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Pie charts showing the proportion of specific pathologies observed in FTLD-tau (a) and FTLD-TDP (b), based on pooled data from eight large clinicopathological studies. The number and percentage associated with each pathology is also shown. FTLDTDP typing is based on the classification by Mackenzie et al.
Source publication
Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific path...
Contexts in source publication
Context 1
... from five large clinicopath- ological studies [31,38,56,67,111] of 544 pathologically confirmed FTLD patients, it appears that some FTLD-tau pathologies are much more common than others. The most common pathology was CBD accounting for 35% of cases, followed by PSP with 31%, PiD with 30% and AGD accounting for the remaining 4% of all FTLD-tau ( Fig. ...
Context 2
... we use the Mackenzie's classification scheme since that scheme was initially shown to have good association with clinical phenotype. Based on data from four clinicopathological studies [35,57,80,111], the most common subtype was FTLD-TDP type 1 accounting for 41% of cases followed by FTLD-TDP type 3 with 34% and then FTLD-TDP-type 2 with 25% (Fig. 2b). There were no cases of FTLD-TDP type 4 in any of these large clinicopathological ...
Similar publications
Objective: To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, welldefined cohort.
Methods: CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (F...
Citations
... For example, considering FTD, there are some predictable relationships between the clinical phenotype and the pathological substrate throughout phenotypic development, such as parkinsonism in tau-FTD or semantic disorder in FTD-TDP [43]. However, FTD-TDP and FTD-tau may be clinically indistinguishable, with overlapping behavioral and language impairment [44]. On the other hand, TDP-43 proteinopathies can express a variety of motor, cognitive, and behavioral clinical features, known as the "FTD-ALS spectrum" [45]. ...
TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer’s disease, Huntington’s disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.
... NanoString GeoMx TM is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. With the understanding that the catalyst of FTLD can be patient specific and extremely variable [39,40,41,42], the current frontier of FTLD and neurodegeneration research has moved towards spatial proteomics approaches, where focused brain region-specific assessments now enable investigators to gain additional insight into the pathologic mechanisms underlying this spectrum of neurodegenerative syndromes. Our data . ...
Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition as a result of FTLD. This spectrum of pathology leads to difficulty in identification of the disease during its progression and consequential varied post mortem clinicopathological diagnoses. NanoString GeoMx™ Digital Spatial Profiling (DSP) is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. We utilized NanoString DSP to investigate the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimer’s disease, FTLD-c9ALS, FTLD-17, FTLD-TDP, FTLD-GRN; n=6 per syndrome) and neurologically healthy controls (NHC). Analysis of 75 different protein biomarkers of interest revealed both a disease and cortical subregion specific biomarker profile. Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Additionally, out of all disease groups within cortical layer 1, II-V and white matter, the FTLD-17 group had the most significant protein dysregulation as compared to NHC--specifically associated with immune cell pathways. Traditional biomarkers of dementia, such as various phosphorylated tau proteins and amyloid-β 42 displayed dysregulation, however our data suggest spatial enrichment in distinct to cortical sublayers. In conclusion, we observed that depending on the variant of disease, specific protein deposits either span multiple levels of cortical geography or only a single layer. Thus, the specific localization of these deposits could potentially be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.
... Brain bank studies suggest that Pick's disease could account for up to 30% of individuals with frontotemporal lobar degeneration and tau pathology at autopsy, and 10% overall of people who have fronto temporal lobar degeneration. 2 The prevalence of frontotemporal lobar degeneration syndromes has been estimated at 10·2 per 100 000 and the incidence at 1·61 per 100 000 personyears, 3 suggesting that the preva lence of Pick's disease could be around 1 per 100 000 with an incidence of around 0·2 per 100 000 person years. ...
... These neurodegenerative maladies are known as primary tauopathies. They represent a heterogeneous group of disorders that are driven by the misfolding and abnormal aggregation of filamentous tau to form different pathological inclusions [323][324][325][326][327][328]. Accumulation of these inclusions leads to the degeneration within the afflicted brain regions. ...
... Accumulation of these inclusions leads to the degeneration within the afflicted brain regions. This gives raise to the specific clinical impairments reflected in a broad spectrum of behavioral, cognitive, and motor symptoms [326,329]. Similar to prion protein, α-synuclein and many other proteins related to the various amyloidosis, tau is capable of formation of the conformationally distinct pathological protein aggregates, or strains. Furthermore, these pathological aggregates can be transmitted between the anatomically connected brain regions, resulting in the spread of pathological protein inclusions [330,331]. ...
