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Midbrain/substantia nigra (SN) imaging with magnetic resonance imaging (MRI) and Transcranial sonography (TCS). A: Susceptibility weighted (SWI) MRI image of a healthy control (HC) at the left column, demonstrating the magnified dorsolateral nigral hyperintensity within the right SN. White arrows mark the dorsolateral nigral hyperintensity in the survey as well as in the magnified illustration. The right column show SWI images of a patient with Parkinson’s disease (PD), demonstrating the absence of the dorsolateral nigral hyperintensity. B: TCS images of mesencaphalic scanning planes showing typically butterfly-shaped mesencephalic brainstems from a HC with a normal midbrain echogenicity in the upper images. A PD patient with an enlarged midbrain echogenicity at the area of the SN (SN-hyperechogenicity) is shown in the lower images.
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Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific patholo...
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... for PD. Intriguingly, the presence of this feature assessed with susceptibility weighted imaging (SWI) at 3T distinguished PD patients from healthy controls in another dataset of the same group [80] as well as in our own large cohort of patients with neurodegenerative parkinsonism [81], with a sensitiv- ity and specificity of >90%, respectively (Fig. 1). In the latter study also all included patients with MSA and PSP exhibited this imaging feature (i.e. sensitivity of 100%), indicating that visual assessment of dorsolat- eral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders [81]. Future ...
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... method which is less expensive, time consum- ing and more widely available compared to radiotracer or MR imaging [82]. An enlarged echogenic area at the anatomical site of the SN in the mesencephalic scanningplane,termedSN-hyperechogenicity,hascon- sistently been found in at least 82% of PD cases but only in up to 23% of healthy controls [82,83] (Fig. 1). In PD patients, the SN-echogenic sign is nei- ther related to disease severity nor does it change over time [82,84] and its longitudinal stability has also been reported in healty controls [85] and idiopathic RBD patients [86]. Although the pathophysiologic under- pinnings of this echo feature are not entirely clear, histopathological ...
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Background
Neuroimaging-biomarkers of Mild Cognitive Impairment (MCI) allow an early diagnosis in preclinical stages of Alzheimer’s disease (AD). The goal in this paper was to review of biomarkers for Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), with emphasis on neuroimaging biomarkers.
Methods
A systematic review was conducted fr...
Citations
... PD is known to have a long prodromal phase which can extend up to 20 years prior to clinical diagnosis (46)(47)(48). This is the latent period over which there is a gradual development of PD pathology prior to the emergence of the characteristic and observable motor signs and symptoms that enable a clinical diagnosis, and which offers a window of opportunity for disease prevention (47,49). ...
... PD is known to have a long prodromal phase which can extend up to 20 years prior to clinical diagnosis (46)(47)(48). This is the latent period over which there is a gradual development of PD pathology prior to the emergence of the characteristic and observable motor signs and symptoms that enable a clinical diagnosis, and which offers a window of opportunity for disease prevention (47,49). Currently, no definite disease-modifying therapies have been identified for PD that can slow, stop or reverse the progression of disease, although considerable research in this field is ongoing (50,51), so clinical management relies on symptomatic treatment. ...
... Parkinson's disease PD has a long natural history, with evidence of neurodegeneration becoming evident 10-20 years before the onset of motor symptoms (47). Data from the Thailand Parkinson's Disease Registry shows that the average age of PD patients at diagnosis is approximately 63 years of age (57). ...
The rising prevalence of Parkinson’s disease (PD) globally presents a significant public health challenge for national healthcare systems, particularly in low-to-middle income countries, such as Thailand, which may have insufficient resources to meet these escalating healthcare needs. There are also many undiagnosed cases of early-stage PD, a period when therapeutic interventions would have the most value and least cost. The traditional “passive” approach, whereby clinicians wait for patients with symptomatic PD to seek treatment, is inadequate. Proactive, early identification of PD will allow timely therapeutic interventions, and digital health technologies can be scaled up in the identification and early diagnosis of cases. The Parkinson’s disease risk survey (TCTR20231025005) aims to evaluate a digital population screening platform to identify undiagnosed PD cases in the Thai population. Recognizing the long prodromal phase of PD, the target demographic for screening is people aged ≥ 40 years, approximately 20 years before the usual emergence of motor symptoms. Thailand has a highly rated healthcare system with an established universal healthcare program for citizens, making it ideal for deploying a national screening program using digital technology. Designed by a multidisciplinary group of PD experts, the digital platform comprises a 20-item questionnaire about PD symptoms along with objective tests of eight digital markers: voice vowel, voice sentences, resting and postural tremor, alternate finger tapping, a “pinch-to-size” test, gait and balance, with performance recorded using a mobile application and smartphone’s sensors. Machine learning tools use the collected data to identify subjects at risk of developing, or with early signs of, PD. This article describes the selection and validation of questionnaire items and digital markers, with results showing the chosen parameters and data analysis methods to be robust, reliable, and reproducible. This digital platform could serve as a model for similar screening strategies for other non-communicable diseases in Thailand.
