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The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA‐binding protein type C (TDP‐C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP‐C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP‐C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post‐mortem examination, the pathognomonic feature of TDP‐C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP‐A and TDP‐B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP‐43 in TDP‐C versus TDP‐A and B. Parallel investigations based on proteomics, somatic mutations, and genome‐wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP‐C. Future work will focus on characterizing the distinctive features of the abnormal TDP‐C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL‐specific markers that modulate vulnerability to TDP‐C. ANN NEUROL 2023;94:1–12 [ABSTRACT FROM AUTHOR]

On average, memory capacity is significantly higher in populations of 50–60 year olds than in populations of 80 year olds. We define SuperAgers as individuals 80 or older whose episodic memory capacity is at least as good as that of cognitively average individuals in their 50s and 60s. SuperAgers therefore have memory capacity that is superior for age. Previous work showed that SuperAgers have greater cortical volumes and greater resistance to age‐related cortical atrophy than "cognitively average" individuals of the same age. Here we report on the cognitive, personality, and neuropathologic characteristics of the first 10 autopsy cases in the Northwestern SuperAging Program. During the follow‐up period, seven SuperAgers maintained episodic memory performance within or above the average range for 50–65 year‐old norms and all 10 SuperAgers maintained episodic memory scores within normal limits for their own age. Extraversion scores tended to be high on the NEO‐PI‐R measure of personality. The 10 autopsy specimens showed variable findings within the spectrum of Alzheimer pathology. The hippocampus and entorhinal cortex contained neurofibrillary degeneration mostly in the Braak II–III stages. However, even these limbic areas contained many healthy appearing neurons and the neocortex was generally free of neurofibrillary degeneration. In contrast, neocortical areas in at least five of the cases contained moderate to high densities of neuritic plaques. These findings need to be placed in context by comparing them to the neuropathology of cognitively average individuals of the same age. Future research on SuperAgers is likely to offer insights into factors that either prevent the emergence of involutional changes in the brain or that makes cognitive function more resistant to their consequences. [ABSTRACT FROM AUTHOR]

The article reports on research which was conducted to investigate whether healthy patients aged 80 and above who were asked to memorize a list of words would do so at a slower rate than patients aged 50 to 60. Researchers evaluated several older subjects whose performance on several memory related tests was above average. They found that those individuals did not show any significant decline on any neuropsychological measures of memory, attention or executive function and that their performance on the memorization test was similar to younger subjects.

Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological function are mainly derived from animal models. Here, we investigated 15 whole‐brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD). Quantitative and qualitative methods were used to investigate differences in neuronal size and density, and the relationship between neuronal processes and vasculature. Double staining was used to evaluate colocalization of neurochemicals. Two topographically distinct populations of neurons emerged: one appearing to arise from developmental subplate neurons and the other embedded within deep, subcortical white matter. Both populations appeared to be neurochemically heterogeneous, showing positive reactivity to acetylcholinesterase (AChE) [but not choline acetyltransferase (ChAT)], neuronal nuclei (NeuN), nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPH‐d), microtubule‐associated protein 2 (MAP–2), somatostatin (SOM), nonphosphorylated neurofilament protein (SMI‐32), and calcium‐binding proteins calbindin‐D28K (CB), calretinin (CRT), and parvalbumin (PV). PV was more richly expressed in superficial as opposed to deep white matter neurons (WMNs); subplate neurons were also significantly larger than their deeper counterparts. NADPH‐d, a surrogate for nitric oxide synthase, allowed for the striking morphological visualization of subcortical WMNs. NADPH‐d‐positive subcortical neurons tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. The presence of AChE positivity in these neurons, but not ChAT, suggests that they are cholinoceptive but noncholinergic. WMNs were also significantly smaller in AD compared to control cases. These observations provide a landscape for future systematic investigations. [ABSTRACT FROM AUTHOR]

Objective: Age‐related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA‐binding protein 43 (TDP‐43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP‐43 and tau, along the well‐charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non‐amnestic dementia due to TDP‐43 proteinopathy associated with frontotemporal lobar degeneration (FTLD‐TDP). Methods: A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD‐TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss. Results: In AD/TDP and FTLD‐TDP, TDP‐43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD‐TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype. Interpretation: We conclude that AD/TDP can be distinguished from AD and FTLD‐TDP based on differential regional distributions of hippocampal tau and TDP‐43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP‐43. ANN NEUROL 2023;94:1036–1047 [ABSTRACT FROM AUTHOR]

Objective: To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with pathological diagnoses of frontotemporal lobar degeneration with transactive response DNA-binding protein-43 (TDP-43) inclusions and to examine the relationships between microglial densities, patterns of focal atrophy, (TDP-43) inclusions, and clinical phenotype.Methods: Activated microglia and TDP-43 inclusions were visualized in whole-hemisphere brain sections using immunohistochemical methods from five participants with PPA-TDP. Unbiased stereology was used to bilaterally quantify human leuckocyte antigen/D related-positive activated microglia and TDP-43 inclusions across five language-related regions. Density and distribution of both markers were compared across cortical regions and hemispheres, and their relationships to patterns of focal atrophy and clinical phenotype were determined.Results: Activated microglia displayed asymmetric distribution favoring the language-dominant hemisphere, consistent with greater postmortem and/or in vivo atrophy in that hemisphere, in PPA-TDP. In one participant with no asymmetric atrophy, quantitative distribution of microglia also lacked asymmetry. Patterns of microglial activation also showed variation that favored areas of high atrophy in regions affiliated with language function, demonstrating concordance between patterns of microglial activation, atrophy, and clinical phenotype. TDP-43 also showed higher inclusion densities in areas of high atrophy than in regions with low atrophy, but no clear relationship with microglia density at a regional level.Interpretation: The initial activation of microglia is most likely a response to cortical abnormalities in PPA-TDP, which contribute to atrophy. The patterns of microglial activation, TDP-43 inclusion deposition, atrophy, and clinical phenotype suggest that activated microglia may make unique contributions to cortical thinning and TDP-43 inclusion formation. Ann Neurol 2018;83:1096-1104. [ABSTRACT FROM AUTHOR]

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD‐TAU) and the TDP‐43 proteinopathy of FTLD‐TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD‐TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD. [ABSTRACT FROM AUTHOR]

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD. [ABSTRACT FROM AUTHOR]