In this work, we explore the intrinsic disorder status of the three members of the synuclein family of proteins - α-, β-, and γ-synucleins. We also analyzed the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members to find potential effects of pathological mutations. Furthermore, we conducted a comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluated their levels of intrinsic disorder using a set of commonly used bioinformatics tools. Next, we conducted a detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members using various web-based disorder analysis and prediction tools, such as RIDAO, D2P2 and FuzDrop. We identify that the interactome of human α-synuclein has relatively higher levels of intrinsic disorder, as compared to the interactomes of human β- and γ- synucleins. These observations highlight the critical importance of intrinsic disorder of human α-synuclein and its interactors in neuronal processes as compared to other proteins of the synuclein family.
... [2][3][4][5][6][7] A range of frontotemporal lobar degeneration (FTLD) proteinopathies can cause bvFTD, 8 including a similar incidence of transactive response DNA-binding protein of 43kDa (TDP-43) pathology (FTLD-TDP) and FTLD-type tau pathology (FTLD-tau) among bvFTD patients. [8][9][10][11][12][13] This clinicopathologic heterogeneity, in addition to limited biomarkers, currently hinder reliable antemortem diagnosis of the causative FTLD-type pathology in bvFTD. 14 Postmortem neuroanatomical changes associated with proteinopathies in bvFTD remain poorly understood. ...
Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP (p=0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.
... These variants align with three primary neuropathological classes: lvPPA with Alzheimer's disease (AD) pathology, agPPA with tau deposition and svPPA with transactive response DNA-binding protein of 43 kD (TDP-43) pathology. [3][4][5] Challenges include complex classification, clinicopathological group overlap and variable neuropathology frequency. 4 Neurodegeneration patient counselling, symptom management and, increasingly, treatment. ...
Background
Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer’s disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction.
Methods
We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k -nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database.
Results
PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies.
Conclusions
Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.
... [3][4][5][6] The patient reported here initially presented with PPAOS and subsequently developed atypical parkinsonism that resembled CBS, which is also commonly associated with 4R tau accumulation. 7 Unexpectedly, postmortem tau immunohistochemistry was almost completely negative; rather, TAR DNA-binding protein 43 (TDP-43) Type A was the primary pathology. Subsequent genetic testing revealed a sequence variation in the progranulin gene (GRN c.1A>C, p.Met1). ...
Objectives
To introduce the first case in which primary progressive apraxia of speech (PPAOS) is associated with TAR DNA-binding protein 43 (TDP-43) instead of 4-repeat tau.
Methods
This patient was identified through a postmortem autopsy. Following an initial diagnostic evaluation, he participated in 3 annual research visits during which speech, language, cognitive, and neurologic assessments were administered. Neuroimaging was also acquired.
Results
Apraxia of speech was diagnosed at his initial visit with a comprehensive neurologic examination further revealing subtle motor findings in the right hand. At subsequent visits, agrammatic aphasia and motor symptoms consistent with corticobasal syndrome were evident. Cognition and behavior remained relatively intact until advanced stages. FDG-PET revealed hypometabolism in the right temporoparietal cortex and left premotor and motor cortices. There was also low-level signal in the right temporoparietal cortex on tau-PET. A sequence variation in the progranulin gene was identified (GRN c.1A>C, p.Met1). Pathologic diagnosis was TDP-43 Type A with an atypical distribution of inclusions in premotor and motor cortices.
Discussion
This case report demonstrates that TDP-43 Type A inclusions in an atypical distribution can present clinically as PPAOS. The sequence variation in the progranulin gene and asymmetric temporoparietal cortex involvement were the strongest indications of the unusual neuropathophysiology prior to autopsy.
... Some patients may have clinical features of both FTD and motor neuron disease (MND), leading to a syndromic diagnosis of FTD-MND 4 . Also, in terms of underlying pathology, tau protein inclusions in the absence of amyloid β deposits are a hallmark of FTD-related tauopathies (i.e., corticobasal degeneration (CBD), progressive supranuclear palsy (PSP)), a subset of FTD neuropathology 5,6 . ...