... These disorders-which are collectively labeled synucleinopathies-are characterized by the aberrant accumulation of insoluble, aSyn-rich inclusions in vulnerable populations of neurons or glial cells. While aSyn aggregation is associated with cytotoxicity [19], it has long been recognized that aSyn-associated neurodegeneration may precede clinical symptom presentation by years or even decades [20]. This extensive preclinical (i.e., prodromal) phase may represent a critical window for disease-altering interventions; therefore, noninvasive biomarkers that can identify and track disease progression in the absence of clinical symptoms are needed. ...
... In human synucleinopathy, the presentation of clinical motor symptoms is often preceded by an extensive 'prodromal' phase characterized by a variety of nonmotor symptoms and/or subtle disruptions to normal motor function [20]. Given our observation that A53T animals showed significant elevations in whole-brain average [ 18 F]ROStrace signal well before the onset of fatal end-stage motor symptoms (~12-16 mo in our A53T colony), we next sought to determine whether A53T mice also show behavioral evidence of a subacute, 'prodromal-like' disease state. ...
... In human PD, it is increasingly recognized that the presymptomatic (i.e., prodromal) phase of disease is likely to be a key window for outcome-altering interventions, as cardinal motor symptoms typically do not develop until substantial neurodegeneration has already occurred [20]. The current PET, staining, and behavioral results indicate that A53T mice also experience a prolonged 'prodromal-like' disease phase, characterized by subtle but consistent behavioral alterations (primarily hyperactivity, limb-clasping, and reduced nesting behavior [61][62][63]) and increased oxidative stress in the absence of widespread neuroinflammation. ...
The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of aSyn aggregation in the synucleinopathies; however, noninvasive methods for detecting oxidative stress in living animals have proven elusive. In this study, we used the reactive oxygen species (ROS)-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace to detect increases in oxidative stress in the widely-used A53T mouse model of synucleinopathy. A53T-specific elevations in [18F]ROStrace signal emerged at a relatively early age (6–8 months) and became more widespread within the brain over time, a pattern which paralleled the progressive development of aSyn pathology and oxidative damage in A53T brain tissue. Systemic administration of lipopolysaccharide (LPS) also caused rapid and long-lasting elevations in [18F]ROStrace signal in A53T mice, suggesting that chronic, aSyn-associated oxidative stress may render these animals more vulnerable to further inflammatory insult. Collectively, these results provide novel evidence that oxidative stress is an early and chronic process during the development of synucleinopathy and suggest that PET imaging with [18F]ROStrace holds promise as a means of detecting aSyn-associated oxidative stress noninvasively.
... The number of people who are living with PD and the resulting disability and deaths are increasing faster than any other neurodegenerative disorders 25 . It is well-known that clinical PD is preceded by a long prodromal period before the onset of the classic motor features 26 . Therefore, it is paramount to identify the risk factors and eliminate/management the risk factors for PD prevention. ...
Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91−1.10) for the moderately isolated group and 1.19 (1.05−1.36) for the most isolated group ( P - trend = 0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.
... However, other patients remain stable or deteriorate in motor scales, and it is unclear if these patients are benefiting from treatment or not, because motor scales show several limitations for the assessment of adult SMA patients [10]. A variety of biomarkers have been investigated for their potential use in the diagnosis and monitoring of neurodegenerative diseases [13][14][15][16][17][18][19][20]; however, the role of these putative biomarkers for predicting or monitoring the response to nusinersen in adult SMA patients is not well known. We hypothesized that specific biomarkers linked to target pathways in neurodegenerative diseases might be useful to assess target engagement in each adult SMA patient and predict the nusinersen treatment response. ...
The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.
... However, comprehensive understanding, essential for effective and curative treatments of the disease, remains elusive and diagnosis faces considerable challenges [10,11]. In recent decades, researchers have focused on the pathological processes of PD manifesting 10-20 years before clinical diagnosis [12,13]. The stage in which patients show various non-motor and/or subtle motor symptoms but are insufficient for PD diagnosis by current criteria is called prodromal PD, whose criteria were updated by the Movement Disorder Society in 2019 [13][14][15]. ...
