Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

Alzheimer's disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation.

The clinical spectrum of Alzheimer's disease (AD) extends well beyond the classic amnestic-predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.

Factors associated with brain volume in major depression in older adults without dementia: results from a large autopsy study.

OBJECTIVE: We examined brain volume and atrophy in individuals with major depressive disorder (MDD) without dementia that were referred to a large autopsy service. We also examined potential risk factors for brain atrophy, including demographics and clinical variables. METHODS: In this study, 1373 participants (787 male) aged 50 years or older who died from natural causes were included. Participants with no reliable informant, with cognitive impairment or dementia, with a medical history of severe chronic disease, or with prolonged agonal state were excluded. Presence of MDD at least once in their lifetime was defined according to the Structured Clinical Interview for DSM. Brain volume was measured immediately after removal from the skull. RESULTS: Mean age at death was 68.6 ± 11.6, and MDD was present in 185 (14%) individuals. Smaller brain volume was associated with older age (p < 0.001), lower education (years; p < 0.001), hypertension (p = 0.001), diabetes (p = 0.006), and female gender (p < 0.001). In the multivariate analysis adjusted for sociodemographics and cardiovascular risk factors, smaller brain volume was not associated with major depression (ß = -0.86, 95% CI = -26.50 to 24.77, p = 0.95). CONCLUSIONS: In this large autopsy study of older adults, MDD was not associated with smaller brain volumes. Regardless of the presence of MDD, in this sample of older adults without dementia, we found that smaller brain volumes were associated with risk factors for brain neurodegeneration such as older age, diabetes, hypertension, and lower education. Copyright © 2017 John Wiley & Sons, Ltd.

Glutathione-mediated effects of lithium in decreasing protein oxidation induced by mitochondrial complex I dysfunction.

The aim of this study was to elucidate whether glutathione is involved in lithium's ability to decrease carbonylation and nitration produced by complex I inhibition, which is consistently found in BD. Neuroblastoma cells were treated with rotenone, a complex I inhibitor. Our results suggest that glutathione is essential for lithium's ability to ameliorate rotenone-induced protein carbonylation, but not nitration.

Validity of the Katz Index to assess activities of daily living by informants in neuropathological studies.

OBJECTIVE: To analyze the evidences of construct validity of the Katz Index for the retrospective assessment of activities of daily living (ADL) by informants, to assist neuropathological studies in the elderly. METHOD: A cross-sectional study analyzed the functional ability of ADL measure by the Katz Index, of 650 cases randomly selected from the Brazilian Brain Bank of the Ageing Brain Study Group (BBBABSG) database. Sample was divided in two subsamples for the analysis (N=325, each) and then stratified according to cognitive decline assessed by the Clinical Dementia Rating Scale (CDR). Factor analyses with calculations of internal consistency and invariance were performed. RESULTS: Factor analysis evidenced a unidimensional instrument with optimal internal consistency, in all subgroups. Goodness of fit indices were obtained after two treatments of covariance, indicating adequacy of the scale for assessing ADL by informants. The scale is invariant to cognitive decline meaning that it can be used for subjects with or without cognitive impairment. CONCLUSION: Katz Index is valid for the retrospective assessment of basic ADL by informants, with optimal reliability.

Surface-Based Probabilistic Fiber Tracking in Superficial White Matter.

The short association fibers or U-fibers travel in the superficial white matter (SWM) beneath the cortical layer. While the U-fibers play a crucial role in various brain disorders, there is a lack of effective tools to reconstruct their highly curved trajectory from diffusion MRI (dMRI). In this work, we propose a novel surface-based framework for the probabilistic tracking of fibers on the triangular mesh representation of the SWM. By deriving a closed-form solution to transform the spherical harmonics (SPHARM) coefficients of 3D fiber orientation distributions (FODs) to local coordinate systems on each triangle, we develop a novel approach to project the FODs onto the tangent space of the SWM. After that, we utilize parallel transport to realize the intrinsic propagation of streamlines on SWM following probabilistically sampled fiber directions. Our intrinsic and surface-based method eliminates the need to perform the necessary but challenging sharp turns in 3D compared with conventional volume-based tractography methods. Using data from the Human Connectome Project (HCP), we performed quantitative comparisons to demonstrate the proposed algorithm can more effectively reconstruct the U-fibers connecting the precentral and postcentral gyrus than previous methods. Quantitative validations were then performed on post-mortem MRIs to show the reconstructed U-fibers from our method more faithfully follow the SWM than volume-based tractography. Finally, we applied our algorithm to study the parietal U-fiber connectivity changes in autosomal dominant Alzheimer's disease (ADAD) patients and successfully detected significant associations between U-fiber connectivity and disease severity.

The relationship of neuropsychiatric symptoms with inflammatory markers in the hippocampus and cingulate cortex of bipolar disorder subjects: A post-mortem study.

Increased levels of inflammation markers have been found in the peripheral tissue of individuals with bipolar disorder (BD), especially during mood episodes. Previous studies found distinctive inflammatory profiles across different brain regions, but potential associations with clinical symptoms are still lacking. This study aims to evaluate the association of neuropsychiatric symptoms with inflammatory markers in the hippocampus and cingulate of individuals with BD. Levels of IL-1ß, IL-6, IL-17A, cortisol, and C-reactive protein (CRP) were measured in the hippocampus and anterior cingulate of 14 BD individuals and their non-psychiatric controls. Neuropsychiatric symptoms present in the three months before death were assessed using the Neuropsychiatric Inventory (NPI). In the BD group, greater NPI scores were associated with higher IL-6 in the hippocampus (p = 0.011) and cingulate (p = 0.038) and higher IL-1ß (p = 0.039) in the hippocampus. After adjusting for age, sex and CDR, IL-1ß and IL-6 were still associated with higher NPI in the hippocampus. In correlation analysis considering both BD and their controls, moderate positive associations were found between NPI and IL-6 and cortisol in the hippocampus (p < 0.001 and p = 0.006) and cingulate (p = 0.024 and p = 0.016), IL-1ß (p < 0.001) and IL-17A in the hippocampus (p = 0.002). No difference in inflammatory markers was found according to type of psychotropic medication used. Hence, in individuals with BD, neuropsychiatric symptoms were differently associated with specific inflammatory cytokines and CRP in the hippocampus and cingulate. These results suggest that the neuroinflammatory changes occurring in BD may be more complex than previously expected and could be associated with clinical manifestations.

Episodic memory improvement in illiterate adults attending late-life education irrespective of low socioeconomic status: insights from the PROAME study.

The majority of people with dementia live in low or middle-income countries (LMICs) where resources that play a crucial role in brain health, such as quality education, are still not widely available. In Brazil, illiteracy remains a prevalent issue, especially in communities with lower socioeconomic status (SES). The PROAME study set out to explore basic education in illiterate adults as a means to improve cognitive reserve. Objective: This manuscript aims to explore the relationship between SES and learning, as well as cognitive outcomes, in an older illiterate population. Methods: This six-month clinical trial (NCT04473235) involved 108 participants, of which 77 concluded all assessments, enrolled in late-life basic education. SES assessments included Quality of Urban Living Index, Municipal Human Development Index and Household SES calculated for each participant. Cognitive assessments encompassed the Free and Cued Selective Reminding Test (FCSRT), a word list to assess reading, and the Beta III matrix. Results: The sample consisted primarily of women, with a mean age of 58.5. Participants improved their reading (p=0.01) and their FCSRT (p=0.003). Regarding episodic memory, women outperformed men (p=0.007) and younger participants improved more than their older counterparts (p=0.001). There was no association observed between SES and cognitive outcomes. Conclusion: Irrespective of SES, participants demonstrated positive outcomes after attending basic education. These findings highlight that late life education could be an important non-pharmacologic preventative measure, especially in LMICs.

A maioria das pessoas com demência vive em países de baixa/média renda, onde recursos essenciais para a saúde cerebral, como educação de qualidade, ainda não são amplamente acessíveis. No Brasil, o analfabetismo ainda é frequente, especialmente em comunidades de baixo nível socioeconômico. O estudo PROAME teve como objetivo explorar a educação básica tardia em pessoas analfabetas como ferramenta para o aumento da reserva cognitiva. Objetivo: Investigar a relação entre nível socioeconômico com aprendizado e com desempenho em testes cognitivos, em adultos analfabetos. Métodos: Este estudo clínico de seis meses (NCT04473235) contou com 108 participantes inscritos no projeto Educação para Jovens e Adultos (EJA), dos quais 77 completaram os testes. O nível socioeconômico de cada participante foi medido usando-se: o Índice de Qualidade de Vida Urbana, o Índice de Desenvolvimento Humano Municipal e o nível socioeconômico doméstico. Avaliações cognitivas incluíram: o Teste de Recordação Seletiva Livre e Guiada (TRSLG), uma lista de palavras para avaliar leitura e a matriz Beta III. Resultados: A amostra era predominantemente feminina, com idade média de 58,5. Os participantes melhoraram a leitura (p=0,01) e o TRSLG (p=0,003). Com relação à memoria episódica, as mulheres tiveram resultados superiores aos dos homens (p=0,007) e participantes mais jovens melhoraram mais que seus colegas mais velhos (p=0,001). Não foi observada nenhuma relação entre o nível socioeconômico e o desempenho cognitivo. Conclusão: Independentemente do nível socioeconômico, participantes obtiveram resultados positivos após frequentar a educação básica. Isso sugere que a educação tardia pode ser uma medida preventiva não farmacológica importante, especialmente em países de baixa/média renda.

The wake- and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimers disease.

BACKGROUND: Sleep-wake dysfunction is an early and common event in Alzheimer's disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxN and MCHN loss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD. METHODS: Postmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter (Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05. RESULTS: We observed a progressive decline in OrxN alongside a relative preservation of MCHN. OrxN decreased by 58% (p=0.03) by Braak stages (BB) 1-2 and further declined to 81% (p=0.03) by BB 5-6. Conversely, MCHN demonstrated a non-statistical significant decline (27%, p=0.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxN loss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched. CONCLUSIONS: To date, OrxN loss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxN correlates with specific neuroinflammation, glial profile changes, and an overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxN loss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.

Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation.

Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau's ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.

The (in)visible Brazilians: A perspective review on the need for brain health and dementia research with Brazilian immigrants in the United States.

Introduction: The Brazilian population in the United States (U.S.), a Latinx subgroup, is rapidly growing and aging but remains underrepresented in U.S. health research. In addition to group-specific genetic and environmental risks, Brazilian immigrants and their offspring in the U.S. likely have cumulative risks for health inequities.It is estimated that 71% of Brazilian immigrants in the U.S. are undocumented, which may limit healthcare access/utilization. Furthermore, mental health is reported as a health priority by Brazilian immigrants in the U.S., and there is a lack of research on Alzheimer's disease and related dementia (AD/ADRD) in this population. Methods: We reviewed the scientific literature using traditional (e.g., PubMed) sources and databases generated by U.S. and Brazilian governments, as well as international organizations, and press articles. Results: This perspective review lists recommendations for researchers, health providers, and policymakers to promote greater inclusion of U.S. Brazilian populations in health research and care. The review identifies research areas in need of attention to address health inequities and promote mental/brain health in Brazilian immigrants and their offspring living in the U.S. These research areas are: 1) epidemiological studies to map the prevalence and incidence of mental/brain health conditions; 2) research on aging and AD/ADRD risk factors among Brazilian populations in the U.S.; and 3) the need for greater representation of U.S-residing Brazilian population in other relevant research areas involving genetics, neuropathology, and clinical trials. Conclusions: The recommendation and research efforts proposed should help to pave the way for the development of community-engagement research and to promote mental/brain health education, improvement of mental/brain health and AD/ADRD services, and the development of culturally-informed intervention to the U.S.-residing Brazilian communities. HIGHLIGHTS: The Brazilian population in the United States is growing but is underrepresented in U.S. health research.Approximately 71% of Brazilian immigrants in the United States are undocumented, with an increased risk for health inequities.Mental health is reported as a central health priority by Brazilian immigrants in the United States.There is a lack of research on Alzheimer's disease and other dementias (ADRD) in Brazilian immigrants in the United States.Epidemiological research is needed to map the prevalence/incidence of mental health conditions and ADRD risk factors among Brazilian immigrants in the United States.

Microcephaly measurement in adults and its association with clinical variables.

OBJECTIVE: To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining. METHODS: In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly measured. A linear regression was used to determine the association of head circumference with brain volume and clinical variables. Microcephaly was defined as head circumference that were two standard deviations below the mean of significant clinical variables. We further applied an association rule mining to find rules associating microcephaly with several sociodemographic and clinical variables. RESULTS: In our sample of 2,508 adults, the mean head circumference was 55.3 ± 2.7cm. Head circumference was related to height, cerebral volume, and sex (p < 0.001 for all). Microcephaly was present in 4.7% of the sample (n = 119). Out of 34,355 association rules, we found significant relationships between microcephaly and a clinical dementia rating (CDR) > 0.5 with an informant questionnaire on cognitive decline in the elderly (IQCODE) ≥ 3.4 (confidence: 100% and lift: 5.6), between microcephaly and a CDR > 0.5 with age over 70 years (confidence: 42% and lift: 2.4), and microcephaly and males (confidence: 68.1% and lift: 1.3). CONCLUSION: Head circumference was related to cerebral volume. Due to its low cost and easy use, head circumference can be used as a screening test for microcephaly, adjusting it for gender and height. Microcephaly was associated with dementia at old age.

Morphometric post-mortem studies in bipolar disorder: possible association with oxidative stress and apoptosis.

Despite extensive research in the last decades, the pathophysiology of bipolar disorder (BD) remains unclear. Access to post-mortem brain tissue of subjects who had BD offers an opportunity to investigate neurobiology and this approach has led to some progress, particularly, due to the availability of more sophisticated molecular and cellular biological methodologies and well characterized brain collections over the past decade. Here we review the findings of morphometric post-mortem studies in BD and interpret them in the context of a potential physiopathological mechanism involving oxidative stress and apoptosis. A review of the literature was conducted to identify post-mortem studies that investigated cellular changes such as number, density and size of neurons and glia, in brains of subjects with BD. We found decreased density of neurons and glia and decreased size of neurons in frontal and subcortical areas of the brain. Based on recent studies that found evidence of increased apoptosis and oxidative stress in BD, we hypothesize that the cell abnormalities described are due to an increase in the apoptotic process that can be triggered, through its intrinsic pathway, by the existence of an exacerbated production of reactive oxygen species and oxidative damage in the disease.

Active lifestyle enhances protein expression profile in subjects with Lewy body pathology.

Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue. OBJECTIVE: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules - MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. METHODS: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated. RESULTS: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24). CONCLUSION: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.

Estudos dos efeitos da atividade física relataram melhora nos sintomas e na qualidade de vida de pacientes com doença de Parkinson (DP). Além disso, alterações morfológicas do cérebro após o exercício físico foram relatadas em modelos animais da DP. No entanto, essas mudanças relacionadas ao estilo de vida não foram avaliadas em tecido cerebral post-mortem. OBJETIVO: Avaliar a expressão de astrócitos, tirosina hidroxilase (TH) e a expressão de proteínas estruturais (neurofilamentos e microtúbulos ­ MAP2) por imuno-histoquímica, em amostras cerebrais post-mortem de indivíduos com corpos de Lewy. MÉTODOS: Amostras com estágio de Braak para DP≥III, classificação neuropatológica, fornecidas pelo biobanco de estudos do envelhecimento foram classificadas em grupos ativos (n=12) e não ativos (n=12), de acordo com o estilo de vida (atividade física), e pareados por idade, sexo e estadiamento de Braak. Analisou-se a substância negra e gânglios da base. RESULTADOS: Idade, sexo e classificação para DP foram semelhantes (p=1,00). Observou-se maior expressão de TH no grupo ativo (p=0,04). Amostras de não ativos revelaram maior expressão de astrócitos no mesencéfalo (p=0,03) e nos gânglios da base (p=0,0004); MAP2 nos gânglios da base (p=0,003); os níveis de neurofilamentos foram maiores na substância negra (p=0,006). CONCLUSÃO: O estilo de vida ativo parece promover efeitos positivos no cérebro, mantendo a síntese de dopamina e a expressão estrutural de proteínas no sistema nigrostriatal e com diminuição da ativação de astrócitos em indivíduos com a mesma classificação neuropatológica para a DP.

Vascular pathology in the aged human brain.

Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. Pathogenetically, AS and SVD share similar mechanisms: plasma protein leakage into the vessel wall, accumulation of lipid-containing macrophages, and fibrosis of the vessel wall. CAA, on the other hand, is characterized by the deposition of the amyloid beta-protein in the vessel wall. Despite these differences between CAA, AS and SVD, apolipoprotein E (apoE) is involved in all three disorders. Such a pathogenetic link may explain the correlations between AS, SVD, CAA, and Alzheimer's disease in the brains of elderly individuals reported in the literature. In addition, AS, SVD, and CAA can lead to tissue lesions such as hemorrhage and infarction. Moreover, intracerebral SVD leads to plasma protein leakage into the damaged vessel wall and into the perivascular space resulting in a blood-brain barrier (BBB) dysfunction. This SVD-related BBB dysfunction is considered to cause white matter lesions (WMLs) and lacunar infarcts. In this review, we demonstrate the relationship between AS, SVD, and CAA as well as their contribution to the development of vascular tissue lesions and we emphasize an important role for apoE in the pathogenesis of vessel disorders and vascular tissue lesions as well as for BBB dysfunction on WML and lacunar infarct development.

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia.

Mental disorders are highly prevalent and important causes of medical burden worldwide. Co-occurrence of neurological and psychiatric symptoms are observed among mental disorders, representing a challenge for their differential diagnosis. Psychiatrists and neurologists have faced challenges in diagnosing old adults presenting behavioral changes. This is the case for early frontotemporal dementia (FTD) and bipolar disorder. In its initial stages, FTD is characterized by behavioral or language disturbances in the absence of cognitive symptoms. Consequently, patients with the behavioral subtype of FTD (bv-FTD) can be initially misdiagnosed as having a psychiatric disorder, typically major depression disorder (MDD) or bipolar disorder (BD). Bipolar disorder is associated with a higher risk of dementia in older adults and with cognitive impairment, with a subset of patients presents a neuroprogressive pattern during the disease course. No mendelian mutations were identified in BD, whereas three major genetic causes of FTD have been identified. Clinical similarities between BD and bv-FTD raise the question whether common molecular pathways might explain shared clinical symptoms. Here, we reviewed existing data on clinical and molecular similarities between BD and FTD to propose biological pathways that can be further investigated as common or specific markers of BD and FTD.

The role of artificial intelligence and machine learning in harmonization of high-resolution post-mortem MRI (virtopsy) with respect to brain microstructure.

Enhanced resolution of 7 T magnetic resonance imaging (MRI) scanners has considerably advanced our knowledge of structure and function in human and animal brains. Post-industrialized countries are particularly prone to an ever-increasing number of ageing individuals and ageing-associated neurodegenerative diseases. Neurodegenerative diseases are associated with volume loss in the affected brain. MRI diagnoses and monitoring of subtle volume changes in the ageing/diseased brains have the potential to become standard diagnostic tools. Even with the superior resolution of 7 T MRI scanners, the microstructural changes comprising cell types, cell numbers, and cellular processes, are still undetectable. Knowledge of origin, nature, and progression for microstructural changes are necessary to understand pathogenetic stages in the relentless neurodegenerative diseases, as well as to develop therapeutic tools that delay or stop neurodegenerative processes at their earliest stage. We illustrate the gap in resolution by comparing the identical regions of the post-mortem in situ 7 T MR images (virtual autopsy or virtopsy) with the histological observations in serial sections through the same brain. We also described the protocols and limitations associated with these comparisons, as well as the necessity of supercomputers and data management for "Big data". Analysis of neuron and/or glial number by using a body of mathematical tools and guidelines (stereology) is time-consuming, cumbersome, and still restricted to trained human investigators. Development of tools based on machine learning (ML) and artificial intelligence (AI) could considerably accelerate studies on localization, onset, and progression of neuron loss. Finally, these observations could disentangle the mechanisms of volume loss into stages of reversible atrophy and/or irreversible fatal cell death. This AI- and ML-based cooperation between virtopsy and histology could bridge the present gap between virtual reality and neuropathology. It could also culminate in the creation of an imaging-associated comprehensive database. This database would include genetic, clinical, epidemiological, and technical aspects that could help to alleviate or even stop the adverse effects of neurodegenerative diseases on affected individuals, their families, and society.

B Lymphocytes and Macrophages in the Perivascular Adipose Tissue Are Associated With Coronary Atherosclerosis: An Autopsy Study.

Background Macrophages and T lymphocytes in the perivascular adipose tissue (PvAT) were previously linked to coronary artery disease. However, the role of these cells and B lymphocytes in the human PvAT adjacent to unstable atherosclerotic plaques has not been investigated. Moreover, previous studies were inconclusive on whether PvAT inflammation was restricted to the surroundings of the atheroma plaque. Methods and Results Coronary arteries were freshly dissected with the surrounding PvAT. Atherosclerotic plaques were classified according to the internationally accepted anatomopathological criteria. Immune cells in the PvAT were detected using immunohistochemistry and then quantified. We used linear and logistic regressions with robust standard errors, adjusted for possible confounding factors. In 246 atherosclerotic plaques (205 stable and 41 unstable plaques) from 82 participants (mean age=69.0±14.4 years; 50% men), the percentage of arterial obstruction was positively correlated with the densities of CD68+ macrophages (P=0.003) and CD20+ B lymphocytes (P=0.03) in the periplaque PvAT. The number of cells was greater in the periplaque PvAT than in the distal PvAT (macrophages, P<0.001; B lymphocytes, P=0.04). In addition, the density of macrophages in the periplaque PvAT was greater in the presence of unstable plaques (P=0.03) and was also greater near unstable plaques than in the distal PvAT (P=0.001). CD3+ T lymphocytes were not associated with percentage of obstruction and stable/unstable plaque composition. Conclusions The density of CD20+ B lymphocytes and CD68+ macrophages in periplaque PvAT was increased with plaque size, and the CD68+ macrophages were greater near unstable atherosclerotic plaques than near stable lesions. This inflammation was more intense in the periplaque PvAT than in the PvAT distal to the atherosclerotic plaques.