Carlos Augusto Pasqualucci

BACKGROUND: Cerebrovascular disease is prevalent in older adults and is associated with cognitive impairment. Although the association between brain infarcts and cognition has been widely investigated, the contribution of vascular disease to cognitive impairment has been less studied, particularly in non-White populations. We investigated the epidemiological and clinical characteristics of vascular disease phenotypes and their association with cognitive abilities in a diverse population. METHODS: In a Brazilian population–based clinicopathological study (recruitment between 2004 and 2024), inclusion criteria were age at death ≥18 years and the availability of an informant. Clinical information and cognitive abilities were assessed through informant interviews. Hyaline arteriolosclerosis (HA) was evaluated in 13 brain areas and categorized as absent, mild, moderate, or severe. Moderate/severe HA defined microvascular disease (Micro[+]). Intracranial atherosclerosis in the circle of Willis was similarly classified, with moderate/severe cases defining macrovascular disease (Macro[+]). Four vascular profiles were compared: Micro[+]/Macro[+], Micro[−]/Macro[+], Micro[+]/Macro[−], and Micro[−]/Macro[−]. Linear regression models adjusted for sociodemographic, clinical, and cerebrovascular/neurodegenerative lesions evaluated the association of cognition with vascular profiles, and microvascular and macrovascular diseases separately. RESULTS: Of 2418 participants, 834 with missing data were excluded, yielding a final sample of 1584 individuals (mean age, 74.3±13.4 years; 776 [49%] women; 982 [62%] White). Microvascular disease was slightly more frequent (31%) than macrovascular (29%). Regarding vascular profiles, 788 (50%) participants were Micro[−]/Macro[−], 334 (21%) Micro[+]/Macro[−], 301 (19%) Micro[−]/Macro[+], and 161 (10%) Micro[+]/Macro[+]. Micro[+] participants were older and more frequently women, and had worse cognitive abilities. Vascular groups were similar regarding most clinical comorbidities. HA (β, 0.81 [95% CI, 0.25–1.36]; P =0.004) and Micro[+]/Macro[+] phenotype (β, 1.25 [95% CI, 0.38–2.12]; P =0.005) were associated with worse cognitive abilities compared with HA-negative and Micro[−]/Macro[−] participants, respectively. CONCLUSIONS: HA was as frequent as intracranial atherosclerosis. HA and the vascular phenotype with both microvascular and macrovascular diseases were associated with worse cognition.

Neuropathologic burden explains part of the clinical expression of dementia. Frailty and sex have been involved in the individual vulnerability to cognitive impairment, yet it remains unclear how they jointly modify the relationship between neuropathology and cognition. This study investigated whether frailty and sex modify the associations of neurodegenerative and cerebrovascular pathologies with cognitive abilities. In a cross-sectional study with participants 60 years or older from the Biobank for Aging Studies, frailty was assessed using a 31-item index, and cognitive abilities were evaluated using the Clinical Dementia Rating sum of boxes (CDR-SB). Neuropathologies, including neurofibrillary tangles (NFT), neuritic plaques (NP), Lewy body disease (LBD), hippocampal sclerosis, and vascular pathologies, were evaluated individually and combined into a neuropathologic comorbidity score (NPC). Multivariable linear regression models were used to investigate the associations between neuropathology and cognitive function, including interaction terms for frailty and sex. We analyzed data from 1,531 participants (mean age 78 ± 9 years; 53% female; 65% White participants). The associations between neuropathology and poor cognitive abilities were stronger in frail participants for NFT (β = 1.84; 95% CI 1.54-2.15; p < 0.001), NP (β = 2.58; 95% CI 2.16-2.99; p < 0.001), transactive DNA-binding protein 43 (β = 3.29; 95% CI 2.32-4.26; p < 0.001), cerebral amyloid angiopathy (β = 3.48; 95% CI 1.94-5.01; p < 0.001), hippocampal sclerosis (β = 4.92; 95% CI 2.66-7.17; p < 0.001), and hyaline arteriolosclerosis (β = 2.20; 95% CI 1.15-3.25; p < 0.001). Frailty and sex modified the associations of Alzheimer disease (AD) pathology and the NPC with cognition. Frail women showed higher predicted CDR-SB scores than frail men at Braak NFT stages III-IV (8.07; 95% CI 7.37-8.78 vs 5.89; 95% CI 5.08-6.71), moderate (11.15; 95% CI 10.19-12.10 vs 8.23; 95% CI 6.92-9.54), and severe Consortium to Establish a Registry for Alzheimer's Disease (CERAD) NP scores (14.34; 95% CI 13.49-15.18 vs 11.95; 95% CI 10.57-13.33). The relationship between neuropathology and cognition was stronger in frail individuals, especially women, who showed more vulnerability to AD pathology. These findings suggest that frailty and sex jointly shape susceptibility to cognitive impairment. As a potentially modifiable clinical condition, frailty represents a meaningful target for interventions aimed at mitigating the cognitive expression of neuropathology, particularly among women. Limitations include informant-based assessments and the cross-sectional design.

Alzheimer’s disease (AD) neuropathological changes (ADNC) are characterized by amyloid plaques and neurofibrillary tangles. The role of nitric oxide synthase (NOS) in disease progression remains unclear. This study investigates the expression of neural, inducible, and endothelial NOS (nNOS, iNOS, eNOS) and 3-nitrotyrosine (3-NT) in the hippocampal subregions of individuals with ADNC and their association with cognitive abilities. Immunohistochemistry was performed on hippocampal samples from 10 individuals with ADNC and 10 age- and sex-matched controls to detect NOS enzymes, and 3-NT expression in CA1, CA2, CA3, and CA4. Logistic ordinal regressions evaluated associations of NOS and 3-NT expression with AD pathology, while linear regressions assessed relationships with cognitive abilities. Overexpression of nNOS was observed in all hippocampal subregions in ADNC participants. iNOS expression was elevated in CA1 and CA3, while eNOS showed increased levels only in CA3. 3-NT was significantly higher in CA3 of ADNC participants. nNOS expression in all hippocampal regions correlated with AD pathology and cognitive impairment. iNOS in CA3 was associated with AD pathology and cognitive scores. No associations were found for eNOS, and 3-NT in CA3 correlated with cognitive impairment. Associations of nNOS and iNOS with neuropathology and cognition suggest a role for NOS in AD pathophysiology.

Neuroinflammation has emerged as an important mechanism in the early stages of neurodegenerative diseases. Experimental models have demonstrated the detrimental role of inflammasomes in the development of Alzheimer’s disease (AD). However, neuropathological studies characterizing NLRP1 and NLRP3 pathways in AD are scarce. In addition, the possible association between inflammasome-induced neuroinflammation and clinicopathological outcomes is unclear. This study aimed to characterize the hippocampal expression of the inflammasome proteins in post-mortem samples of individuals with pure AD neuropathological change (ADNC) compared to controls from an admixed Latin American sample (n = 28 per group). We also investigated potential associations of inflammasome expression with neuropathological burden and cognitive abilities. The expression of NLRP1, NLRP3, caspase-1, ASC, gasdermin D, IL-1β, IL-18, amyloid β, and hyperphosphorylated tau (p-tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB), using immunohistochemistry and morphometry. We also performed the alignment of serial sections and 3D reconstruction of ADNC samples to verify the spatial locations of NLRP3/ASC and AD pathology across the hippocampus. We used ordinal logistic regression to investigate potential associations between inflammasome proteins and AD pathology, while linear regression assessed relationships between inflammasome and cognitive abilities. NLRP3, ASC, caspase-1, IL-1β, and IL-18 were overexpressed in CA and SUB of individuals with ADNC compared to controls. NLRP3 pathway correlated with AD pathology and CDR-SB, mainly in CA and SUB. Our results suggest that hippocampal NLRP3, but not NLRP1, inflammasome was associated with pathologic burden and cognitive impairment in AD and may contribute to the selective vulnerability to AD pathology.

Background: Cognitive impairment and disability are frequent among the oldest-old population, particularly in low- and middle-income countries (LMIC), where this population is rapidly increasing. However, studies on people aged 90 or older are scarce in these settings. Here we analyze the characteristics of the Brazilian Very Old 90+ (BRAVO 90+) study, a population-based sample of 90+ older adults who died in Sao Paulo, Brazil. Objective: To describe clinical and functional characteristics and investigate factors associated with cognitive impairment in Brazilian adults 90 years or older. Methods: Data were collected at the time of death. Postmortem cognitive evaluation regarding cognitive abilities three months before death was performed using the Clinical Dementia Rating (CDR) scale. We investigated factors associated with cognitive impairment selected by a Lasso regression. Results: Among 409 participants (mean age = 94 ± 3 years; 72% women; 69% white; average education = 3.3 ± 3.6 years), hypertension, diabetes, and heart failure were prevalent. Most participants had disabilities. The leading causes of death verified by autopsy were pulmonary edema, pneumonia, and ischemic myocardial disease. Although 48% scored a CDR greater or equal to 1, only 51% had a previous dementia diagnosis. Sedentary behavior, osteoarthritis, and depression were associated with higher odds of cognitive impairment, while married status, greater body mass index, hypertension, and neoplasia were related to lower odds. Conclusions: Cognitive impairment and disability were common among Brazilians aged 90+. The BRAVO 90+ study will provide valuable insights into dementia and resilience in this population.

