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Recent therapeutic advances provide heightened motivation for accurate diagnosis of the underlying biologic causes of dementia. This review focuses on the importance of clinical recognition of limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE affects approximately one-quarter of older adults and produces an amnestic syndrome that is commonly mistaken for Alzheimer's disease (AD). Although AD and LATE often co-occur in the same patients, these diseases differ in the protein aggregates driving neuropathology (Aβ amyloid/tau vs TDP-43). This review discusses signs and symptoms, relevant diagnostic testing, and potential treatment implications for LATE that may be helpful for physicians, patients, and families. ANN NEUROL 2023;94:211-222., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Plasma phosphorylated tau (p-tau 181 ) 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-tau 181 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-tau 181 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-tau 181 and postmortem neuron loss., Results: A Wilcoxon test showed plasma p-tau 181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau 181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau 181 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-tau 181 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-tau 181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings., Interpretation: We found strong evidence that plasma p-tau 181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818., (© 2022 American Neurological Association.)

Objective: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology., Methods: Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups., Results: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected., Interpretation: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021;90:751-762., (© 2021 American Neurological Association.)

Objective: Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases., Methods: We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371)., Results: The TMEM106B rs1990622 T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622 T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622 C , dominant model. Among PD patients, rs1990622 T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores., Interpretation: Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811., (© 2019 American Neurological Association.)

Objective: To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies., Methods: In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features., Results: Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = -0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = -3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = -3.62, df = 12.00, p = 0.004) among the 5 core pathology regions., Interpretation: In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA. Ann Neurol 2019;85:630-643., (© 2019 American Neurological Association.)

Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD., Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing., Results: SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F 1, 54 = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F 1, 43-49 = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t 27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F 1, 43 = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t 41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t 41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F 1, 40-43 = 1.6-2.0, p > 0.1)., Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271., (© 2018 American Neurological Association.)

Objective: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants., Methods: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models., Results: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%)., Interpretation: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748., (© 2018 American Neurological Association.)

Objective: To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP-43) proteinopathy patients while accounting for Alzheimer's disease (AD) copathology., Methods: Patients had autopsy-confirmed FTLD with tauopathy (n = 31), TDP-43 proteinopathy (n = 49), or AD (n = 26) with antemortem CSF. CSF tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, and anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem CSF tau levels with postmortem tau pathology adjusting for demographics., Results: Multivariate regression found an independent association of ante mortem CSF phosphorylated tau levels with postmortem cerebral tau pathology in FTLD (Beta = 1.3; 95% confidence interval = 0.2-2.4; p < 0.02). After excluding patients with coincident AD-associated tau pathology accompanying sporadic FTLD, we found lower CSF phosphorylated tau levels in the TDP-43 group (median = 7.4pg/ml; interquartile range [IQR] = 6.0, 12.3; n = 26) compared to the tauopathy group (median = 12.5pg/ml; IQR = 10.7, 15.0; n = 23; Z = 2.6; p < 0.01)., Interpretation: CSF phosphorylated-tau levels are positively associated with cerebral tau burden in FTLD. In vivo detection of AD copathology in sporadic FTLD patients may help stratify clinical cohorts with pure neuropathology in which low CSF phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for FTLD biomarker development and validation. Ann Neurol 2017;82:247-258., (© 2017 American Neurological Association.)

Objective: We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome., Methods: Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 +/- 16.0 [standard deviation] months) subsequent to their PiB scan., Results: Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered "amyloid-positive." All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients "reverted to normal.", Interpretation: These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD.