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The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles—3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias. [ABSTRACT FROM AUTHOR]

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo 18F-florbetapir amyloid PET and 18F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months. Florbetapir and flortaucpir PET standard uptake value ratios (SUVRs) were quantified from 8 left and right hemisphere brain regions with stereological quantification of amyloid plaques and NFTs from corresponding postmortem sections. Pearson's correlations and measures of asymmetry were used to examine relationships between imaging and autopsy measurements. The three visits prior to death revealed decline of language measures, with marked progression of atrophy. Florbetapir PET presented with an atypical focal pattern of uptake and showed a significant positive correlation with postmortem amyloid plaque density across the 8 regions (r = 0.92; p = 0.001). Flortaucipir PET had a left-lateralized distribution and showed a significant positive correlation with NFT density (r = 0.78; p = 0.023). Flortaucipir PET and NFT density indicated a medial temporal lobe sparing presentation of ADNC, demonstrating that AD does not always target the medial temporal lobe. This study adds additional evidence, in a non-amnestic phenotype of ADNC, that there is a strong correlation between AD PET biomarkers, florbetapir and flortaucipir, with quantitative neuropathology. The atypical and focal presentation of plaque density and florbetapir PET uptake suggests not all amyloid pathology presents as diffuse across neocortex. [ABSTRACT FROM AUTHOR]

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes. [ABSTRACT FROM AUTHOR]