Background: A biological mechanism in cancer promotion may have a protective role against AD¹. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described², 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.Method: 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.Result: 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).Conclusion: 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 risk³.1. 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.

Background: The two main catecholaminergic members of the isodendritic core nuclei are the substantia nigra (SN) and the locus coeruleus (LC). Despite cytoarchitectural and neurochemical similarities between the two nuclei, the LC is significantly more vulnerable to early degenerative changes in tauopathies like Alzheimer’s disease (AD) as compared to the SN. Here, we seek to use the gradient of vulnerability in these catecholaminergic nuclei to identify pathways associated with vulnerability in early AD pathological stages.Method: This cohort includes individuals with no neuropathologic entities and Alzheimer’s disease proteinopathic stages. Individuals with TDP‐43, Lewy Body, or Chronic Traumatic Encephalopathy pathologic entities were excluded. The LC and SN was dissected from frozen human brainstem tissue using macroscopic anatomic features. To compare the LC and SN, only cases below Braak III with sufficient RNA from both nuclei were included. The Nanostring nCounter platform was used to probe specific pathways related to neurodegenerative processes. DBH and SLC6A3 served as confirmatory readouts of accurate anatomic sampling of the LC and SN. Differential gene expression analysis was used to evaluate patterns of gene expression that differentiate the two nuclei. Annotated gene sets were evaluated using global significance scores (GSS), a representation of cumulative t‐statistics for relevant genes.Result: The LC and SN were collected from 26 cases (Figure 1) eligible for this analysis. Accurate dissections were confirmed by differential expression of DBH (p = 1.38e‐9) and SLC6A3 (p = 4.5e‐16). Among the differentially expressed genes (Figure 2), genes associated with microglia activation (GSS = 2.35), oxidative stress (GSS = 2.17), and lipid metabolism (GSS = 2.00) significantly differentiated the LC and SN.Conclusion: The LC and SN serve as examples of differentially vulnerable nuclei at the earliest neuropathologic stages of AD. Cell intrinsic factors, physiological demands, vascular contributions, and exposure to extrinsic factors like toxins are thought to contribute to the LC’s early vulnerability. Here, we show that neuroinflammation and oxidative stress pathways are likely central to differential vulnerability at the earliest stages of Alzheimer’s disease and may represent targets for intervention in prodromal stages.

Background: Given the progressive nature of neurodegenerative pathologies, great effort has been made to create diagnostic tools for detecting neurodegenerative changes in their early stages. However, the lack of information about the frequency of neurodegenerative changes in mid‐age adults impacts biomarker interpretation and sensitivity improvement. In addition, recent clinicopathological studies have shown than even a low Alzheimer’s disease (AD) neuropathological burden can significantly impact neuropsychiatric function. Finally, clinicopathological studies point to a role of small cerebrovascular changes in the cognitive decline of individuals with zero or low neurodegenerative burden; however, it remains unclear if small vascular brain lesions can impact cognition in younger mid‐age individuals.Method: We evaluated the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic and heterogeneous group under 65 years of age at the moment of death, most of them with low educational level (Table 1). A semi‐structured interview with an informant was performed to obtain socioeconomic and clinical data. Internationally accepted neuropathological criteria were used for pathologic diagnosis.Result: Some degree of neurofibrillary pathology was found in 53% (n = 145) of the individuals, while neuritic plaques were found in 10% (n = 26) of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was similar among individuals with and without cognitive impairment. However, a higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neuropsychiatric symptoms was noted in 59% (n = 160) of the cases. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was also observed in the entire sample (n = 275) (Table 1).Conclusion: Our data shows that AD neuropathological changes can begin in mid‐age and corroborates findings from other series with predominantly older Caucasians of high scholarity that have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction.