Search

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16–0.95) and recent use (0.39, 95% CI: 0.16–0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

The spread of neurofibrillary tau pathology in Alzheimer disease (AD) mostly follows a stereotypical pattern of topographical progression but atypical patterns associated with interhemispheric asymmetry have been described. Because histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns. Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest in 57 autopsy cases comparing bilateral cortical regions and hemispheres. Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed, whereas marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak Stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and were more frequent in advanced (IV–VI) versus early (I–III) stages. One atypical lobar topographical pattern in which occipital tau pathology density exceeded frontal lobe scores was identified in 4 cases favoring a left dominant asymmetry. We speculate that asymmetry and atypical topographical progression patterns may be associated with atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer's Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer's Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

Two population-based studies key to advancing knowledge of brain aging are the Honolulu-Asia Aging Study (HAAS) and the Nun Study. Harmonization of their neuropathologic data allows cross comparison, with findings common to both studies likely generalizable, while distinct observations may point to aging brain changes that are dependent on sex, ethnicity, environment, or lifestyle factors. Here, we expanded the neuropathologic evaluation of these 2 studies using revised NIA-Alzheimer's Association guidelines and compared directly the neuropathologic features of resistance and apparent cognitive resilience. There were significant differences in prevalence of Alzheimer disease neuropathologic change, small vessel vascular brain injury, and Lewy body disease between these 2 studies, suggesting that sex, ethnicity, and lifestyle factors may significantly influence resistance to developing brain injury with age. In contrast, hippocampal sclerosis prevalence was very similar, but skewed to poorer cognitive performance, suggesting that hippocampal sclerosis could act sequentially with other diseases to impair cognitive function. Strikingly, despite these observed differences, the proportion of individuals resistant to all 4 diseases of brain or displaying apparent cognitive resilience was virtually identical between HAAS and Nun Study participants. Future in vivo validation of these results awaits comprehensive biomarkers of these 4 brain diseases.

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost. A 28 autopsy brain-retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings.

Cerebral white matter injury (WMI) contributes to cognitive dysfunction associated with pathological aging. Because reactive astrocyte-related factors contribute to remyelination failure after WMI, we sought accurate, cost-effective, and reproducible histopathological approaches for quantification of morphometric features of reactive astrogliosis in aged human white matter in patients with vascular brain injury (VBI). We compared 7 distinct approaches to quantify the features of glial fibrillary acidic protein (GFAP)-labeled astrocytes in the prefrontal white matter of brains from patients with VBI (n = 17, mean age 88.8 years) and controls that did not exhibit VBI (n = 11, mean age 86.6 years). Only modern stereological techniques (ie, optical fractionator and spaceballs) and virtual process thickness measurements demonstrated significant changes in astrocyte number, process length, or proximal process thickness in cases with VBI relative to controls. The widely employed methods of neuropathological scoring, antibody capture assay (histelide), area fraction fractionator, and Cavalieri point counting failed to detect significant differences in GFAP expression between the groups. Unbiased stereological approaches and virtual thickness measurements provided the only sensitive and accurate means to quantify astrocyte reactivity as a surrogate marker of WMI in human brains with VBI.

The 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer’s Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes.

Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) β42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ɛ4/ɛ4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE ɛ3/ɛ3 or APOE ɛ3/ɛ4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and β-amyloid (Aβ42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.

We used a novel approach to molecular quantification in standard fixed and embedded tissue to measure amyloid β 42 (Aβ42) and paired helical filament-τ (PHF-τ) in frontal, temporal, and parietal cortices from 325 consecutive brain autopsies collected as part of a population-based study of brain aging and incident dementia in the Seattle area. We observed significant effects of APOE ɛ4 on Aβ42 levels in both diagnostic groups by disease stage and region. In contrast, we did not observe a significant effect of APOE ɛ4 on PHF-τ levels by disease stage in any region. Levels of Aβ42 and PHF-τ in cerebral cortex were correlated more strongly in the Dementia group, and these measures had independent explanatory power for dementia beyond those of standard neuropathologic indices. Associations between Lewy body disease and Aβ42 or PHF-τ levels and between Aβ42 levels and microvascular brain injury suggested that these comorbid diseases enhanced the penetrance of Alzheimer disease. Our novel approach brings additional insights into the molecular pathogenesis of common causes of dementia and may serve as a platform for future studies pursuing associations between molecular changes in Alzheimer disease and genetic or environmental risk.