... In both FTD and AD patient groups, no signi cant correlation was observed between the concentrations of Aβ1-42 and MoCA scores. This absence of correlation may not be surprising in patients with FTD since these conditions typically involve minimal or no amyloid pathology in the brain 5 . On the other hand, our ndings in AD patients align with prior research, indicating a stronger correlation between cognitive measures and tau markers when compared to Aβ1-42 in AD 28, 29 . ...
Objective
Currently available literature on the relationships between cerebrospinal fluid (CSF) biomarkers and cognitive performance in frontotemporal dementia (FTD) is very limited and inconclusive. In this study, we investigated the association of cognition, as measured with Montreal Cognitive Assessment (MoCA), with CSF levels of total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and amyloid β 1–42 (Aβ1–42) in a group of patients with FTD and Alzheimer’s disease (AD).
Methods
We conducted a retrospective cohort study with participants selected from the electronic records of patients seen at Yale New Haven Hospital’s Memory Clinic, CT, USA. We included 61 patients, 28 with FTD (mean age = 64.1) and 33 with AD (mean age = 66.8).
Results
T-tau levels negatively and significantly correlated with total MoCA scores as well as the different MoCA index scores in both the FTD (r=-0.469, p < 0.05) and AD (r=-0.545, p < 0.01) groups. There were no significant associations with MoCA scores and p-tau181 levels in patients with FTD (r=-0.224, p > 0.05), unlike patients with AD, who exhibited significant correlations (r=-0.549, p < 0.01). Also, Aβ1–42 levels were not significantly correlated with MoCA scores in either of the FTD and AD groups.
Conclusion
CSF concentrations of t-tau are inversely correlated to cognitive performance in patients with FTD and both t-tau and p-tau181 in AD. These findings provide valuable insights into the relationship between clinical cognitive performance and tau-related pathology in FTD.
... Some patients may have clinical features of both FTD and motor neuron disease (MND), leading to a syndromic diagnosis of FTD-MND 4 . Also, in terms of underlying pathology, tau protein inclusions in the absence of amyloid β deposits are a hallmark of FTD-related tauopathies (i.e., corticobasal degeneration (CBD), progressive supranuclear palsy (PSP)), a subset of FTD neuropathology 5,6 . ...
... In both FTD and AD patient groups, no signi cant correlation was observed between the concentrations of Aβ1-42 and MoCA scores. This absence of correlation may not be surprising in patients with FTD since these conditions typically involve minimal or no amyloid pathology in the brain 5 . On the other hand, our ndings in AD patients align with prior research, indicating a stronger correlation between cognitive measures and tau markers when compared to Aβ1-42 in AD 28, 29 . ...
Objective: Currently available literature on the relationships between cerebrospinal fluid (CSF) biomarkers and cognitive performance in frontotemporal dementia (FTD) is very limited and inconclusive. In this study, we investigated the association of cognition, as measured with Montreal Cognitive Assessment (MoCA), with CSF levels of total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and amyloid β 1–42 (Aβ1–42) in a group of patients with FTD and Alzheimer’s disease (AD).
Methods: We conducted a retrospective cohort study with participants selected from the electronic records of patients seen at Yale New Haven Hospital’s Memory Clinic, CT, USA. We included 61 patients, 28 with FTD (mean age=64.1) and 33 with AD (mean age=66.8).
Results: T-tau levels negatively and significantly correlated with total MoCA scores as well as the different MoCA index scores in both the FTD (r=-0.469, p<0.05) and AD (r=-0.545, p<0.01) groups. There were no significant associations with MoCA scores and p-tau181 levels in patients with FTD (r=-0.224, p>0.05), unlike patients with AD, who exhibited significant correlations (r=-0.549, p<0.01). Also, Aβ1–42 levels were not significantly correlated with MoCA scores in either of the FTD and AD groups.
Conclusion: CSF concentrations of t-tau are inversely correlated to cognitive performance in patients with FTD and both t-tau and p-tau181 in AD. These findings provide valuable insights into the relationship between clinical cognitive performance and tau-related pathology in FTD.
... GM atrophy is a key feature in PAOS (Josephs et al., 2011), with involvement of the premotor cortex and spread over time into the TA B L E 2 Comparative AUROC analysis between control and PAOS groups. (Tetzloff et al., 2018). ...
Background
Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure.
Methods
Twenty‐two PAOS patients and 26 age‐ and sex‐matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions.
Results
Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus.
Conclusions
DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.
