RESUMEN
Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI ≤ 5 years before death and postmortem ordinal ratings of amyloid-[Formula: see text], tau, TDP-43, and [Formula: see text]-synuclein. Regional volumes were related to pathology using linear mixed-effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in the training and testing datasets. Tau, TDP-43, and [Formula: see text]-synuclein burden were inversely associated with regional volumes, but amyloid-[Formula: see text] was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and [Formula: see text]-synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Masculino , Femenino , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Sustancia Gris/patología , Proteínas tau/metabolismo , Gliosis/patología , Atrofia/patología , Amiloide , Sinucleínas , Proteínas de Unión al ADN/metabolismo , Biomarcadores , Enfermedad de Alzheimer/patologíaRESUMEN
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 relatively uniform along 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 versus bvFTD-TDP (p=0.039). Using a ratio of SMI32-ir to model known long-range connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio in bvFTD-tau versus 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 versus 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.
RESUMEN
TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.
Asunto(s)
Anexinas , Proteínas de Unión al ADN , Degeneración Lobar Frontotemporal , Humanos , Anciano , Anexinas/genética , Anexinas/metabolismo , Femenino , Masculino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/patología , Degeneración Lobar Frontotemporal/metabolismo , Persona de Mediana Edad , Anciano de 80 o más Años , Proteinopatías TDP-43/patología , Proteinopatías TDP-43/genética , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/metabolismo , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismoRESUMEN
BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.
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Esclerosis Amiotrófica Lateral , Disfunción Cognitiva , Enfermedad de la Neurona Motora , Humanos , Masculino , Persona de Mediana Edad , Femenino , Esclerosis Amiotrófica Lateral/diagnóstico , Proteína C9orf72/genética , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/complicaciones , Disfunción Cognitiva/genética , Disfunción Cognitiva/complicaciones , Cognición/fisiología , Pruebas NeuropsicológicasRESUMEN
TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Proteinopatías TDP-43 , Humanos , Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/patología , Enfermedad de Alzheimer/patología , Proteinopatías TDP-43/patología , Degeneración Lobar Frontotemporal/patología , Proteínas de Unión al ADN/genéticaRESUMEN
Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer's disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogeneous mix of 161 pathological combinations. The presence of multiple additive pathologies associated with older age, increasing disease duration, APOE e4 allele and presence of dementia across the clinical groups. Fifteen to 67 combinations occurred in each group, with the unimpaired group defined by 35 combinations. Most combinations occurred at a <5% prevalence including 86 that were present in only one or two individuals. To better understand this heterogeneity, we organized the pathological combinations into five broad categories based on their age-related frequency: (i) 'Ageing only' for the unimpaired group combinations; (ii) 'ND only' if only the expected pathology for that individual's clinical phenotype was present; (iii) 'Other ND' if the expected pathology was not present; (iv) 'ND + ageing' if the expected pathology was present together with ageing-related pathologies at a similar prevalence as the unimpaired group; and (v) 'ND + associated' if the expected pathology was present together with other pathologies either not observed in the unimpaired group or observed at a greater frequency. ND only cases comprised a minority of cases (19-45%) except in the amyotrophic lateral sclerosis (56%) and multiple system atrophy (65%) groups. The ND + ageing category represented 9-28% of each group, but was rare in Alzheimer's disease (1%). ND + associated combinations were common in Alzheimer's disease (58%) and Lewy body disease (37%) and were observed in all groups. The Ageing only and Other ND categories accounted for a minority of individuals in each group. This observed heterogeneity indicates that the total pathological burden in ND is frequently more than a primary expected clinicopathological correlation with a high frequency of additional disease- or age-associated pathologies.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad por Cuerpos de Lewy/patología , Esclerosis Amiotrófica Lateral/patología , Estudios RetrospectivosRESUMEN
We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.
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Proteínas de Unión al ADN , Progresión de la Enfermedad , Demencia Frontotemporal , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Unión al ADN/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Demencia Frontotemporal/fisiopatología , Estudios LongitudinalesRESUMEN
INTRODUCTION: Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia-related neuropathologies is unknown. METHODS: This cross-sectional study included 469 autopsy cases from 2011 to 2023. The relationships between neighborhood disadvantage measured by Area Deprivation Index (ADI) percentiles categorized into tertiles, cognition evaluated by the last Mini-Mental State Examination (MMSE) scores before death, and 10 dementia-associated proteinopathies and cerebrovascular disease were assessed using regression analyses. RESULTS: Higher ADI was significantly associated with lower MMSE score. This was mitigated by increasing years of education. ADI was not associated with an increase in dementia-associated neuropathologic change. Moreover, the significant association between ADI and cognition remained even after controlling for changes in major dementia-associated proteinopathies or cerebrovascular disease. DISCUSSION: Neighborhood disadvantage appears to be associated with decreased cognitive reserve. This association is modified by education but is independent of the major dementia-associated neuropathologies.
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Trastornos Cerebrovasculares , Reserva Cognitiva , Demencia , Deficiencias en la Proteostasis , Humanos , Estudios Transversales , Características del VecindarioRESUMEN
INTRODUCTION: Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. METHODS: Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. RESULTS: There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. DISCUSSION: Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.
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Enfermedad de Alzheimer , Biomarcadores , Sustancia Gris , Tomografía de Emisión de Positrones , Lóbulo Temporal , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Lóbulo Temporal/patología , Lóbulo Temporal/diagnóstico por imagen , Masculino , Femenino , Anciano , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , Biomarcadores/sangre , Péptidos beta-Amiloides/metabolismo , Ovillos Neurofibrilares/patología , Imagen de Difusión por Resonancia MagnéticaRESUMEN
INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.
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Enfermedad de Alzheimer , Resiliencia Psicológica , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau , Ovillos Neurofibrilares/patología , Imagen por Resonancia Magnética , Péptidos beta-AmiloidesRESUMEN
INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed ß-amyloid (Aß+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aß+ from Aß-. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aß+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aß+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aß- individuals (HR = 3.11; p = 2.6e-09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aß. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aß status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aß/tau. Plasma NfL predicted longitudinal cognitive decline in both Aß+ and Aß- individuals.
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Péptidos beta-Amiloides , Biomarcadores , Enfermedades Neurodegenerativas , Proteínas de Neurofilamentos , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Biomarcadores/sangre , Femenino , Masculino , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Anciano , Proteínas de Neurofilamentos/sangre , Enfermedades Neurodegenerativas/sangre , Enfermedades Neurodegenerativas/diagnóstico , Péptidos beta-Amiloides/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Progresión de la Enfermedad , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Persona de Mediana Edad , Fosforilación , Cognición/fisiologíaRESUMEN
Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were obtained in up to 13 gray matter (GM) and adjacent white matter (WM) cortical brain regions sampled from 53 tauopathy and 66 TDP-43 proteinopathy autopsy patients. First, we constructed a weighted non-directed graph for each group, where nodes are defined as GM and WM regions sampled and edges in the graph are weighted using the group-level Pearson's correlation coefficient for each pairwise node comparison. Additionally, we performed mediation analyses to test mediation effects of WM pathology between anterior frontotemporal and posterior parietal GM nodes. We find greater correlation (i.e., edges) between GM and WM node pairs in tauopathies compared with TDP-43 proteinopathies. Moreover, WM pathology strongly correlated with a graph metric of pathology spread (i.e., node-strength) in tauopathies (r = 0.60, p < 0.03) but not in TDP-43 proteinopathies (r = 0.03, p = 0.9). Finally, we found mediation effects for WM pathology on the association between anterior and posterior GM pathology in FTLD-Tau but not in FTLD-TDP. These data suggest distinct tau and TDP-43 proteinopathies may have divergent patterns of cellular propagation in GM and WM. More specifically, axonal spread may be more influential in FTLD-Tau progression. Network analyses of digital histopathological measurements can inform models of disease progression of cellular degeneration in the human brain.SIGNIFICANCE STATEMENT In this study, we uniquely perform two complimentary computational approaches to model and contrast microscopic disease progression between common frontotemporal lobar degeneration (FTLD) proteinopathy subtypes with similar clinical syndromes during life. Our models suggest white matter (WM) pathology influences cortical spread of disease in tauopathies that is less evident in TDP-43 proteinopathies. These data support the hypothesis that there are neuropathologic signatures of cellular degeneration within neurocognitive networks for specific protienopathies. These distinctive patterns of cellular pathology can guide future efforts to develop tissue-sensitive imaging and biological markers with diagnostic and prognostic utility for FTLD. Moreover, our novel computational approach can be used in future work to model various neurodegenerative disorders with mixed proteinopathy within the human brain connectome.