... In recent decades, researchers have focused on the pathological processes of PD manifesting 10-20 years before clinical diagnosis [12,13]. The stage in which patients show various non-motor and/or subtle motor symptoms but are insufficient for PD diagnosis by current criteria is called prodromal PD, whose criteria were updated by the Movement Disorder Society in 2019 [13][14][15]. ...
Parkinson’s disease (PD) is a common neurodegenerative disorder with a prolonged prodromal phase. Higher urinary bis(monoacylglycerol)phosphate (BMP) levels associate with LRRK2 (leucine-rich repeat kinase 2) and GBA1 (glucocerebrosidase) mutations, and are considered as potential noninvasive biomarkers for predicting those mutations and PD progression. However, their reliability has been questioned, with inadequately investigated genetics, cohorts, and population. In this study, multiple statistical hypothesis tests were employed on urinary BMP levels and sequences of 90 PD-risk single nucleotide polymorphisms (SNPs) from Parkinson’s Progression Markers Institution (PPMI) participants. Those SNPs were categorized into four groups based on their impact on BMP levels in various cohorts. Variants rs34637584 G/A and rs34637584 A/A (LRRK2 G2019S) were identified as the most relevant on increasing urinary BMP levels in the PD cohort. Meanwhile, rs76763715 T/T (GBA1) was the primary factor elevating BMP levels in the prodromal cohort compared to its T/C and C/C variants (N370S) and the PD cohort. Proteomics analysis indicated the changed transport pathways may be the reasons for elevated BMP levels in prodromal patients. Our findings demonstrated that higher urinary BMP levels alone were not reliable biomarkers for PD progression or gene mutations but might serve as supplementary indicators for early diagnosis and treatment.
... A frank loss of LC NE neurons and decreased NE tone in the rest of the brain has been documented in people with PD with in vivo neuromelanin-sensitive MRI 32,33 , [ 11 C]methyl-reboxetine PET imaging studies 34,35 and post mortem immunohistochemical 36, 37 and biochemical 38 studies. Interestingly, a similar pattern of global NE denervation has been observed in people with REM sleep behavior disorder (RBD) [39][40][41] , an established prodromal stage of PD or other synucleinopathies 42,43 , suggesting that LC injury occurs earlier than dopaminergic dysfunction. Indeed, mood dysfunction often emerges early and prior to a PD diagnosis 27,44,45 . ...
Parkinson’s disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.
... Parkinson's disease (PD) is one of the most severe socially significant neurodegenerative diseases, which can be triggered by either exogenous neurotoxins, such as pesticides, heavy metals, and side products of synthetic heroin [1,2], or endogenous neurotoxins, mainly oligomeric α-synuclein, and the oxidation product of dopamine (DA) [3,4]. PD develops over up to 30 years, in the so-called preclinical stage-without the manifestation of parkinsonian motor symptoms, which are used to diagnose this disease [5][6][7][8]. Over such a long period, endogenous and exogenous neurotoxins cause the death of about half of the nigral dopaminergic (DAergic) neurons, which are a key link in the regulation of motor function [1,3,5,7,9,10]. ...
... The above-mentioned characteristics regarding the pathogenesis of PD explain why the current symptomatic treatment of PD patients with DA agonists and l-3,4-dihydroxyphenylalanine (L-DOPA), an immediate precursor to DA, is unable to stop the progression of the disease and avoid disability in patients [8,11,12]. Therefore, one of the highest priorities of neurology is the development of techniques that allow the early (preclinical) diagnosis of PD. Significant progress has already been made in this area of research [13]. ...
Studying the initial molecular mechanisms of the pathogenesis of Parkinson’s disease (PD), primarily in the nigrostriatal dopaminergic system, is one of the priorities in neurology. Of particular interest is elucidating these mechanisms in the preclinical stage of PD, which lasts decades before diagnosis and is therefore not available for study in patients. Therefore, our main goal was to study the initial molecular mechanisms of the pathogenesis of PD in the striatum, the key center for dopamine regulation in motor function, in a mouse model of the earliest preclinical stage of PD, from 1 to 24 h after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was shown that the content of tyrosine hydroxylase (TH), the first enzyme in dopamine synthesis, does not change within 6 h after the administration of MPTP, but decreases after 24 h. In turn, TH activity increases after 1 h, decreases after 3 h, remains at the control level after 6 h, and decreases 24 h after the administration of MPTP. The concentration of dopamine in the striatum gradually decreases after MPTP administration, despite a decrease in its degradation. The identified initial molecular mechanisms of PD pathogenesis are considered as potential targets for the development of preventive neuroprotective treatment.
... Desde lo clínico cuenta con una tríada motora clásica descrita, la cual consiste en temblor, rigidez y bradicinesia 3,4 . Su instauración sigue un curso progresivo en donde los síntomas premotores anteceden la aparición de esta triada clásica y algunos síntomas no motores se agregan, tanto de forma temprana o tardía, en las diferentes etapas de la enfermedad 5,6 . En relación con los síntomas premotores, el abordaje fisiopatológico más consistente es la teoría de Braak, donde se establece que diferentes mecanismos moleculares generan una disfunción celular o conducen a la muerte celular, con una progresión ascendente o en dirección caudo-cefálica, desde el bulbo raquídeo hasta alcanzar las estructuras límbicas y la neocorteza conforme se da la acumulación de α-sinucleína y avanza el daño mitocondrial 7 . ...
... Tras su agrupación en oligómeros, la proteína es capaz de formar poros de inserción en la membrana que pueden llevar a muerte celular, alteraciones sinápticas y disfunción mitocondrial 16 . Los puntos iniciales a los que subyace la acumulación y agregación de α-sinucleína pueden ser múltiples, entre ellos: la sobreproducción de la proteína por la senescencia de los mecanismos proteolíticos o la presencia de mutaciones que aumentan la probabilidad de un mal plegamiento y la producción relativa de la α-sinucleína [5][6][7]17 . La teoría de Braak propone que la acumulación de α-sinucleína se da siguiendo un orden predecible en dirección ascendente, desde el sistema nervioso entérico hasta alcanzar estructuras encefálicas 14,18 . ...
El diagnóstico de enfermedad de Parkinson (ED) se basa en las principales manifestaciones motoras: bradicinesia en combinación con temblor en reposo, rigidez o ambos. Cuando se realiza el diagnóstico basado en la sintomatología motora clínica típica ya se han perdido hasta el 60 % de las neuronas dopaminérgicas de la sustancia negra pars compacta mesencefálica. La identificación de los síntomas premotores son un marcador temprano para sospechar la aparición futura de la enfermedad, así como su progresión y gravedad. La hipótesis sobre la patogénesis que mejor expone la progresión de la enfermedad es la teoría de Braak. Esta se basa en la aparición y presencia de cuerpos de Lewy en diferentes estructuras anatómicas, las cuales representadas en cada uno de sus seis estadios y podrían ser la explicación biológica de los síntomas premotores, motores y no motores. La detección temprana de los síntomas premotores puede tener repercusiones positivas en el enfoque, seguimiento, diagnóstico y tratamiento de la EP. El propósito de este artículo es identificar las aproximaciones neurológicas descritas por la teoría de Braak para los síntomas premotores de la enfermedad de Parkinson de acuerdo con la literatura publicada en los últimos 20 años.
... Clinically, PD is characterized by typical motor symptoms, such as bradykinesia, resting tremor, rigidity, and gait abnormalities as well as a variety of non-motor symptoms like psychiatric conspicuousness, such as anxiety, depression, cognitive decline and sleep-disorders, as well as sensory deficits, and autonomic dysfunctions [10][11][12]. Due to their early appearance during the prodromal phase of PD, non-motor symptoms have emerged not only as definitive symptoms but also as potential diagnostic markers. The studies conducted by Braak and colleagues, along with several subsequent post-mortem studies, have shown aSyn pathology in the olfactory bulb and dorsal motor nucleus of the vagus nerve (Ncl. ...
... First, cell loss without functional deficit was observed in prodromal stages, probably due to both reserve capacities of the remaining neuronal populations but also because of compensatory changes. These compensatory changes can likely be exhausted without substantial further cell loss 19,85,86 . It is possible that such compensation underlies the relatively preserved locomotor functions one week post lesion using low doses of 6-OHDA, while these mechanisms cannot cope with higher doses as well as break down by the second week post lesion. ...
Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice. Abbreviations PD Parkinson's disease 6-OHDA 6-Hydroxy-dopamine DA Dopamine DAergic Dopaminergic SNc Substantia nigra pars compacta TH Tyrosine-hydroxylase TH + Tyrosine-hydroxylase immunopositive LD Low dose OPEN
