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.

The aorta, which has a complex intrinsic biology and sophisticated mechanical properties for conducting the blood ejected from the left ventricle to the rest of the systemic arterial bed, is the largest and strongest artery in the body. It carries roughly 200 million liters of blood in an average lifetime. Any process that undermines the architecture threatens the structure, stability, and functionality of the aorta. In this regard, acute aortic dissection (AAD) requires special attention because it is the most catastrophic acute illness of the aorta; it has high morbidity and mortality because of potentially fatal complications. AAD has, therefore, become an important topic of recent research, and knowledge about this disease has improved during the past few years. Up-to-date knowledge about the natural history, epidemiology, presentation, physiopathology, evolution, management, follow-up, and long-term outcomes of AAD are summarized in this review.

Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer’s disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20–30 years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.

Certain neuronal populations, including the cholinergic neurons of the basal forebrain (BFCN) and the noradrenergic neurons of the locus coeruleus (LC), are selectively vulnerable to pathology and loss early in the course of aging and Alzheimer's disease (AD). We have shown that BFCN in the human brain show a substantial loss of the calcium binding protein, calbindin-D 28K (CB), over the course of normal aging, which is associated with formation of neurofibrillary tangles and loss of BFCN in AD. The purpose of this study was to determine if, similar to the BFCN, LC neurons contain CB or the other two ubiquitous calcium binding proteins (CBP) parvalbumin and calretinin, and if so, whether these proteins display an age-related loss from LC neurons. Immunostaining for CBPs and tyrosine hydroxylase (TH), a marker of catecholaminergic neurons, were used in sections from the LC of young and aged human brains. Parvalbumin and calretinin immunoreactivities were completely absent from human LC neurons. A subpopulation of LC neurons (~10%) contained CB immunoreactivity. Quantitative analysis using sections stained concurrently for visualization of CB and TH revealed no age-related loss of the former from the LC neurons. These findings indicate that, unlike the BFCN, age-related loss of CB does not figure prominently in the selective vulnerability of LC neurons to tangle formation and degeneration in AD.

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.

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Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive "pre-inclusions" have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of preinclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20–30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers (“Normal Elderly”), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p< 0.05)—including younger individuals 20–30 years their junior (p< 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p< 0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20–30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.SIGNIFICANCE STATEMENTAverage aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer's disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern University SuperAging Research Program studies unique individuals known as SuperAgers, individuals ≥80 years old who show exceptional memory that is at least as good as individuals 20–30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and – remarkably – even compared with individuals 20–30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.