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Proteinopatías TDP-43 , Tauopatías , Atrofia , Progresión de la Enfermedad , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Humanos , Proteinopatías TDP-43/patología , Tauopatías/patología , Proteínas tauRESUMEN
OBJECTIVE: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau181 in ALS. METHODS: Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non-impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss. RESULTS: A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W = 827, p = 0.0072), thoracic (W = 469, p = 0.00025), and lumbosacral regions (W = 851, p = 0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex (p = 0.41). Cerebrospinal spinal fluid p-tau181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. INTERPRETATION: We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Proteínas tau , Enfermedad de Alzheimer/patología , Curva ROC , Área Bajo la Curva , Biomarcadores , Degeneración NerviosaRESUMEN
BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Estudios Transversales , Imagen por Resonancia Magnética , Cerebelo , EncéfaloRESUMEN
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/genética , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/prevención & control , Enfermedades Asintomáticas , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/prevención & controlRESUMEN
INTRODUCTION: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods. METHODS: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. RESULTS: Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. CONCLUSION: We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. HIGHLIGHTS: Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Enfermedades Neurodegenerativas/complicaciones , Imagen por Resonancia Magnética , Proteínas de Unión al ADNRESUMEN
Alzheimer's disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedades Neurodegenerativas/patología , Ovillos Neurofibrilares/patología , Hipocampo/patología , Microglía/patología , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genéticaRESUMEN
Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Sustancia Blanca , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Humanos , Sustancia Blanca/patología , Proteínas tau/metabolismoRESUMEN
Alzheimer's disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic variants of Alzheimer's disease (AD). In this study, autopsy-confirmed patients with ADNC, were classified into amnestic (aAD, N = 40) and non-amnestic (naAD, N = 39) groups based on clinical criteria. We performed digital assessment of tissue sections immunostained for phosphorylated-tau (AT8 detects pretangles and mature tangles), D421-truncated tau (TauC3, a marker for mature tangles and ghost tangles), and E391-truncated tau (MN423, a marker that primarily detects ghost tangles), in hippocampal subfields and three cortical regions. Linear mixed-effect models were used to test regional and group differences while adjusting for demographics. Both groups showed AT8-reactivity across hippocampal subfields that mirrored traditional Braak staging with higher burden of phosphorylated-tau in subregions implicated as affected early in Braak staging. The burden of phosphorylated-tau and TauC3-immunoreactive tau in the hippocampus was largely similar between the aAD and naAD groups. In contrast, the naAD group had lower relative distribution of MN423-reactive tangles in CA1 (ß = - 0.2, SE = 0.09, p = 0.001) and CA2 (ß = - 0.25, SE = 0.09, p = 0.005) compared to the aAD. While the two groups had similar levels of phosphorylated-tau pathology in cortical regions, there was higher burden of TauC3 reactivity in sup/mid temporal cortex (ß = 0.16, SE = 0.07, p = 0.02) and MN423 reactivity in all cortical regions (ß = 0.4-0.43, SE = 0.09, p < 0.001) in the naAD compared to aAD. In conclusion, AD clinical variants may have a signature distribution of overall phosphorylated-tau pathology within the hippocampus reflecting traditional Braak staging; however, non-amnestic AD has greater relative mature tangle pathology in the neocortex compared to patients with clinical amnestic AD, where the hippocampus had greatest relative burden of C-terminally cleaved tau reactivity. Thus, varying neuronal susceptibility to tau-mediated neurodegeneration may influence the clinical expression of ADNC.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Hipocampo/patología , Lóbulo Temporal/metabolismo , Ovillos Neurofibrilares/patologíaRESUMEN
INTRODUCTION: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. METHODS: We assessed regional and interindividual variation in longitudinal change on 18 F-flortaucipir PET imaging in 24 amyloid beta (Aß)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aß- and 132 Aß+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. RESULTS: In atypical AD, 18 F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas. DISCUSSION: Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.