Frailty, characterized by increased physical vulnerability, is associated with a higher incidence and severity of cognitive impairment and also a higher burden of neurodegenerative and cerebrovascular diseases. This study investigates the association between frailty and neurodegenerative and cerebrovascular pathologies. Cross-sectional analysis using clinical and neuropathological data from individuals aged 60 or older, enrolled in the Biobank for Aging Studies between 2004 and 2023. A 42-item frailty index was constructed. Cognitive impairment was defined as a clinical dementia rating score (CDR) of 0.5 or over and participants were stratified according to cognitive status. Linear regression models, adjusting for age, sex, education and race, explored the association between frailty and neuropathology, including Alzheimer´s disease (AD), argyrophilic grain disease (AGD), Lewy-type pathology (LBP), hippocampal sclerosis, cerebral amyloid angiopathy (CAA), lacunar infarcts, hyaline arteriosclerosis, TDP-43 pathology and a neuropathological comorbidity score (NPC). We examined data from 1.343 subjects. The group with cognitive impairment was older, predominantly female, had lower education, a higher frailty index, and no race differences (Table 1). This group also exhibited a higher prevalence of all neuropathologies previously described (Table 2). In adjusted analyses, frailty was associated with AD Braak staging (β = 0.022, 95% CI=0.017; 0.028, p<0.001 ), CERAD score (β = 0.021, CI 95% = 0.013; 0.029 p<0.001), CAA (β = 0.065, 95% CI = 0.039; 0.092 p<0.001), LBD (β = 0.051, 95% CI = 0.027; 0.075 p<0.001), hippocampal sclerosis (β= 0.053, CI 95% = 0.008; 0.100 p=0.022), lacunar infarcts (β=0.071, CI 95%= 0.046; 0.097 p<0.001), siderocalcinosis (β=0.033, CI 95%= 0.015; 0.051 p<0.001), hyaline arteriosclerosis (β=0.065, CI 95%= 0.050-0.081 p<0.001) and NPC score (Table 3) (β=0.032, CI 95%= 0.024; 0.040 p<0.001). Frailty was not associated with AGD and TDP-43. Frailty was associated with several neuropathological markers of neurodegenerative and cerebrovascular diseases. More studies are warranted to investigate how this association relates to relevant outcomes such as cognitive impairment.

Excessive daytime sleepiness is a common and early symptom of Alzheimer’s disease (AD). The subcortical wake-promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake-promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor-adrenergic neurons. The preserved histaminergic neurons could be a potential target for addressing sleep dysfunction when neurons in the wake-promoting system degenerate. We aimed to map neuropathological and molecular events in poorly understood histaminergic neurons across AD progression in the human TMN to help understand pathogenic features and guide therapeutic strategies. We used unbiased stereology and double-immunohistochemistry to quantify pTau (CP13) accumulation, the number of histaminergic, and total neurons in the TMN in subjects across progressive Braak stages (n = 20). Data were analyzed using the Wilcoxon signed-rank test. We used a customized Neuropathology nCounter® (Nanostring) panel for proteomic analysis. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <0.05. TMN total neuronal count remained constant across Braak groups (BG), underscoring TMN’s resilience to AD compared to other wake-promoting neurons. Histaminergic (HDC+CP13-) neurons declined between BG 0-2 and 5-6 (p = 0.013). The number, proportion, and density of pTau inclusions in histaminergic and total TMN neurons increased across BG (p<0.05) (Fig. 1, Table 1). In Braak 5-6 over 0-2, we found 284 differentially expressed genes in TMN, of which 171 were upregulated. Gene ontology analysis demonstrated upregulation of cytokine-cytokine receptor interaction pathways (p = 0.015). In Braak 5-6 over 0-2, histamine decarboxylase (HDC) expression was downregulated (lfc = -0.819, p = 0.37) with increased expression of histamine receptors HRH1 (lfc = 1.26, p = 0.028) and HRH2 (lfc = 1.76, p = 0.019) (Fig. 2). Stereological data revealed that the decline in histaminergic neurons is associated with pTau accumulation and reduced histamine synthesis rather than neuronal loss. This is corroborated by a decrease in HDC expression and an upregulation of histaminergic receptor expression (potentially compensatory) in late Braak stages. Interventions focused on pTau removal may succeed in reinstating histaminergic neuro-transmission/-modulation, improving cognition, and restoring sleep-wake dysfunction in AD patients.

Alzheimer’s Disease(AD) patients experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus(SCN), which is spatially well-conserved but a tiny nucleus in the hypothalamus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak0) and 39 subjects with progressive ADNC stages. We quantified neuronal numbers-arginine vasopression(AVP) and vasoactive intestinal protein(VIP) neurons- plus ADNC burden in SCN. We performed analysis in adjacent hypothalamic nuclei as regional controls: supraoptic nucleus(SON) and paraventricular nucleus(PVN) both sites of AVP+ neurons. Moreover, we performed In-situ proteomics using GeoMx Digital Spatial Profiling(DSP) in the three nuclei (total of 897 ROIs), including probes for 39 proteins commonly dysregulated in AD. SCN neurons in Braak 6 had sixteen times higher p-tau levels than Braak0. Neurofibrillary tangles were found exclusively in SCN(Fig. 1). However, there was not significant p-tau upregulation in SON and PVN in all the same stage. Additionally, the SCN showed increases in glial proteins already in Braak1(Fig. 2), whereas these proteins remained unaltered in the other nuclei, including that they displayed a milder pattern of protein dysregulation in Braak1, consistent with its lower tau expression observed in histology and DSP. Our study sheds light on the previously unexplored molecular and pathological changes occurring in SCN during AD progression. The SCN is vulnerable to AD-tau pathology and show immune dysregulation even at Braak1 but protected against beta-amyloid accumulation. This vulnerability pattern in SCN supports the idea that SCN dysfunction contributes to circadian rhythm disturbances in AD, observed even in the stage before the onset of cognitive disorder. Furthermore, the preservation of SON, a neighboring nucleus with AVP neurons but not directly connected in a neuronal circuit with the SCN, corroborates that SCN is early vulnerable to AD. PVN neurons exhibited similar but milder pattern of protein dysregulation in the early stages to the SCN, implying the effect may be caused by the efferent projection from the SCN. These results open up opportunities for tailored interventions to alleviate circadian rhythm disruptions in AD.

INTRODUCTION:Alzheimer's disease (AD) selectively affects certain brain regions, yet the mechanisms of selective vulnerability remain poorly understood. The neuromodulatory subcortical system, which includes nuclei exhibiting a range of vulnerability and resilience to AD-type degeneration, presents a framework for uncovering these mechanisms. METHODS:We leveraged transcriptomics and immunohistochemistry in paired samples from human post mortem tissue representing a vulnerable and resilient region-the locus coeruleus (LC) and substantia nigra (SN). These regions have comparable anatomical features but distinct vulnerability to AD. RESULTS:We identified significant differences in cholesterol homeostasis, antioxidant pathways, KRAS signaling, and estrogen signaling at a bulk transcriptomic level. Notably, evidence of sigma-2 receptor upregulation was detected in the LC. DISCUSSION:Our findings highlight pathways differentiating the LC and SN, potentially explaining the LC's selective vulnerability in AD. Such pathways offer potential targets of disease-modifying therapies for AD. HIGHLIGHTS:Intraindividual comparative RNAseq was used to study selective vulnerability. Metallothionein genes are significantly enriched in the substantia nigra. Cholesterol homeostatic genes are significantly enriched in the locus coeruleus. The locus coeruleus is likely more susceptible to toxic amyloid beta oligomers.

Alzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p-tau) and beta-amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always coincide with p-tau, making the latter an excellent marker of pathological tau burden. We showed in experimental studies that truncated tau (tr-tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p-tau in neurons at late AD stages; however, only about 40% of tr-tau positive neurons also show p-tau positivity. This makes tr-tau a potential AD marker previously invisible at neuropathological investigation or potential target of diagnostic tool development. We sought to determine how early in AD tr-tau is detected and to what degree tr-tau and p-tau neuronal populations overlap at early AD stages. Our analysis included 56 cases (Table 1) from across all AD Braak stages (BB = 0-6; N = 56). We used multiplex immunofluorescence to probe tr-tau (D13, D402, TauC3) and p-tau (PHF1) species in the same tissue slides of postmortem human brain tissue. We then quantified neuronal tau pathology and colocalization in images of entorhinal cortex (EC) and inferior temporal gyrus (ITG) as areas representative of p-tau pathology in intermediate AD stages. We detected D13 tr-tau in lower BB and in greater quantities than p-tau at low BB (Fig. 1A). The EC accumulated more D13 tr-tau than the ITG in early BB (Fig. 1B). Overlap between D13 tr-tau and p-tau was minimal in both regions from early to late BB, with 0% at BB = 3 in both regions and 16.7% and 16.1% at BB = 5 in EC and ITG, respectively (Fig. 2). Neuronal D13 tr-tau deposits develop in AD before p-tau pathology. Across AD Braak stages, the % of overlapping between D13 tr-tau and p-tau positive neuronal populations is moderate at best; these results suggest neuronal accumulation of D13 tr-tau occurs in a selectively vulnerable manner. This corroborates D13 tr-tau as a potential biomarker of tau pathology in AD overlooked by p-tau screening. Future plans include analysis of these pathological markers between clinically typical and atypical variants of AD.

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study. This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction. Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.

Lewy body disease (LBD) is a neurodegenerative condition marked by the accumulation of neuronal alpha-synuclein, leading to both Parkinson’s disease and Lewy body dementia. It is regarded as the second most common neurodegenerative disease associated with aging. However, there is limited knowledge of LBD prevalence in the general population, particularly among non-whites. Our study aimed to investigate the prevalence of LBD in a large, diverse population-based clinicopathological cohort. Additionally, we sought to explore the associations of LBD with comorbid neuropathology, clinical outcomes, and APOE genotyping. We investigated cases from the Biobank for Aging Studies from the University of São Paulo, collected between 2004 and 2023. Clinical and sociodemographic information were gathered from the next of kin using structured and validated protocols, including parkinsonism score (PS) assessment through Tanner’s questionnaire. Neuropathological evaluations adhered to USA/NACC guidelines, using immunohistochemistry to detect beta-amyloid, tau, alpha-synuclein, and TDP43. 1,669 participants with complete sociodemographic, clinical, and neuropathological data were enrolled. LBD was detected in 0,84% of 50-59 age group and the frequency increased with age reaching 15% in 90+ group. There was a trend of lower LBD presence in Black/Brown, but higher in Asians. LBD was associated with age, and higher CDR-SOB and PS scores (Table 1). LBD prevalence increased with worse Braak-NFT, CERAD, and LATE. The presence of LBD was associated with CDR-SOB score in Braak PD stages ≥ III. However, Braak PD scores were not related to PS scores in adjusted analyses (Table 2). LBD interacted with LATE, CERAD, and Braak-NFT on cognitive scores (Figure 1); no difference was observed in interaction with sex and race. Upon conducting a stratified analysis, LATE had a significant impact on cognitive abilities and LBD presence in limbic-neocortical reas (ß = 2.30, 95%IC = 0.61; 8.59, p = 0.024). In an admixed population, LBD is present since middle age. The trend of less frequent LBD in Black/Brown warrants further investigations. LBD was associated with higher CDR-SOB scores in neocortical phases (V-VI) and more pronounced in participants with LATE.

Nitric oxide (NO) is involved in synaptic transmission and cerebral plasticity, playing a role in the memory process. However, in states of brain inflammation, hypoxia, or ischemia, there is induction of inducible nitric oxide synthase (iNOS) expression by astrocytes and pyramidal cells in the brain. Under conditions of chronic activation, there is a decoupling of iNOS dimers, leading to a massive generation of superoxide anion and peroxynitrite, O2.- and ONNO- respectively, with a significant neurotoxic role by oxidative stress. We aimed to quantify the expression of iNOS and 3-nitrotyrosine (3-NT, an oxidative marker of ONNO-) in the hippocampus of individuals with AD neuropathological changes (ADNC)compared to individuals without AD pathology and investigate the association of iNOS and 3-NT expression with cognition abilities and AD pathology. We evaluated the expression of the enzymes iNOS and 3-NT using immunohistochemistry in the cornu ammonis (CA) and dentate gyrus from hippocampi from subjects with ADNC and the sex-matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of iNOS and 3-NT with cognition and AD pathology. Sociodemographic and clinical variables were similar between the control and ADNC groups (Table 1). In individuals with ADNC, iNOS was overexpressed in the CA1 (p = 0.029) and CA3 (p = 0.030). Similarly, 3-NT was overexpressed in CA3 (p = 0.039), shown in Figure 1. No expression was seen in the dentate gyrus for iNOS and 3-NT. Increased levels of iNOS in CA3 were associated with AD pathology reported in CERAD score (β = 12.44, IC95% = 0.88;24;00, p = 0.036) and Braak staging (β = 25.48, IC95% = 6.12;44.84, p = 0.012), and with cognitive abilities (β = 73.05, IC95% = 29.25;149.90, p = 0.025). Increased 3-NT levels in CA3 were associated only with cognitive abilities (β = 1.48, IC95% = 0.08;2.87, p = 0.038) (Table 2). CA3 neurons shows a particular susceptibility to accumulate iNOS and 3-NT during AD progression. The association between iNOS and functional cognition underscore the role of oxidative stress in AD pathogenesis. Of note, CA2 sector, a resistant region to AD showed no signs of oxidative stress in AD.

The atherosclerotic plaque in carotid arteries has been associated with dementia. Clinic radiological studies in older adults suggest that the composition of atherosclerotic plaque in the carotid artery can predict vascular dementia (VD) or mixed dementia. The proposed study aims to assess components of atherosclerotic plaques in the carotid arteries, particularly concerning cerebrovascular lesions using racially diverse autopsy samples. We used data from the Biobank for Aging Studies at the University of São Paulo Medical School. We included participants aged 50 years or older at the time of death with a post-mortem interval of less than 24 hours and a next of kin who had at least weekly contact with the deceased (n = 505). The plaque composition was evaluated using the Atherosclerotic Plaque Analyzer (APA) software. Cerebrovascular lesions included lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy evaluated microscopically in 13 samples areas. Logistic regression models adjusted for sociodemographic and clinical variables were used to investigate the associations between plaque composition and cerebrovascular deceased. After the exclusions for missing data, 193 participants were included (mean age 79.4±10.0 years, 51.3% were women, and 61% were White) (Table 1). A higher percentage of lipid deposition in the plaque was associated with higher odds of cerebral amyloid angiopathy (OR = 1.01, 95% CI = 1.03; 1.27, p = 0.007). We found no association between the other plaque components and cerebrovascular diseases (Table 3). In an autopsy study, the deposition of lipids in the carotid atheroma plaque was associated with cerebral amyloid angiopathy. Further autopsy studies in larger samples are needed to confirm our findings.

Prior research investigating sex and racial differences in amyloid pathology burden has yielded inconsistent findings. We examined the impact of sex and other confounding factors on neuritic plaque burden and cognitive outcomes. This study included 1,857 individuals, with post-mortem brain tissues, from the Biobank for Aging Studies of the University of São Paulo Medical School, collected from 2004-2023. In a subset of subjects, global ancestry was analyzed dichotomously, using a 2% cutoff for African Ancestry (AFR), first quartile of the AFR distribution. We employed multinomial logistic regression and general linear models to explore the associations of sex, reported race (White versus Black and Brown groups combined), AFR, and APOE4 genotype on CERAD scores and cognitive outcomes measured by Clinical Dementia Rating Scale Sum of Boxes(CDR-SOB) while adjusting for age at death and education. Women (48% of the sample) were older than men (76.8±12.3 yo versus 71.4±12.3 yo, p<0.001). Men had higher educational attainment with a mean(SD) of 5.5(4.2) years and 3.9(3.9) years in women, (p<0.001). Dementia prevalence was higher in women (31% vs.18.5%, p<0.001). The sample was predominantly white (64.7%), followed by black (23.1%), and Asian (2.2%). 76.7% of men and 76.5% of women had AFR+ (p = 0.96). Women had higher odds of ‘Frequent’ CERAD scores with OR( 95% CI) = 2.3(1.42-3.72), p<0.001) Table 1 (Frequent-Sparse or None) model 2 . Black race was associated with lower odds of ‘Moderate’ CERAD scores compared to whites. A significant three-way interaction among sex, APOE4, and race showed that Black men without APOE4 had lower odds of ‘Moderate’ and ‘Frequent’ CERAD scores (Table 1) . Similar trends were found with Sex*APOE4*AFR. Testing the association of CERAD scores with cognitive outcomes, higher CERAD scores were associated with lower CDR-SOB (P<0.001), and sex moderated this effect showing that women with ‘Moderate’ CERAD scores had worse cognitive outcomes than men (Figure 1) . Notably, black race (Figure 2), but not AFR (Figure 3), modified the interaction between sex and CERAD on cognitive outcomes. Women exhibited increased susceptibility to amyloid pathology, resulting in more pronounced cognitive impairment, suggesting that sex-specific genetic, biological, and sociocultural factors may play a role in women’s higher AD vulnerability.

Racial differences in dementia prevalence and incidence were found with higher dementia burden in African descendants. Previous neuropathological studies were conducted mostly in white participants in convenience samples. Further studies in diverse populations are important to foster the understanding of race differences in dementia pathology. We aimed to compare the frequencies of neuropathological lesions between black and white participants and the association of cognitive abilities and race in an autopsy study. In a cross-sectional community-based autopsy study, samples were collected at the Biobank for Aging Studies from 2004 to 2023. A family member reported the deceased’s race. The frequency of neurodegenerative and cerebrovascular lesions was evaluated using immunohistochemistry and hematoxylin-eosin staining in 13 selected cerebral areas. We also examined the association between cognitive abilities with the Clinical Dementia Rating Scale and race. Neuropathologists were blinded to cognitive outcomes. To examine the associations of race with neuropathology and cognitive abilities, we used regression models adjusted for age, sex, education, clinical variables, and apolipoprotein E genotyping. In 1,815 participants, the mean age was 74.0±12.5 years old, 50% were women, 34% were black, the mean education was 4.7±4.1 years, and 35% had cognitive impairment. Small vessel disease (SVD) (OR = 1.74, 95% CI = 1.29-2.35, p<0.0001), siderocalcinosis (OR = 1.70, 95% CI = 1.23-2.34, 0.001), and neuropathological comorbidity (OR = 1.35, 95% CI = 1.12-1.63; p = 0.001) were more frequent in blacks compared to whites, while neuritic plaques were less frequent (OR = 0.61, 95% CI = 0.44-0.83, p = 0.002). Likewise, AD diagnosis was more frequent in whites (Whites: 39%; Blacks: 33%), while vascular dementia was more common among black participants (Whites: 24%; Blacks: 32%). Race was not associated with cognitive abilities, nor was an effect modifier in the association between neuropathology and cognition. In a large community-based autopsy study, AD pathology was more frequent in whites, while vascular pathology and neuropathological comorbidity were more frequent in blacks. Cognitive abilities were similar between race groups, and race was not an effect modifier in the associations of cognition with neuropathologies. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.

Trisomy 13, known as Patau syndrome, is a common aneuploidy with a well-known clinical phenotype. This case report describes a trisomy 13 patient with unusual autopsy findings, including features resembling the Beckwith-Wiedemann Spectrum. Due to abnormalities of gestational ultrasounds, a prenatal karyotype of amniotic fluid cells was performed, which resulted in 47, XY+13. Autopsy microscopy studies identified leptomeningeal glioneuronal heterotopia, which was not described as belonging to Patau syndrome. Other atypical findings were diffuse hyperplasia of pancreatic islets of Langerhans and adrenals enlargement with marked adrenocortical cytomegaly, characteristically seen in the Beckwith-Wiedemann Spectrum. Molecular genetic tests were not performed for the Beckwith-Wiedemann Spectrum. Still, due to the rarity of both disorders, this report may support the evidence that trisomy 13 can affect tissue organization and lead to unusual histopathologic features resembling classic overgrowth disorders.

Background:The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes. Objective:We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association. Methods:In 1,170 participants, sociodemographic data, clinical history, and cognitive post-mortem evaluation were assessed with an informant. Neuropathological evaluation was performed in all cases. Linear regression models were used to investigate the association between neuropathological lesions (exposure variable) and BMI (outcome) adjusted for demographic, clinical, and cognitive variables in the whole sample, and in only those with normal cognition. Corrections for multiple comparisons were performed. In addition, a mediation analysis was performed to investigate the direct and indirect effects of cognitive abilities on the association between neuropathology and BMI. Results:Individuals with lower BMI had a higher burden of neuropathological lesions and poorer cognitive abilities. Only neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI, while other neurodegenerative and cerebrovascular lesions were not. NFT were indirectly associated with BMI through cognitive abilities, and also directly, even in participants with normal cognition. Conclusions:Neurofibrillary tangles were directly associated with low BMI even in individuals with preclinical Alzheimer's disease.

Importance:Microplastic (MP) pollution is an emerging environmental and health concern. While MPs have been detected in various human tissues, their presence in the human brain has not been documented, raising important questions about potential neurotoxic effects and the mechanisms by which MPs might reach brain tissues. Objective:To determine the presence of MPs in the human olfactory bulb and to analyze their characteristics such as size, morphology, color, and polymeric composition. Design, Setting, and Participants:This case series study used a cross-sectional design involving the analysis of olfactory bulb tissues obtained from deceased individuals during routine coroner autopsies. The sampling procedures were conducted at São Paulo City Death Verification Service, with laboratory analysis carried out at the Brazilian Synchrotron Light Laboratory (LNLS). Participants included 15 adult individuals who had been residents of São Paulo for more than 5 years and underwent coroner autopsies. Exclusion criteria included previous neurosurgical interventions. Data analysis was performed in April 2024. Exposure:The primary exposure assessed was the presence of MPs in the olfactory bulb, analyzed through direct tissue examination and digested tissue filtration followed by micro-Fourier transform infrared spectroscopy. Main Outcomes and Measures:The main outcomes were the identification and characterization of MPs within the olfactory bulb, including their size, morphology, color, and polymeric composition. Results:The median age of the 15 deceased individuals was 69.5 years, ranging from 33 to 100 years, with 12 males and 3 females. MPs were detected in the olfactory bulbs of 8 out of 15 individuals. A total of 16 synthetic polymer particles and fibers were identified, with 75% being particles and 25% being fibers. The most common polymer detected was polypropylene (43.8%). Sizes of MPs ranged from 5.5 μm to 26.4 μm for particles, and the mean fiber length was 21.4 μm. Polymeric materials were absent in procedural blank and negative control filters, indicating minimal contamination risk. Conclusions and Relevance:This case series provides evidence of MPs found in the human olfactory bulb, suggesting a potential pathway for the translocation of MPs to the brain. The findings underscore the need for further research on the health implications of MP exposure, particularly concerning neurotoxicity and the potential for MPs to bypass the blood-brain barrier.

A biological mechanism in cancer promotion may have a protective role against AD 1 . Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described 2 , most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample. This cross-sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full-body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4. 689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post-mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = -0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = -0.49, 95% CI = -0.98; -0.03] (Table 2). In a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk 3 . 1. Ospina-Romero M, Glymour MM, Hayes-Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515. 2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249-1254. 3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22-33.

In recent decades, there have been significant advances in the diagnosis of diffuse gliomas, driven by the integration of novel technologies. These advancements have deepened our understanding of tumor oncogenesis, enabling a more refined stratification of the biological behavior of these neoplasms. This progress culminated in the fifth edition of the WHO classification of central nervous system (CNS) tumors in 2021. This comprehensive review article aims to elucidate these advances within a multidisciplinary framework, contextualized within the backdrop of the new classification. This article will explore morphologic pathology and molecular/genetics techniques (immunohistochemistry, genetic sequencing, and methylation profiling), which are pivotal in diagnosis, besides the correlation of structural neuroimaging radiophenotypes to pathology and genetics. It briefly reviews the usefulness of tractography and functional neuroimaging in surgical planning. Additionally, the article addresses the value of other functional imaging techniques such as perfusion MRI, spectroscopy, and nuclear medicine in distinguishing tumor progression from treatment-related changes. Furthermore, it discusses the advantages of evolving diagnostic techniques in classifying these tumors, as well as their limitations in terms of availability and utilization. Moreover, the expanding domains of data processing, artificial intelligence, radiomics, and radiogenomics hold great promise and may soon exert a substantial influence on glioma diagnosis. These innovative technologies have the potential to revolutionize our approach to these tumors. Ultimately, this review underscores the fundamental importance of multidisciplinary collaboration in employing recent diagnostic advancements, thereby hoping to translate them into improved quality of life and extended survival for glioma patients.

The association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one-fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia-related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association. Neuropathological study in a population-based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model. Individuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants. Neurofibrillary tangles were associated with lower BMI independent of cognitive abilities.