in striatal medium spiny neurons (MSNs) and cholinergic interneurons, in cerebellar Purkinje neurons, and at mATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1 in a concentration-dependent manner. Our data indicate that ongoing CAG expansions are not sufficient for cell death, and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity. was not certified by peer review)
... CAG重复部分的常染色体显性遗传引起 [29] . 纹状体变 性是HD的病理标志, HD患者伴随着皮质与白质束的 进行性萎缩 [30] 和小脑退化 [31] . 成人HD患者主要表现为 运动过度, 但患者也会经历无法自主控制正常步态运 动的状态, 包括运动迟缓、运动不持续、姿势反射丧 失、共济失调和肌张力障碍等 [29] . ...
... The developmental peak of PCs occurs in the postnatal period in mice. A variety of diseases (e.g., spinocerebellar ataxia [5,6], idiopathic tremor [7,8], Huntington's disease [9] and Autism Spectrum Disorder [10]) are accompanied by PC degeneration, which is a key factor causing disordered cerebellar function. A variety of genes have been found to be involved in the maintenance of PC physiological function [11,12], but the precise molecular mechanisms underlying the development and survival of PCs are unclear. ...
Purkinje cells (PCs), as a unique type of neurons output from the cerebellar cortex, are essential for the development and physiological function of the cerebellum. However, the intricate mechanisms underlying the maintenance of Purkinje cells are unclear. The O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuity. In this study, we demonstrate that the O-GlcNAc transferase (OGT) in PCs maintains the survival of PCs. Furthermore, a loss of OGT in PCs induces severe ataxia, extensor rigidity and posture abnormalities in mice. Mechanistically, OGT regulates the survival of PCs by inhibiting the generation of intracellular reactive oxygen species (ROS). These data reveal a critical role of O-GlcNAc signaling in the survival and maintenance of cerebellar PCs.
... The cerebellum is connected to the cerebral cortex, regulating precise motor, cognitive, executive and emotional functions and playing a role in the cerebro-cerebellar network [18,29,76,77,82]. Morphological studies [29,[83][84][85] have also confirmed extensive links between the cerebellum and cerebral cortex, subcortical structures, and they are an important part of feed-forward and feedback circuits. Our results are in agreement with previously mentioned studies. ...
Parkinson’s disease (PD) is a highly heterogeneous disorder that is difficult to diagnose. Therefore, reliable biomarkers are needed. We implemented a method constructing a regional radiomics similarity network (R2SN) based on the amplitude of low-frequency fluctuation (ALFF). We classified patients with PD and healthy individuals by using a machine learning approach in accordance with the R2SN connectome. The ALFF-based R2SN exhibited great reproducibility with different brain atlases and datasets. Great classification performances were achieved both in primary (AUC = 0.85 ± 0.02 and accuracy = 0.81 ± 0.03) and independent external validation (AUC = 0.77 and accuracy = 0.70) datasets. The discriminative R2SN edges correlated with the clinical evaluations of patients with PD. The nodes of discriminative R2SN edges were primarily located in the default mode, sensorimotor, executive control, visual and frontoparietal network, cerebellum and striatum. These findings demonstrate that ALFF-based R2SN is a robust potential neuroimaging biomarker for PD and could provide new insights into connectome reorganization in PD.
... HD is caused by a trinucleotide repeat expansion in exon 1 of the HTT gene (≥40 CAG repeats) and is characterized by loss of medium spiny neurons in the striatum and pyramidal neurons of layers 5 and 6 of the motor cortex [10,11]. Damage later extends to most areas of brain including the thalamus and cerebellum [12][13][14][15][16][17][18]. Aggregation of the expanded mutant Huntingtin protein (mHTT) in the brain results in cellular dysfunction, and the rate of aggregation is directly proportional to the uninterrupted CAG repeat length [19][20][21][22]. ...
Background:
Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity.
Objective and methods:
Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep.
Results:
Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination.
Conclusion:
This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.
... The accumulation of mHTT in the dorsal striatum and the consequent atrophy of this region is a neuropathological hallmark of HD (Ru¨b et al., 2016). Atrophy is also observed in other brain areas like cerebral cortex, cerebellum, hypothalamus, hippocampus, thalamus and brainstem, all of which contribute for the constellation of clinical symptoms observed in HD (Rüb et al., 2013;Ru¨b et al., 2014). Fig. 1. ...
Huntington’s disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1β and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms.
... However, different experimental approaches have shown its role in some types of memory, 1,2 planning and sensory discrimination, [3][4][5] language, 6,7 reward, 8,9 sexual behavior 10-12 and motor control during sexual performance. 13,14 Accordingly, it has been argued that an anatomical and functional relationship must exist between the cerebellum and the basal ganglia, which would help explain some mechanisms behind motor disorders such as Parkinson's disease, 15 Huntington, 16 attention deficit disorder, 17 depression, 18 and obsessive-compulsive disorder, among others. 19 One former study carried out on macaques showed an anatomical relationship between the basal ganglia and the cerebellum through a disynaptic connection of the cerebellar dentate nucleus (DN) that crossed from the thalamus to the striatum. ...
Introduction: The cerebellar response has been studied for years with different models of
alteration of other brain structures to understand its complex functioning and its relationship with the rest of the body. Studies in patients with Parkinson’s disease (PD) showed that the cerebellar function is modified by deficit of the basal ganglia; which supports the hypothesis that both structures are related anatomically and functionally.
Methods: In our study, the ventrolateral striatum (VLS) of the basal ganglia was altered by
an electrolytic lesion, in order to produce a similar jaw frequency of jaw tremor movements presented in parkinsonism, thereafter we analyzed the effect of the lesion on the expression of multiunit activity (MUA) of the cerebellum.
Results: We found cerebellar activation during mandibular movements and increment during oral jaw tremor movements. In addition, the amplitude of baseline MUA registered in animals with alteration of the VLS decreased with respect to the intact group.
Conclusions: Accordingly, we conclude that cerebellar changes in MUA may be due to a
decrease in the cerebellar inflectional or as a possible compensatory function between cerebellum and basal ganglia.
... He also detected that the mainly segmental loss of Purkinje cells is inconsistent across the HD brains examined. In contrast, Rüb et al. [33] found Purkinje cell loss in the cerebellum and loss of neurons in the four cerebellar nuclei. In a recent study, significant Purkinje cell loss was correlated with motor impairments, whereas no loss was associated with a major mood-phenotype in HD [34]. ...
Neuropathology of Huntington's disease (HD) presents with progredient neuronal cell loss mainly in the striatum, but also in multiple other brain areas suggesting HD as a multisystem neurodegenerative disorder. Mutant huntingtin aggregates are the characteristic hallmark of HD. The aggregates are misfolded proteins varying in location, form, size and structural composition indicating a complex involvement in neurotoxicity. The question if and how the aggregates and many interacting protein partners may lead to cell death is continuously a matter of debate. The role of mutant huntingtin is more than ever of paramount importance as present genetic therapeutic approaches try to target downregulation of the Huntingtin gene expression and/or lowering the corresponding protein. In this context-and these aspects are focussed-it is of crucial interest to elucidate the regional distribution as well as the cellular and subcellular localization of aggregates in established animal models of HD and in affected HD brains.
... 88,89 Astrogliosis occurs in multiple brain regions in Huntington's disease, including the cerebellum. 90 In this study, both the white and grey matter of a specific cortical functional region were used for comparative analysis. The dorsomedial prefrontal cortex is associated with social cognition, 91 which is impaired early in Huntington's disease. ...