Many neurodegenerative disorders involve the abnormal accumulation of proteins. In addition to the pathologic hallmarks of neurofi-brillary tangles and β-amyloid plaques in Alzheimer disease (AD), here we show that abnormal accumulations of gephyrin, an inhibitory receptor-anchoring protein, are highly correlated with the neuropathologic diagnosis of AD in 17 AD versus 14 control cases. Furthermore, gephyrin accumulations were specific for AD and not seen in normal controls or other neurodegenerative diseases including Parkinson disease, corticobasal degeneration, and frontotemporal degeneration. Gephyrin accumulations in AD overlapped with β-amyloid plaques and, more rarely, neurofibrillary tangles. Biochemical and proteomic studies of AD and control brain samples suggested alterations in gephyrin solubility and reveal elevated levels of gephyrin lower-molecular-weight species in the AD insoluble fraction. Because gephyrin is involved in synaptic organization and synaptic dysfunction is an early event in AD, these findings point to its possible role in the pathogenesis of AD.

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

4-Hydroxy-2-nonenal (HNE), a potent toxin formed in the brain from oxidation of polyunsaturated fatty acids, is increased in Alzheimer disease (AD), where it is a proposed effector of amyloid β peptide-mediated neurotoxicity. Detoxification of HNE via the mercapturic acid pathway (MAP) is the primary means by which other organs, such as liver, limit its toxic effects. Here we examined the distribution and activity of MAP detoxification for HNE in cerebrum. Our results showed that rat cerebral cortex and especially synaptosomes were less well equipped to detoxify HNE via the MAP than liver. Glutathione transferases (GSTs) catalyze the committed step in the MAP; GST-mu and GST-pi, but not GST-alpha, were detected in neurons and astrocytes in cerebrum from AD patients and controls. MAP activity in frontal cortex of AD patients was modestly but significantly increased compared to controls. These data suggest that lipid peroxidation may present a greater toxic burden to cerebrum than to other organs, and that a component of response to injury in late stage AD is a slight increase in MAP activity.

Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD.

A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Aβ peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH); aldose reductase; aldehyde reductase; and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex, hippocampus, basal ganglia, and midbrain; all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.

Although α-synuclein (α-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length α-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout α-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the α-syn epitopes detected in GCIs. Notably, carboxy-terminal α-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of α-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal α-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight α-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that α-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in α-syn.

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson disease (PD). Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of MPTP-mediated dopaminergic neurodegeneration. To further clarify the role of superoxide anion radical (·O2−) and to study the possible involvement of hydroperoxides in MPTP-mediated neurodegeneration, MPTP neurotoxicity was induced in mice deficient in either CuZn superoxide dismutase (SOD), a scavenger enzyme for ·O2−, or cellular glutathione peroxidase (GSHPx-1), a scavenger enzyme for hydroperoxides. Littermate control and homozygous deficient mice were injected intraperitoneally with a total cumulative dose of 0, 75, or 150 mg/kg of MPTP delivered over 5 d. All mice were killed 5 d after the last injection and the brains were processed for immunohistological analysis for tyrosine hydroxylase (TH) in the striatum and the substantia nigra pars compacta (SNc), as well as for direct measurements of dopamine concentrations in the striatum. The intensity of TH immunoreactivity in the striatum was evaluated by measuring the relative optical density (OD) with NIH IMAGE, and expressed as Log (OD of striatum)/Log (OD of white matter). Degeneration of TH-containing neurons was assessed by counting TH-positive neurons in the SNc. We found that this MPTP exposure protocol produced dose-dependent depletion of TH immunoreactivity and dopamine in the striatum in littermate control mice and both strains of knockout mice; however, reduction in TH immunoreactivity and dopamine content were significantly greater in CuZn-SOD or GSHPx-1 deficient mice compared with littermate controls. MPTP exposure did not significantly alter the number of TH-positive neurons in the SNc in littermate control or knockout mice. These data suggest that some of the deleterious effects of MPTP on striatal dopaminergic nerve terminals are mediated by both ·O2− and hydroperoxides, and that they occur prior to dopaminergic neurodegeneration in the SNc. The similarity between the MPTP model and PD raises the possibility that both types of ROS may play a significant role in the early pathogenesis of dopaminergic neurodegeneration in PD.