Huntington’s disease is a devastating neurodegenerative disorder that onsets in late adulthood as progressive and terminal cognitive, psychiatric and motor deficits. The disease is genetic, triggered by a CAG repeat (polyQ) expansion mutation in the Huntingtin gene and resultant huntingtin protein. Although the mutant huntingtin protein is ubiquitously expressed, the striatum degenerates early and consistently in the disease. The polyQ mutation at the N-terminus of the huntingtin protein alters its natural interactions with neural phospholipids in vitro, suggesting that the specific lipid composition of brain regions could influence their vulnerability to interference by mutant huntingtin; however, this has not yet been demonstrated in vivo. Sphingolipids are critical cell signalling molecules, second messengers and membrane components. Despite evidence of sphingolipid disturbance in Huntington’s mouse and cell models, there is limited knowledge of how these lipids are affected in human brain tissue. Using post-mortem brain tissue from five brain regions implicated in Huntington’s disease (control n = 13, Huntington’s n = 13), this study aimed to identify where and how sphingolipid species are affected in the brain of clinically advanced Huntington’s cases. Sphingolipids were extracted from the tissue and analysed using targeted mass spectrometry analysis; proteins were analysed by western blot. The caudate, putamen and cerebellum had distinct sphingolipid changes in Huntington’s brain whilst the white and grey frontal cortex were spared. The caudate of Huntington’s patients had a shifted sphingolipid profile, favouring long (C13–C21) over very-long-chain (C22–C26) ceramides, sphingomyelins and lactosylceramides. Ceramide synthase 1, which synthesizes the long-chain sphingolipids, had a reduced expression in Huntington’s caudate, correlating positively with a younger age at death and a longer CAG repeat length of the Huntington’s patients. The expression of ceramide synthase 2, which synthesizes very-long-chain sphingolipids, was not different in Huntington’s brain. However, there was evidence of possible post-translational modifications in the Huntington’s patients only. Post-translational modifications to ceramide synthase 2 may be driving the distinctive sphingolipid profile shifts of the caudate in advanced Huntington’s disease. This shift in the sphingolipid profile is also found in the most severely affected brain regions of several other neurodegenerative conditions and may be an important feature of region-specific cell dysfunction in neurodegenerative disease.
... As the primary cell of the cerebellar cell, purkinje cells play an important role in the coordination and learning of the motor system. Previous studies have reported that the inevitable loss of purkinje causes various motor disorders, such as autism, ataxia, and Huntington's disease (37). ...
Background: Diabetes mellitus can lead to histomorphometrical changes in the brain. Recent studies have shown that Aloe vera gel has antioxidant and neuroprotective effects, which is independent of glucose-lowering effects. Objectives: The present study aimed to investigate the effects of A. vera gel on histomorphometrical changes of cerebellum following streptozotocin (STZ)-induced diabetic male rats. Methods: A total of 25 male Wistar rats were randomly allocated into five groups as follows: (1) the control group received normal saline; (2) A. vera gel group; (3) diabetic group (normal saline); (4) treatment group diabetic rats, which received A. vera; and (5) diabetic rats which received insulin. A single dose of STZ [60 mg/kg; intraperitoneal (IP)] was used for the induction of diabetes in rats. All the treatments were administered daily for eight weeks. Subsequently, histomorphometrical changes were evaluated in the cerebellum of the rats. Results: The results showed that the number of granular and purkinje cells reduced in the cerebellum granulosa region, while the number of glial cells increased in the molecular region of the cerebellum in diabetic rats compared to the control group (P < 0.05). These changes were improved in treated rats by insulin or A. vera. Also, the thickness of molecular, purkinje, granular, and white matter layers at the apex of lobules and depth of sulcus in the diabetic group had a significant reduction compared to other groups (P < 0.001). Conclusions: Our results confirmed that improvement of the cerebellar tissue changes in diabetic rats following the use of A. vera gel is comparable to insulin. However, more investigations are required to determine the protective effects of A. vera gel against diabetes-induced cerebellum histomorphometrical changes.
... This atrophy of the striatum constitutes the neuropathological hallmark of HD [22]. Aside from the striatum, atrophy is also observed in the cerebral cortex, cerebellum, hypothalamus, hippocampus, and select nuclei within the thalamus and brainstem [22][23][24][25][26][27][28]. ...
Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.
... While striatal degeneration is a pathologic hallmark of HD, longitudinal imaging studies have demonstrated progressive atrophy of the cortex and white matter tracts as well (Tabrizi et al., 2012). There is additional evidence to suggest that degeneration of the cerebellum occurs (Rüb et al., 2013). These pathologic changes help to explain the motor heterogeneity observed clinically in patients with HD. ...
Disturbances of gait occur in all stages of Huntington’s disease (HD) including the premanifest and prodromal stages. Individuals with HD demonstrate the slower speed of gait, shorter stride length, and increased variability of gait parameters as compared to controls; cognitive disturbances in HD often compound these differences. Abnormalities of gait and recurrent falls lead to decreased quality of life for individuals with HD throughout the disease. This scoping review aims to outline the cross-disciplinary approach to gait evaluation in HD and will highlight the utility of objective measures in defining gait abnormalities in this patient population.
... For example, in Huntington dis ease, huntingtin is expressed in most tissues, and although its expression is highest in the nervous system, the protein is not confined to areas susceptible to neurodegeneration 239 . Although many other polyQ diseases cause pronounced cerebellar ataxia, this symptom is considered rare in Huntington disease, even though mutant huntingtin inclusions are observed in the cerebellum 240 . ...
... For example, in Huntington dis ease, huntingtin is expressed in most tissues, and although its expression is highest in the nervous system, the protein is not confined to areas susceptible to neurodegeneration 239 . Although many other polyQ diseases cause pronounced cerebellar ataxia, this symptom is considered rare in Huntington disease, even though mutant huntingtin inclusions are observed in the cerebellum 240 . ...
The human genome contains more than one million short tandem repeats, and expansion of a subset of these repeat tracts underlies more than 50 human disorders. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.
... The statistical maps (right) compare regional activity without PVC normalized to cerebellar activity to a group of age matched controls using (MI Neurology, Siemens) displayed in Z-scores with color scale shown. of the different brain structures, we chose the cerebellum as reference. A prior study have described early changes in this structure and suggests that the degeneration of cerebellum is early and independent from the striatal atrophy [27]. We found no visual atrophy of the cerebellum of our participants. ...
Background
Huntington’s disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions.
Objective
Evaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs).
Methods
21 HDGECs and 17 controls had a hybrid 2-[ ¹⁸ F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAP S ).
Results
We found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAP S and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAP S scores. Statistical parametric mapping confirmed the results.
Conclusions
A hybrid 2-[ ¹⁸ F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.
... Nonetheless, how these abnormalities play a contributing role in the pathophysiology of the disease is still a matter of debate. From a neuropathological point of view, HD is characterized by a bilateral and symmetrical neuronal loss in the neostriatum, mainly caused by the extensive demise of GABAergic medium spiny stellate projections neurons (52)(53)(54)(55)(56)(57). The lack of any inhibitory cerebellar effect in patients with dystonia may contribute to the loss of M1 inhibition and the development of incorrect motor programs and maladaptive behaviors (58,59). ...
Introduction: In recent years, a growing body of literature has investigated the use of non-invasive brain stimulation (NIBS) techniques as a putative treatment in Huntington's Disease (HD). Our aim was to evaluate the effects of cerebellar transcranial Direct Current Simulation (ctDCS) on the motor outcome in patients affected by HD, encompassing at the same time the current knowledge about the effects of NIBS both on motor and non-motor dysfunctions in HD.
Materials and Methods: Four patients (two females) were enrolled and underwent ctDCS (both anodal or sham, elapsed by at least 3 months: 2.0 mA, 20 min per day, 5 days a week). Clinical scores were assessed by using the Unified Huntington's Disease Rating Scale – part I (UHDRS-I), immediately before ctDCS (T0), at the end of the 5-days treatment (T1) and 4 weeks later (T2).
Results: Anodal ctDCS improved motor scores compared to baseline (p = 0.0046), whereas sham stimulation left them unchanged (p = 0.33, Friedman test). In particular, following anodal ctDCS, UHDRS-I score significantly improved, especially regarding the subitem “dystonia,” both at T1 and T2 compared to sham condition (p < 0.05; Wilcoxon matched-pairs signed test).
Conclusions: ctDCS improved motor scores in HD, with effects lasting for about 4 weeks after tDCS completion. This is the first study discussing the putative role of cerebellar non-invasive simulation for the treatment of HD.
... Ataxia represents a syndrome that is composed of numerous signs and symptoms that are characterized by the presence of gait ataxia, dystasia, dysmetria, dysdiadokokinesia, dysarthria, presence of pendular reflexes, kinetic tremors among others (10). Although some studies have demonstrated pathological changes in the cerebellum as Purkinje cells degeneration (11)(12)(13), clinical studies to evaluate cerebellar signs in HD are scarce. ...
Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum.
Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD.
Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity.
Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001).
Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.
... HD manifests a triad of signs, including severe motor dysfunction with involuntary movements (chorea), cognitive impairment and neuropsychiatric symptoms. Even though mutant htt severely affects striatal neurons, other areas, such as cortex, hippocampus, amygdala or cerebellum, display synaptic alterations, atrophy, and/or neuronal death 5,6 . ...
RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington’s disease (HD) patients’ putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.
... Medium spiny neurons of the striatum region are exceptionally vulnerable to mHTT [1]. Nonetheless, neuronal dysfunction and neurodegeneration have also been reported in the cerebral cortex [5], cerebellum [6] and substantia nigra [7,8]. ...
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by severe symptoms, including motor impairment, cognitive decline, and psychiatric alterations. Several systems, molecules, and mediators have been associated with the pathophysiology of HD. Among these, there is the Renin-Angiotensin System (RAS), a peptide hormone system that has been associated with the pathology of neuropsychiatric and neurodegenerative disorders. Important alterations in this system have been demonstrated in HD. However, the role of RAS components in HD is still unclear and needs further investigation. Nonetheless, modulation of the RAS components may represent a potential therapeutic strategy for the treatment of HD.
Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases.
Neuroimaging is increasingly being included in clinical trials of Huntington’s disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.
Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.
Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt–Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.
Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA’s suppression of disease-associated repeat expansions, which may extend to other DNA processes.
Background:
Huntington's disease (HD) is characterized by a loss of control of motor function that causes the presence of abnormal eye movements at early stages.
Objective:
To determine if, compared to normal sheep, HD sheep have abnormal eye movements.
Methods:
We measured eye movements in a transgenic sheep (Ovis aries) model of HD using a purpose-built, head-mounted sheep oculometer. This allows us to measure saccades without the need for either behavioral training or head fixation. At the age of testing (6 years old), the HD sheep were pre-manifest. We used 21 sheep (11 HD, 10 normal).
Results:
We found small but significant differences in eye movements between normal (control) and HD sheep during vestibular ocular reflex (VOR)- and vestibular post-rotational nystagmus (PRN)-based tests.
Conclusions:
Two measures were identified that could distinguish normal from HD sheep; the number of PRN oscillations when tested in the dark and the gain (eye movement to head movement ratio) during the VOR when tested in the light. To our knowledge, this is the first study in which eye movements have been quantified in sheep. It demonstrates the feasibility of measuring and quantifying human-relevant eye movements in this species. The HD-relevant deficits show that even in 'premanifest' sheep there are measurable signs of neurological dysfunction that are characterized by loss of control of eye movements.
Biomarkers are of great importance in the prediction of onset and follow-up of patients with Huntington’s disease (HD). Neuroimaging is a convenient biomarker, because of its non-invasive character. Since technology is continuously evolving, we are increasingly able to visualize detailed neural structures and functions. Furthermore, it could also identify new targets for therapeutic interventions. In this chapter, we review findings in neuroimaging research applied to HD. First, we will describe the neuroanatomical structures and cellular processes, which are important in the pathophysiology of HD and are therefore particularly interesting to focus on. We will then discuss the different imaging modalities; from structural to functional, from commonly used to novel imaging strategies. Striatal- and cortical-volume loss on conventional MRI and decrease in uptake of radiotracers on PET are currently the most robust markers of disease progression. The use of other MRI-metabolites, specific PET radioligands, DTI, and fMRI may have the potential to detect HD pathology earlier and more accurately but needs further investigation. These neuroimaging markers, possibly combined, can be useful clinical outcome measures in clinical trials and could improve the management and treatment of future patients.
Evaluating and quantifying the many aspects of movement -- from open-field locomotion and stepping patterns in rodent models to stride trajectory and postural sway in human patients -- are key to understanding brain function. Various experimental approaches have been used in applying these lines of research to investigate the brain mechanisms underlying neurodegenerative disease. Although valuable, data on movement are often limited by the shortcomings inherent in the data collection process itself. Steve Fowler and his research group have been instrumental in pioneering a technology that both minimizes these pitfalls in studies of rodent behavior and has applications to research on human patients. At the center of this technology is the force-plate actometer, developed by the Fowler group to assess multiple aspects of movement in rodent models. Our review highlights how use of the actometer and related behavioral measurements provides valuable insight into Huntington’s disease (HD), an autosomal dominant condition of progressively deteriorating behavioral control. HD typically emerges in mid-life and has been replicated in multiple genetically engineered mouse models. The actometer also can be a valuable addition to cutting-edge neuronal and synaptic technologies that are now increasingly applied to studies of behaving animals. In short, the impact of the Fowler contribution to the neuroscience of movement is both meaningful and ongoing.
Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are neurodegenerative disorders characterized by progressive structural and functional loss of specific neuronal populations, protein aggregation, an insidious adult onset, and chronic progression. Modeling AD, PD, and HD in animal models is useful for studying the relationship between neuronal dysfunction and abnormal behaviours. Animal models are also excellent tools to test therapeutic approaches. Numerous genetic and toxin-induced models have been generated to replicate these neurodegenerative disorders. These differ in the genetic manipulation employed or the toxin used and the brain region lesioned, and in the extent to which they mimic the neuropathological and behavioral deficits seen in the corresponding human condition. Each model exhibits unique advantages and drawbacks. Here we present a comprehensive overview of the numerous AD, PD, and HD animal models currently available, with a focus on their utilities and limitations. Differences among models might underlie some of the discrepancies encountered in the literature and should be taken into consideration when designing new studies and testing putative therapies.
GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors. SIGNIFICANCE STATEMENT: α6-Containing GABAA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABAA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.
Background and Objectives
Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo .
Methods
In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with ¹¹ C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for ¹¹ C-UCB-J with the centrum semiovale as reference region. ¹⁸ F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest– and voxel-based analyses were performed. Correlations between clinical scores and ¹¹ C-UCB-J PET data were calculated.
Results
Eighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced ¹⁸ F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, ¹¹ C-UCB-J and ¹⁸ F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment.
Discussion
Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. ¹¹ C-UCB-J PET is more sensitive than ¹⁸ F-FDG-PET for detection of extrastriatal changes in early HD.
Classification of Evidence
This study provides Class III evidence that ¹¹ C-UCB-J PET accurately discriminates individuals HD from normal controls.
Huntington’s disease is a chronic neurodegenerative disorder caused by mutations in the huntingtin gene which results in abnormal expansion of trinucleotide repeats. The disease most severely affects the striatum but studies have shown that pathologic changes are widespread. Patients present with progressive cognitive, psychiatric, and motor symptoms that are initially hyperkinetic in the form of choreoathetosis. The diagnosis is largely based on a combination of neurologic manifestations, family history, and genetic analysis. While the primary role of neuroimaging is the exclusion of alternative diagnoses, Huntington’s disease demonstrates characteristic structural changes on MRI, and volumetric studies may detect early changes several years before diagnosis. Positron emission tomography (PET) demonstrates metabolic abnormalities in involved pathways which in some studies have been associated with motor and cognitive dysfunction, disease severity, and duration of symptoms. As there are no specific biomarkers for HD, systems and processes studies with PET include glucose metabolism, blood flow, dopaminergic system, microglial activation, and phosphodiesterase activity, as well as the density and distribution of various neurotransmitter receptors.
Background
Neurologists refer to numerous “syndromes,” consisting of specific combinations of clinical manifestations, following a specific progression pattern, and with the support of blood analysis (without genomic-proteomic parameters) and neuroimaging findings (MRI, CT, perfusion SPECT, or ¹⁸F-FDG-PET scans). Neurodegenerative “diseases,” on the other hand, are defined by specific combinations of clinical signs and histopathological findings; these must be confirmed by a clinical examination and a histology study or evidence of markers of a specific disorder for the diagnosis to be made. However, we currently know that most genetic and histopathological alterations can result in diverse syndromes. The genetic or histopathological aetiology of each syndrome is also heterogeneous, and we may encounter situations with pathophysiological alterations characterising more than one neurodegenerative disease. Sometimes, specific biomarkers are detected in the preclinical stage.
Development
We performed a literature review to identify patients whose histopathological or genetic disorder was discordant with that expected for the clinical syndrome observed, as well as patients presenting multiple neurodegenerative diseases, confirming the heterogeneity and overlap between syndromes and diseases. We also observed that the treatments currently prescribed to patients with neurodegenerative diseases are symptomatic.
Conclusions
Our findings show that the search for disease biomarkers should be restricted to research centres, given the lack of disease-modifying drugs or treatments improving survival. Moreover, syndromes and specific molecular or histopathological alterations should be managed independently of one another, and new “diseases” should be defined and adapted to current knowledge and practice.
Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington’s disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent brain imaging analyses have provided conflicting results regarding the cerebellar changes during the progression of this disease. To help in resolving this controversy, we examined the cerebellar gray matter structural integrity from a cohort of HD patients. Whole brain voxel-based morphometry (VBM) and spatially unbiased atlas template of the human cerebellum (SUIT) analyses were done from T1-weighted brain images. Our results showed a significant cerebellar degeneration without any sign of volume increase. The highest cerebellar degeneration was identified in Crus I right lobule, Crus II bilaterally, and left VIIb, and left VIIIa lobules. The cerebellar degeneration signature, which controls for severity of degeneration, showed a degeneration pattern that included regions I–IV, Crus II, VIIb, VIIIa, VIIIb and X.
Purpose
Functional MRI has played a fundamental role in Parkinson's disease(PD) study. In this paper, we performed an independent component analysis (ICA) based on functional networks to reveal the intricate variations on the morphology and functional properties of brain. Our analysis aims at discovering the differences between PD patients with sensorimotor function impairment and normal controls(NC), thus helping to understand the coordination neurological function degeneration in PD objectively.
Method
We investigated the blood oxygen level dependent(BOLD) functional MRI obtained at a 3.0 T MRI scanner. 30 PD patients and 28 NC subjects underwent the scan in resting state. The signals of sensory and motor coordinative control areas in the sensorimotor, insula and cerebellum networks acquired by ICA(Independent Component Analysis)were applied to analyze the functional alterations. Specifically, intra-network analysis was performed with signals in local networks, and inter-network analysis was conducted by functional network connectivity (FNC) with signals across different networks. Two sample T test was carried out to detect the significant (p < 0.05, FDR p < 0.05) functional abnormality in PD patients.
Conclusion
We identified an obvious increase in bilateral posterior insula, but decrease in bilateral cerebellum hemisphere, supplementary motor area(SMA) and precentral gyrus paracentral lobule of left postcentral gyrus. Besides, we found a significantly increased connection between independent component (IC) 13 which was located in right postcentral gyrus and cerebellum. Decreased connections were detected between sensory and motor cortex in sensorimotor network and between cerebellum and insula network by FNC analysis in PD patients as well.
Discussion
Parkinson's disease derives from the degeneration of the dopaminergic neurons in substantia nigra, and results in decreased secretion of inhibitory neurotransmitter. The significant differences between PD and NC groups in our research maybe explain the clinical manifestations of prominent bradykinesia and multiple extrapyramidal symptoms.
Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington’s disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain develop recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.
The basal ganglia are a group of closely connected cell masses, forming a more or less continuum, extending from the telencephalon to the midbrain tegmentum (Sect. 11.3). A few notes on the development of the basal ganglia are presented in Sect. 11.2. This complex comprises the striatum (the nucleus caudatus and the putamen, largely separated by the internal capsule), the globus pallidus, the subthalamic nucleus and the substantia nigra. The output of the basal ganglia is aimed at the ventral anterior (VA) and ventrolateral (VL) thalamic nuclei or VA-VL complex, the centromedian thalamic nucleus, the habenula, the pedunculopontine tegmental nucleus and the superior colliculus. In most non-primate mammals, the caudate and putamen are not clearly separated by an internal capsule and are known as the caudate-putamen complex or striatum. In primates, the globus pallidus consists of external or lateral and internal or medial segments. In other mammals, the entopeduncular nucleus is the homologue of the internal segment. The caudate nucleus, the putamen and the globus pallidus form the dorsal part of the striatal complex. The nucleus accumbens and the olfactory tubercle form the ventral striatum. The rostral part of the substantia innominata forms a ventral extension of the globus pallidus and is known as the ventral pallidum.
Zusammenfassung
Die Huntington-Erkrankung (HD) ist eine autosomal-dominante neurodegenerative Erkrankung, die vornehmlich zwischen dem 30. und 50. Lebensjahr auftritt. Verursacht wird sie durch eine Genmutation auf dem Chromosom 4, welche zu einer Tripletexpansion (CAG) führt. Weniger als 10% der Betroffenen erkranken vor dem 20. Lebensjahr. Die beim Erwachsenen typischen choreatiformen Bewegungsmuster tauchen beim Jugendlichen erst im späteren Verlauf auf, können aber auch ganz fehlen. Etwa ein Drittel der Jugendlichen entwickelt eine Epilepsie.
Wir präsentieren sechs Fälle kindlicher/juveniler HD und beschreiben vergleichend zur adulten HD Erstsymptome, genetische Befunde und weitere Besonderheiten.
Die klinische Präsentation und auch der Erkrankungsverlauf der jugendlichen HD-Patienten unterscheiden sich mitunter deutlich von der adulten Form. Es imponieren initial vor allem Teilleistungsstörungen bei den Kindern sowie psychiatrische Symptome wie Depression und Aufmerksamkeitsstörungen bei den Jugendlichen.
Aufgrund der niedrigen Prävalenz juveniler HD sowie der variablen klinischen Symptomatik ist eine Diagnosestellung im Kindes- und Jugendalter schwierig und gelingt oftmals erst mit einer zeitlichen Latenz. Die frühe Diagnosestellung kann allerdings wichtig sein, insbesondere, um soziale und schulische Probleme zu entschärfen.
Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein, Striatum atrophy in HD leads to a progressive disturbance of psychiatric, motor, and cognitive function. Recent studies of HD patients revealed that the degeneration of cerebellum is also observed independently from the striatal atrophy during early HD stage and may contribute to the motor impairment and ataxia observed in HD. Cerebellar Purkinje cells (PCs) are responsible for the proper cerebellar pathways functioning and motor control. Recent studies on mouse models of HD have shown that the abnormality of the biochemical functions of PCs are observed in HD, suggesting the contribution of PC dysfunction and death to the impaired movement coordination observed in HD. To investigate ataxic symptoms in HD we performed a series of experiments with the yeast artificial chromosome transgenic mouse model of HD (YAC128). Using extracellular single-unit recording method we found that the portion of the cerebellar PCs with bursting and irregular patterns of spontaneous activity drastically rises in aged YAC128 HD mice when compared with wild type littermates. Previous studies demonstrated that SK channels are responsible for the cerebellar PC pacemaker activity and that positive modulation of SK channel activity exerted beneficial effects in different ataxic mouse models. Here we studied effects of the SK channels modulator chlorzoxazone (CHZ) on the motor behavior of YAC128 HD mice and also on the electrophysiological activity and neuroanatomy of the cerebellar PCs from these mice. We determined that the long-term intraperitoneal injections of CHZ alleviated the progressive impairment in the firing pattern of YAC128 PCs. We also demonstrated that treatment with CHZ rescued age-dependent motor incoordination and improved the cerebellar morphology in YAC128 mice. We propose that abnormal changes in the PC firing patterns might be a one of the possible causes of ataxic symptoms in HD and in other polyglutamine disorders and that the pharmacological activation of SK channels may serve as a potential way to improve the activity of cerebellar PCs and relieve the ataxic phenotype in HD patients.
Abstract Huntington’s disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.
Argyrophilic grain disease (AGD) is a sporadic, very late-onset tauopathy, accounting for approximately 4-13% of neurodegenerative dementias. AGD may manifest with a range of symptoms such as cognitive decline and behavioral abnormalities. To date, no study has been able to demonstrate a distinct clinical syndrome associated with AGD. The diagnosis is exclusively based on postmortem findings, the significance of which remains controversial because up to 30% of AGD cases are diagnosed in subjects without any cognitive impairment, while AGD findings often overlap with those of other neurodegenerative processes. Nevertheless, the presence of AGD is likely to have a significant effect on cognitive decline. The neuropathological hallmarks of AGD are argyrophilic grains, pre-neurofibrillary tangles in neurons and coiled bodies in oligodendrocytes found mainly in the entorhinal cortex and hippocampus. This review aims to provide an up-to-date overview of AGD, emphasizing pathological aspects. Additionally, the findings of a Brazilian case series are described.
Huntington's disease (HD) is an incurable and fatal hereditary neurodegenerative disorder of mid-life onset characterized by chorea, emotional distress, and progressive cognitive decline. HD is caused by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Recent studies suggest that epigenetic modifications may play a key role in HD pathogenesis. Alterations of the epigenetic "histone code" lead to chromatin remodeling and deregulation of neuronal gene transcription that are prominently linked to HD pathogenesis. Furthermore, specific noncoding RNAs and microRNAs are associated with neuronal damage in HD. In this review, we discuss how DNA methylation, post-translational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis. In addition, we summarize the therapeutic effects of histone deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD. Our understanding of the role of these epigenetic mechanisms may lead to the identification of novel biological markers and new therapeutic targets to treat HD.
A POLYGLUTAMINE expansion (encoded by a CAG repeat) in specific proteins causes neurodegeneration in Huntington's disease (HD) and four other disorders1–6, by an unknown mechanism thought to involve gain of function or toxicity of the mutated protein7,8. The pathological threshold is 37–40 glutamines in three of these diseases, whereas the corresponding normal proteins contain polymorphic repeats of up to about 35 glutamines1–3. The age of onset of clinical manifestations is inversely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal depends on the length of the polyglutamine expansion, and the antibody also detects specific pathological proteins expected to contain such expansion, in SCA2 and in autosomal dominant cere-bellar ataxia with retinal degeneration, whose genes have not yet been identified9–13.
We have prepared an atlas of the human cerebellum using high-resolution magnetic resonance-derived images warped into the proportional stereotaxic space of Talairach and Tournoux. Software that permits simultaneous visualization of the three cardinal planes facilitated the identification of the cerebellar fissures and lobules. A revised version of the Larsell nomenclature facilitated a simple description of the cerebellum. This atlas derived from a single individual was instrumental in addressing longstanding debates about the gross morphologic organization of the cerebellum. It may serve as the template for more precise identification of cerebellar topography in functional imaging studies in normals, for investigating clinical–pathologic correlations in patients, and for the development of future probabilistic maps of the human cerebellum.
In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula-nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed.
Thenar reflexes following electrical stimulation of the median nerve (containing proprioceptive and cutaneous afferents) and the radial superficial nerve (cutaneous afferents only) were investigated in 23 patients with manifest Huntington's disease (HD) at an early stage, in 17 clinically healthy descendants of HD-patients and in 18 patients with choreatic hyperkinesia due to various aetiologies other than HD. In 61% of the patients with early HD the long-latency reflexes (LLR) were uni- or bilaterally absent in response to both median nerve and radial superficial nerve stimulation. The remaining patients had a diminished mean amplitude and mean duration of their LLR. In contrast, offspring and patients with symptomatic chorea had preserved LLR which did not differ in amplitude or duration from normal controls. Additionally, the mean amplitude and mean duration of the Hoffmaan-reflex (HR) was found to be increased in patients with HD and their offspring but not in patients with other aetiologies. It is concluded (1) that the loss of LLR is not related to the choreatic hyperkinesia itself but to the degeneration of a hitherto poorly defined neuronal circuit in HD; (2) that among a variety of diseases presenting with chorea, the loss of LLR seems to be specific for HD; (3) that the testing of hand muscle reflexes in choreatic movement disorders is helpful for the differential diagnosis of early HD but not for the detection of gene carriers among offspring of patients with HD.
Huntington's disease (HD) results from the expansion of a polyglutamine encoding CAG repeat in a gene of unknown function. The wide expression of this transcript does not correlate with the pattern of neuropathology in HD. To study the HD gene product (huntingtin), we have developed monoclonal antibodies raised against four different regions of the protein. On western blots, these monoclonals detect the approximately 350 kD huntingtin protein in various human cell lines and in neural and non-neural rodent tissues. In cell lines from HD patients, a doublet protein is detected corresponding to the mutated and normal huntingtin. Immunohistochemical studies in the human brain using two of these antibodies detects the huntingtin in perikarya of some neurons, neuropiles, varicosities and as punctate staining likely to be nerve endings.
The total cortical and striatal neurone and glial numbers were estimated in five cases of Huntington's disease (three males, two females) and five age- and sex-matched control cases. Serial 500-microns-thick gallocyanin-stained frontal sections through the left hemisphere were analysed using Cavalieri's principle for volume and the optical disector for cell density estimations. The average cortical neurone number of five controls (mean age 53 +/- 13 years, range 36-72 years) was 5.97 x 10(9) +/- 320 x 10(6), the average number of small striatal neurones was 82 x 10(6) +/- 15.8 x 10(6). The left striatum (caudatum, putamen, and accumbens) contained a mean of 273 x 10(6) +/- 53 x 10(6) glial cells (oligodendrocytes, astrocytes and unclassifiable glial profiles). The mean cortical neurone number in Huntington's disease patients (mean age 49 +/- 14 years, range 36-75 years) was diminished by about 33% to 3.99 x 10(9) +/- 218 x 10(6) nerve cells (P < or = 0.012, Mann-Whitney U-test). The mean number of small striatal neurones decreased tremendously to 9.72 x 10(6) +/- 3.64 x 10(6) (-88%). The decrease in total glial cells was less pronounced (193 x 10(6) +/- 26 x 10(6)) but the mean glial index, the numerical ratio of glial cells per neurone, increased from 3.35 to 22.59 in Huntington's disease. Qualitatively, neuronal loss was most pronounced in supragranular layers of primary sensory areas (Brodmann's areae 3,1,2; area 17, area 41). Layer IIIc pyramidal cells were preferentially lost in association areas of the temporal, frontal, and parietal lobes, whereas spared layer IV granule cells formed a conspicuous band between layer III and V in these fields. Methodological issues are discussed in context with previous investigations and similarities and differences of laminar and lobar nerve cell loss in Huntington's disease are compared with nerve cell degeneration in other neuropsychiatric diseases.
We review here the eye movements in patients with Huntington's disease (HD), concentrating upon saccades as they show the most prominent abnormalities. Inability to suppress reflexive glances to suddenly appearing novel visual stimuli and delayed initiation of voluntary saccades, including predictive saccades, are early and consistent findings. These two abnormalities can be interpreted in the context of a model, based upon the idea that the frontal lobes and basal ganglia contribute more to the control of voluntary than to reflexive types of saccades. Most patients eventually also show slow saccades but they are most prominent when the disease is early-onset. Slowing of saccades may reflect involvement of both the higher-level cerebral centers that trigger saccades and the areas in the brain stem that produce premotor saccade commands. The study of eye movements in HD has led to a fruitful interaction between basic science and clinical investigation, and has served as a paradigm for examining higher-level defects in saccadic eye movement control in patients with various degenerative, neurological diseases or with focal cerebral hemispheral lesions.
In general the cerebellum is crucial for the control but not the initiation of movement. Voluntary eye movements are particularly useful for investigating the specific mechanisms underlying cerebellar control because they are precise and their brain-stem circuitry is already well understood. Here we describe single-unit and inactivation data showing that the posterior vermis and the caudal fastigial nucleus, to which it projects, provide a signal during horizontal saccades to make them fast, accurate, and consistent. The caudal fastigial nucleus also is necessary for the recovery of saccadic accuracy after actual or simulated neural or muscular damage causes horizontal saccades to be dysmetric. Saccade-related activity in the interpositus nucleus is related to vertical saccades. Both the caudal fastigial nucleus and the flocculus/paraflocculus are necessary for the normal smooth eye movements that pursue a small moving spot. By using eye movements, we have begun to uncover basic principles that give us insight into how the cerebellum may control movement in general.
Für die, die es genau wissen wollen!
Verteilungsfreie Methoden werden vor allem zur statistischen Hypothesenprüfung bei kleineren Stichproben mit nicht normal-verteilten Daten eingesetzt. Kurz und knapp werden diese verteilungsfreien, non-parametrischen Verfahren in der "Kurzgefassten Statistik" von Jürgen Bortz vorgestellt. Hier, in der 3. Auflage der "Verteilungsfreien Methoden in der Biostatistik", werden die Verfahren so aufbereitet, dass auch Leser ohne spezielle mathematische Vorkenntnisse den Rechengang nachvollziehen können. Dazu dienen einfache Zahlenbeispiele aus der Psychologie, der Biomedizin und den Sozialwissenschaften, die anhand eines einheitlichen Schemas die jeweiligen Verfahren veranschaulichen. Mit 47 Signifikanztafeln.
Sowohl als Einführungslektüre als auch als detailliertes Nachschlagewerk geeignet!
Purpose of review This review summarizes recent neuropathological findings in spinocerebellar ataxia type 3 and discusses their relevance for clinical neurology. Recent findings The extent of the spinocerebellar ataxia type 3 related central nervous neurodegenerative changes has been recently systematically investigated in a series of pathoanatomical studies. These studies showed that the extent of the central nervous degenerative changes of spinocerebellar ataxia type 3 has been underestimated so far. The newly described pattern of central nervous neurodegeneration includes the visual, auditory, vestibular, somatosensory, ingestion-related, dopaminergic and cholinergic systems. These pathological findings were correlated with clinical findings and explain a variety of the spinocerebellar ataxia type 3 symptoms observed in clinical practice. Summary Systematic pathoanatomical analysis of spinocerebellar ataxia type 3 brains helps to understand the structural basis of this neurodegenerative disease and offers explanations for a variety of disease symptoms. This better understanding of the neuropathology of the condition has implications for the treatment of spinocerebellar ataxia type 3 patients and represents a basis for further biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive ataxic disorder.
In this chapter the author has tried to make the data on the gross anatomy of the human cerebellum and its nuclei more accessible to its users and t emphasize the magnitude of the cerebrocerebellar connections in the human brain. The recent literature is almost restricted to the anatomy of the rodent and feline cerebellum, with some excursions to nonhuman primates, and that new information on the fiber connections of the human cerebellum is almost completely lacking. The most complete account of the fiber connections of the human cerebellum comes from von Bechterew's review of myelogenetic studies of the human brain. As a consequence, much of the anatomy of the human cerebellum still rests on assumptions and interpretations of animal studies. The chapter discusses external form, development, and subdivision of the human cerebellum, cerebellar nuclei, cerebellar peduncles, afferent fiber systems, the vestibulocerebellum, and longitudinal zonation of the cerebellum.
Huntington’s disease (HD) is caused by an expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss in the striatum and cortex and to the appearance of neuronal intranuclear inclusions of mutant huntingtin. Huntingtin plays a role in protein trafficking, vesicle transport, postsynaptic signaling, transcriptional regulation, and apoptosis. Thus, a loss of function of the normal protein and a toxic gain of function of the mutant huntingtin contribute to the disruption of multiple intracellular pathways. Furthermore, excitotoxicity, dopamine toxicity, metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy have been implicated in the progressive degeneration observed in HD. Nevertheless, despite the efforts of a multidisciplinary scientific community, there is no cure for this devastating neurodegenerative disorder. This review presents an overview of the mechanisms that may contribute for HD pathogenesis. Ultimately, a better understanding of these mechanisms will lead to the development of more effective therapeutic targets.
The Huntington's disease (HD) gene has been mapped in 4p16.3 but has eluded identification. We have used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect. A new gene, IT15, isolated using cloned trapped exons from the target area contains a polymorphic trinucleotide repeat that is expanded and unstable on HD chromosomes. A (CAG)n repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4p16.3 haplotypes. The (CAG)n repeat appears to be located within the coding sequence of a predicted approximately 348 kd protein that is widely expressed but unrelated to any known gene. Thus, the HD mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
Huntington's disease may present at any age, but most typically manifests between the ages of 35 and 45 years as a slowly progressive neurodegenerative movement disorder with cognitive and behavioral impairment. It is an autosomal-dominant disorder that has a substantial impact on family structure and dynamics in terms of providing care for affected family members and, for the offspring of an affected parent, dealing with at-risk status. Therapy that slows the progressive neuronal dysfunction or degeneration is unavailable, so pharmacotherapy is currently aimed primarily at managing behavioral and psychiatric symptoms, and, in selected cases, controlling severe chorea. Effective intervention by clinicians is possible, however, in terms of providing patients and families with accurate information about the disease, counseling them about availability of genetic testing at specialized centers, and in giving them sound advice regarding work, driving, relationships, finances, research participation, and support groups.
Ballooned neurones (BNs) are one of the pathological hallmarks of several neurodegenerative diseases, including Pick's disease, corticobasal degeneration and argyrophilic grain disease (AGD). They have also been described in Alzheimer disease (AD), but the frequency of BNs in AD has not been systematically addressed. In the present study, immunohistochemistry for alphaB-crystallin was used as a sensitive method to detect BNs to determine the frequency of BNs in the limbic lobe in AD. At least a few BNs were detected in the limbic lobe of virtually all AD cases, and their density correlated with Braak stage, as well as the density of neurofibrillary tangles and senile plaques in the limbic lobe. The density of BN tended to be greater in AD cases with concurrent AGD than in pure AD. Given the high prevalence of AD in brain banks for neurodegenerative disease and the frequent presence of BNs in these areas with alphaB-crystallin immunohistochemistry, the present findings further indicate that BNs confined to the limbic lobe lack specificity in diagnostic neuropathology.
A protocol has been established for the staining of myelin in frozen sections. While the new method is relatively fast and simple, it eliminates the problems routinely encountered with myelin stains such as blotchiness and uneven staining. Modifications were introduced into the procedures in order to obtain excellent fiber staining results on a wide variety of tissue.
Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Huntington's disease has served as a model for the study of other more common neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. These disorders all share features including: delayed onset; selective neuronal vulnerability, despite widespread expression of disease-related proteins during the whole lifetime; abnormal protein processing and aggregation; and cellular toxic effects involving both cell autonomous and cell-cell interaction mechanisms. Pathogenic pathways of Huntington's disease are beginning to be unravelled, offering targets for treatments. Additionally, predictive genetic testing and findings of neuroimaging studies show that, as in some other neurodegenerative disorders, neurodegeneration in affected individuals begins many years before onset of diagnosable signs and symptoms of Huntington's disease, and it is accompanied by subtle cognitive, motor, and psychiatric changes (so-called prodromal disease). Thus, Huntington's disease is also emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which is characterized by psychiatric symptoms, involuntary choreiform movements and dementia with maximum degeneration occurring in striatum and cerebral cortex. Several studies implicate mitochondrial dysfunction to the selective neurodegeneration happening in this disorder. Calcium buffering imbalance and oxidative stress in the mitochondria, critically impaired movement across axons and abnormal fission or fusion of this organelle in the cells are some of the salient features that results in the loss of mitochondrial electron transport chain (ETC) complex function in HD. Although several models involving mutant huntingtin, excitotoxins and mitochondrial complex-II inhibitors have been used to explore the disease, it is not clear how disturbances in mitochondrial functioning is associated with such selective neurodegeneration, or in the expression of huntingtonian phenotypes in animals or man. We have carefully assessed various mitochondrial abnormalities observed in human patient samples, postmortem HD brains, cellular, vertebrate and invertebrate models of the disease, to conclude that ETC dysfunction is an integral part of the disease and justify a causal role of mitochondrial ETC dysfunction for the genesis of this disorder.
J. Neurochem. (2010) 114, 1–12.
Polyglutamine expansion mutation in huntingtin causes Huntington’s disease (HD). How mutant huntingtin (mHtt) preferentially kills striatal neurons remains unknown. The link between mitochondrial dysfunction and HD pathogenesis stemmed from postmortem brain data and mitochondrial toxin models. Current evidence from genetic models, containing mHtt, supports mitochondrial dysfunction with yet uncertain nature and cause. Because mitochondria composition and function varies across tissues and cell-types, mitochondrial dysfunction in HD vulnerable striatal neurons may have distinctive features. This review focuses on mHtt and the striatum, integrating experimental evidence from patients, mice, primary cultures and striatal cell-lines. I address the nature (specific deficits) and cause (mechanisms linked to mHtt) of HD mitochondrial dysfunction, considering limitations of isolated vs. in situ mitochondria approaches, and the complications introduced by glia and glycolysis in brain and cell-culture studies. Current evidence relegates respiratory chain impairment to a late secondary event. Upstream events include defective mitochondrial calcium handling, ATP production and trafficking. Also, transcription abnormalities affecting mitochondria composition, reduced mitochondria trafficking to synapses, and direct interference with mitochondrial structures enriched in striatal neurons, are possible mechanisms by which mHtt amplifies striatal vulnerability. Insights from common neurodegenerative disorders with selective vulnerability and mitochondrial dysfunction (Alzheimer’s and Parkinson’s diseases) are also addressed.
Recent progress in oculomotor research has enabled new insights into the functional neuroanatomy of the human premotor oculomotor brainstem network. In the present review, we provide an overview of its functional neuroanatomy and summarize the broad range of oculomotor dysfunctions that may occur in Huntington's disease (HD) patients. Although some of these oculomotor symptoms point to an involvement of the premotor oculomotor brainstem network in HD, no systematic analysis of this functional system has yet been performed in brains of HD patients. Therefore, its exact contribution to oculomotor symptoms in HD remains unclear. A possible strategy to clarify this issue is the use of unconventional 100-microm-thick serial tissue sections stained for Nissl substance and lipofuscin pigment (Nissl-pigment stain according to Braak). This technique makes it possible to identify the known nuclei of the premotor oculomotor brainstem network and to study their possible involvement in the neurodegenerative process. Studies applying this morphological approach and using the current knowledge regarding the functional neuroanatomy of this human premotor oculomotor brainstem network will help to elucidate the anatomical basis of the large spectrum of oculomotor dysfunctions that are observed in HD patients. This knowledge may aid clinicians in the diagnosis and monitoring of the disease.
The striatum, pallidum and subthalamic nucleus were studied by combined morphometric methods in serial sections of 13 brains of normal adults and of 15 patients with choreatic diseases. In addition the volume of the hemispheres and of the cortex were measured. All data obtained were corrected by the shrinkage factor to represent fresh brain values. In Huntington's chorea the pallidum was more severely affected than is commonly appreciated. The average volume reduction was of the same degree (lateral-57%, medial-50%) as that of the striatum (-56%). The absolute number of nerve cells of the pallidum decreased in both segments by about 40%. The reduction of the volume and of the number of nerve cells was not reduced in the three subcortical nuclei studied. For the first time it has been shown that there is no increase in the absolute number of glial cells in the striatum. The increased numerical density of glial cells is caused by shrinkage. The loss of nerve cells of the pallidum and subthalamic nucleus is caused mainly by a primary process. Huntington's chorea is a multifocal process. Morphometric data do not suggest that subchorea is a variant of Huntington's chorea. Chorea minor is regarded as a multifocal process with varying affliction of the striatum, pallidum and subthalamic nucleus. An increase in the number of glial cells and, as a rule, a moderate loss of nerve cells were found in this disease.
EMG of involuntary muscle contractions and their correlation with clinical pictures in Huntington's disease disclosed a series of motor disorder from chorea to parkinsonism. Irregular brief contractions appearing reciprocally in flexor or extensor muscles were observed in typical chorea with hypotonia. Tonic nonreciprocal contractions appeared in the rigid form. In athetoid movement or dystonic postures, more slowly nonreciprocal fluctuating contractions appeared. In some cases phasic contractions changed from a reciprocal to nonreciprocal pattern by psychic stress. In contrast to the activation of motoneurons in choreatic movements, involuntary brief suppression of voluntary contraction appears in typical chorea. Difference in involuntary movements and muscle tone may result from quantitative differences in involvement of striatal neurons which are the origin of parallel pathways proposed by DeLong and colleagues.
This report concerns ultrastructural and immunohistochemical studies on ballooned neurons of ten patients with Creutzfeldt-Jakob disease (CJD). While abundant ballooned neurons and severe white matter degeneration was seen in six Japanese cases, only occasional ballooned neurons and no white matter degeneration was observed in four cases from the files of Montefiore Medical Center. Ultrastructurally, the ballooned neurons contained granule-coated fibrils of 25 to 40 nm in width and 10-nm neurofilaments. The immunohistochemical studies revealed that most ballooned neurons expressed alpha B-crystallin, with deposits of reaction products observed in the cytoplasm. A similar intracellular staining pattern was also seen with the antibody to phosphorylated neurofilament proteins (pNFP). Although the proportion of stained ballooned neurons was less, a positive reaction was also observed with antibodies against ubiquitin, stress-response protein 27 (srp 27) and synaptophysin, but not with an antibody to srp 72. Our findings suggest that expression of pNFP and synaptophysin by ballooned neurons may reflect axonal impairment and that the presence of alpha B-crystallin, srp 27 and ubiquitin may be related to the degenerative processes that neurons undergo in CJD.
The entorhinal territory consists of the entorhinal and transentorhinal regions spreading over the ambient gyrus and anterior portions of the parahippocampal gyrus. The transentorhinal region mediates between the adjoining temporal isocortex laterally and the entorhinal region medially. The entorhinal cortex consists of a molecular layer, followed by an external principal stratum, a cell-sparse lamina dissecans, an internal principal stratum and--within the underlying white matter--a profound cellular layer. The principal strata can each be divided into three layers Pre alpha, beta, gamma, and Pri alpha, beta, gamma. Data obtained from experimental investigations in monkeys reveal that the entorhinal territory serves as a relay station for information from both isocortical association areas and centers of the limbic system. After processing within the entorhinal cortex, this information is transferred to the hippocampal formation via the perforant path. Pathological changes within the entorhinal territory impair this continuous data transfer and contribute to a decline of cognitive functions. Entorhinal involvement associated with impaired cognitive functions is described in cases of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, dementia with argyrophilic grains and Huntington's disease.
Traditionally, a clinical diagnosis of Huntington disease (HD) presents no problems in patients with a positive family history, consistent with autosomal dominant inheritance, chorea or other extrapyramidal motor signs, and progressive mental decline (1). However, due to the slowly progressive nature of the disease and the slow evolution of signs and symptoms, it is often difficult to determine when at risk individuals are showing early signs. Moreover, the clinical recognition of both early and late-onset cases, and of choreic patients in whom a family history is lacking, presents special diagnostic challenges.
In recent years, much progress has been made in the recognition of early clinical signs of the disease. Factors which have contributed to this understanding include the longitudinal study of large cohorts of at-risk individuals, particularly in Venezuela, the data from predictive testing programs, and the application of positron emission tomography (PET)-scanning to individuals without overt chorea. We are now able to identify persons at risk as being affected before they display overt and obvious involuntary movements.
The available information on the world distribution of Huntington's disease (HD) from population surveys and death rate analysis is summarised and discussed in the light of genetic studies. It is concluded that most European populations, both Northern and Southern, show a relatively high prevalence (4-8 per 100,000), and that the disorder may also be frequent in India and parts of central Asia. HD is notably rare in Finland and in Japan, but data for Eastern Asia and Africa are inadequate. The disorder may have been underestimated in the American black population. Populations derived from recent European immigration show frequencies and origins of HD comparable to those expected from their own origins and expansion; there is no evidence to suggest that the HD gene has spread disproportionally and its selective effect may be close to neutral. Multiple separate introductions of the gene have been the rule in large populations. Several major foci of HD exist as the result of rapid population expansion. It is likely that a number of separate mutations for HD will be shown to be responsible for the disease, but that the high frequency of HD in European populations will prove to be the result of one or a very small number of mutations, probably of great antiquity.
In postmortem brain specimens from 163 clinically diagnosed cases of Huntington's disease (HD) the striatum exhibited marked variation in the severity of neuropathological involvement. A system for grading this severity was established by macroscopic and microscopic criteria, resulting in five grades (0-4) designated in ascending order of severity. The grade correlates closely with the extent of clinical disability as assessed by a rating scale. In five cases of clinically diagnosed HD there were no discernible neuropathological abnormalities (grade 0), suggesting that the anatomical changes lag behind the development of clinical abnormalities. In eight cases, neuropathological changes could only be recognized microscopically (grade 1). The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4; astrocytes are greatly increased in grades 2-4. These studies indicate that analyses of the CN in grade 4 would reflect mainly its astrocytic composition with a component of remote neurons projecting to the striatum. Because of the relative preservation of the lateral half of the head of the CN in grades 1-2, these regions would reflect early cellular and biochemical changes in HD.
Clinical records were evaluated for 163 Huntington's disease patients in whom postmortem brain specimens had been graded for degree of neuropathologic involvement in the striatum. Juvenile/adolescent onset (4 to 19 years of age) was associated with very severe neuropathologic involvement produced by an apparent rapid degenerative process. Cases of early (20 to 34 years) and midlife (35 to 49 years) onset had respectively less severe striatal involvement, suggesting a slower degenerative progression. High correlations among the grade of neuropathologic involvement, cell counts of neurons, and a rating of physical disability suggest that each represents a common underlying degenerative process of the disease. The relationship between the age at onset and the extent of neuropathologic involvement suggests that a single mechanism may determine both onset and rate of degenerative disease progression.
We investigated 13 patients with Huntington's disease and assessed gait by filming and by gait analyzer before and after increasing haloperidol dosage, until chorea was suppressed or side effects intervened. The severity of chorea and ataxia was scored blindly from videotapes. Gaits were abnormal in 12 of 13 patients and 5 of 6 patients who had symptoms for less than 5 years. Clinical characteristics included wide-based station, lateral swaying, spontaneous knee flexion, variable cadence, and parkinsonian features. Biomechanical analysis illustrated that gait characteristics varied in each walk, with a mean decrease in velocity, stride length, and cadence. Haloperidol treatment decreased chorea but did not affect gait patterns. Ataxia occurs early in the disease, has a distinct but variable pattern, is unrelated to chorea, and is not improved by haloperidol.
A technique is described which permits rapid processing of neural tissue for light microscopic analysis of sections of 1-40 microns thickness. This technique was developed as an alternative to paraffin embedding. When compared to paraffin, polyethylene glycol (PEG) offers the following advantages: 10-15 degrees C lower embedding temperatures, net tissue shrinkage of less than 5% vs approximately 50% in paraffin, and approximately one-half the embedding time. Tissue orientation during embedding and sectioning is particularly easy to control, e.g. 500 microns brain slices can be routinely flat-embedded and sectioned at 5 microns to form excellent ribbons. Since PEG is water-soluble, tissue may be dehydrated with a series of aqueous PEG solutions; the embedding matrix is easily removed by washing with a variety of aqueous buffers. These procedures allow subsequent electron microscopic analysis of material with generally well preserved ultrastructure. However, PEG is hygroscopic, thus tissue blocks become soft and difficult to section in high (greater than 90%) relative humidity. PEG was found to be compatible with intracellular staining with Lucifer yellow, horseradish peroxidase enzyme histochemistry, aqueous histofluorescence and immunocytochemical demonstration of neuronal peptides and glial fibrillary acidic protein.
We studied, in a "blind" and quantitative fashion, the density of cerebellar Purkinje cells in 17 adult cases of Huntington's disease (HD), 17 patients with other movement disorders, 17 with schizophrenia, and 23 normal controls. There was a highly significant reduction in Purkinje cell density in HD compared with any of the other three groups. A much smaller difference in neuronal density between patients with other movement disorders and normal controls was barely significant. Eight of the 17 HD patients and only 1 of the other 57 subjects had Purkinje cell density less than 50% of the mean for the normal controls. The low density of Purkinje cells in HD could not be attributed to aging, seizures, or cause of death, nor was it merely a part of a generalized brain atrophy. The loss of large Purkinje cells suggests that the neuronal loss in HD may not be restricted to small and medium-size neurons.
The clinical features are outlined and the neuropathological changes described in 3 cases (2 adults and 1 child) of Huntington's disease with severe atrophy of the cerebellum. Onset occurred at the ages of 56, 55 and 3 and death at 70, 62 and 6 years, respectively. All cases presented with cerebellar ataxia and this is also recorded in one relative of each adult case. The family history of Huntington's disease was not ascertained until the later stages of each patient's illness. At necropsy, the 3 cases showed the characteristic striatal and cerebral cortex atrophy and the shrunken cerebellum showed diffuse thinning of the molecular and granular layers with almost complete loss of Purkynĕ cells.
The occurrence of H-reflexes over both the anterior tibial muscle and the thenar muscle on both sides was investigated in 15 patients suffering from Huntington's disease, 8 clinically inconspicuous offspring, and 30 healthy normal controls. The following results were obtained: 1. An obvious H-reflex over the anterior tibial muscle was found in 12 of 15 patients; there was no H-reflex in only 3 patients. 2. After stimulation on the median nerve there was an H-reflex in 12 of 13 patients investigated. 3. In 5 of 8 clinically inconspicuous offspring there was an H-reflex after peroneal [4] or median [5] nerve stimulation. In 30 normal controls, 1 displayed a weak H-reflex over the anterior tibial muscle, 9 showed a weak H-reflex after median nerve stimulation. 5. The possibility is discussed that an abnormal H-reflex might be an early sign of central reflex disinhibition in otherwise asymptomatic offspring.
Frontal sections of the temporal lobe including the transentorhinal/entorhinal region, amygdala, and/or hippocampus from human adult brains are studied for cytoskeleton changes using immunostaining with the antibodies AT8 and Alz-50 and selective silver impregnation methods for neurofibrillary changes of the Alzheimer type. For the purpose of correlation, the two methods are carried out one after the other on the same section. Layer pre-alpha in the transentorhinal/entorhinal region harbours nerve cells which are among the first nerve cells in the entire brain to show the development of neurofibrillary changes. This presents the opportunity for study of both early events in the destruction of the cytoskeleton in individual neurons, and to relate changes which occur in the neuronal processes in the absence of alterations in their immediate surroundings to those happening in the soma. Immunoreactions with the AT8 antibody in particular reveal a clear sequence of changes in the neuronal cytoskeleton. Group 1 neurons present initial cytoskeleton changes in that the soma, dendrites, and axon are completely marked by granular AT8 immunoreactive material. These neurons appear quite normal and turn out to be devoid of argyrophilic material when observed in silver-stained sections. Group 2 neurons show changes in the cellular processes. The terminal tuft of the apical dendrite is replaced by tortuous varicose fibres and coarse granules. The distal portions of the dendrites are curved and show appendages and thickened portions. Intensely homogeneously immunostained rod-like inclusions are encountered in these thickened portions and in the soma. A number of these rod-like inclusions are visible after silver staining, as well. Group 3 neurons display even more pronounced alterations of their distal--most dendritic portions. The intermediate dendritic parts lose immunoreactivity, but the soma is homogeneously immunostained. Silver staining reveals in most of the distal dendritic parts neuropil threads, and in the soma a classic neurofibrillary tangle. Group 4 structures are marked by accumulations of coarse AT8-immunoreactive granules. Silver staining provides evidence that the fibrillary material has become an extraneuronal, "early" ghost tangle. Finally, group 5 structures present "late" ghost tangles in silver-stained sections but fail to demonstrate AT8 immunoreactivity. It is suggested that the altered tau protein shown by the antibody AT8 represents an early cytoskeleton change which eventually leads to the formation of argyrophilic neurofibrillary tangles and neuropil threads.
The basal ganglia comprise several nuclei in the forebrain, diencephalon, and midbrain thought to play a significant role in the control of posture and movement. It is well recognized that people with degenerative diseases of the basal ganglia suffer from rigidly held abnormal body postures, slowing of movement, involuntary movements, or a combination of these a abnormalities. However, it has not been agreed just what the basal ganglia contribute to normal movement. Recent advances in knowledge of the basal ganglia circuitry, activity of basal ganglia neurons during movement, and the effect of basal ganglia lesions have led to a new hypothesis of basal ganglia function. The hypothesis states that the basal ganglia do not generate movements. Instead, when voluntary movement is generated by cerebral cortical and cerebellar mechanisms, the basal ganglia act broadly to inhibit competing motor mechanisms that would otherwise interfere with the desired movement. Simultaneously, inhibition is removed focally from the desired motor mechanisms to allow that movement to proceed. Inability to inhibit competing motor programs results in slow movements, abnormal postures and involuntary muscle activity.
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are usually sporadic multi-system degenerations associated with filamentous tau inclusions in neurons and glia. As such they can be considered sporadic tauopathies in contrast to familial tauopathies linked to mutations in the tau gene. Mutations have not been found in the tau gene in either PSP or CBD. The clinical syndromes and neuroimaging of typical cases of PSP and CBD are distinct; however, atypical cases are described that have overlapping clinical and pathologic features. Both PSP and CBD have similar biochemical alterations in the tau protein, with the abnormal tau protein containing predominantly four-repeat tau. While there is overlap in the pathology in PSP and CBD, there are sufficient differences to continue the present day trend to consider these separate disorders. Several important pathologic features differentiate PSP from CBD. Ballooned neurons are frequent and nearly a sine qua non for CBD, but they are found in PSP at a frequency similar to that of other neurodegenerative diseases, such as Alzheimer's disease. Astrocytic lesions are different, with tufted astrocytes found in motor cortex and striatum in PSP and astrocytic plaques in focal atrophic cortices in CBD. The most characteristic neuronal tau pathology in CBD is wispy, fine filamentous inclusions within neuronal cell bodies, while affected neurons in PSP have compact, dense filamentous aggregates characteristic of globose neurofibrillary tangles. Thread-like processes in gray and white matter are much more numerous and widespread in CBD than in PSP. The brunt of the pathology in CBD is in the cerebrum, while the basal ganglia, diencephalon and brainstem are the targets of PSP. Further clinicopathologic studies will refine our understanding of these disorders and open the possibility that common etiologic factors may be identified for these unusual sporadic tauopathies.
Corticobasal degeneration (CBG) is an increasingly recognized neurodegenerative disease with both motor and cognitive dysfunction. The diagnosis is probably underestimated because of the heterogeneity of clinical features, overlap with symptoms, and pathologic findings of other neurodegenerative diseases. The most characteristic initial motor symptoms are akinesia, rigidity, and apraxia. Dystonia and alien limb phenomena are frequently observed. There is often a parkinsonian picture with failure or lack of efficacy of dopaminergic medical therapy. Cognitive decline, prompting the diagnosis of dementia, may be the most common presentation of CBD that is misdiagnosed. Pathology is characterized by an asymmetric frontoparietal neuronal loss and gliosis with ballooned, achromatic cortical neurons, nigral degeneration, and variable subcortical involvement. Neuroimaging and electrophysiologic studies may help with the diagnosis but are not specific. Treatment is primarily symptomatic and minimally effective, especially after the first several years of symptoms. CBD should be considered in the differential diagnosis of patients with motor and cognitive dysfunction presenting with cortical and subcortical features. Further studies to elucidate molecular abnormalities and biological markers associated with CBD are needed to improve clinical diagnosis and treatment of patients with this disorder.