Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aß: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

Grey matter networks in women and men with dementia with Lewy bodies.

Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB.

Evaluation of Differential Diagnostics Potential of Uniform Data Set 2 Neuropsychology Battery Using Alzheimer's Disease Biomarkers.

OBJECTIVE: This study aims to evaluate the efficacy of the Uniform Data Set (UDS) 2 battery in distinguishing between individuals with mild cognitive impairment (MCI) attributable to Alzheimer's disease (MCI-AD) and those with MCI due to other causes (MCI-nonAD), based on contemporary AT(N) biomarker criteria. Despite the implementation of the novel UDS 3 battery, the UDS 2 battery is still used in several non-English-speaking countries. METHODS: We employed a cross-sectional design. A total of 113 Czech participants with MCI underwent a comprehensive diagnostic assessment, including cerebrospinal fluid biomarker evaluation, resulting in two groups: 45 individuals with prodromal AD (A+T+) and 68 participants with non-Alzheimer's pathological changes or normal AD biomarkers (A-). Multivariable logistic regression analyses were employed with neuropsychological test scores and demographic variables as predictors and AD status as an outcome. Model 1 included UDS 2 scores that differed between AD and non-AD groups (Logical Memory delayed recall), Model 2 employed also Letter Fluency and Rey's Auditory Verbal Learning Test (RAVLT). The two models were compared using area under the receiver operating characteristic curves. We also created separate logistic regression models for each of the UDS 2 scores. RESULTS: Worse performance in delayed recall of Logical Memory significantly predicted the presence of positive AD biomarkers. In addition, the inclusion of Letter Fluency RAVLT into the model significantly enhanced its discriminative capacity. CONCLUSION: Our findings demonstrate that using Letter Fluency and RAVLT alongside the UDS 2 battery can enhance its potential for differential diagnostics.

Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration.

Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aß) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aß pathway, the plasmin system may affect cognition through synaptic activity.

Mild behavioral impairment in early Alzheimer's disease and its association with APOE and BDNF risk genetic polymorphisms.

BACKGROUND: Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. METHODS: We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. RESULTS: MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. CONCLUSIONS: MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Serum PAI-1/BDNF Ratio Is Increased in Alzheimer's Disease and Correlates with Disease Severity.

We previously demonstrated that serum levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits both the tissue plasminogen activator (tPA) and plasmin activity, are increased in patients with Alzheimer's disease. tPA/plasmin not only prevents the accumulation of ß-amyloid in the brain but also is involved in the synthesis of the brain-derived neurotrophic factor (BDNF), a neurotrophin whose levels are reduced in Alzheimer. In the present study, we compared BDNF serum levels in Alzheimer patients with dementia to those in Alzheimer patients with amnestic mild cognitive impairment and to cognitively healthy controls. Moreover, we examined whether the PAI-1/BDNF ratio correlates with disease severity, as measured by Mini-Mental State Examination. Our results showed that BDNF serum levels are lower (13.7% less) and PAI-1 levels are higher in Alzheimer patients with dementia than in Alzheimer patients with amnestic mild cognitive impairment patients (23% more) or controls (36% more). Furthermore, the PAI-1/BDNF ratio was significantly increased in Alzheimer patients as compared to amnestic mild cognitive impairment (36.4% more) and controls (40% more). Lastly, the PAI-1/BDNF ratio negatively correlated with the Mini-Mental score. Our results suggest that increased PAI-1 levels in Alzheimer, by impairing the production of the BDNF, are implicated in disease progression. They also indicate that the PAI-1/BDNF ratio could be used as a marker of Alzheimer. In support of this hypothesis, a strong negative correlation between the PAI-1/BDNF ratio and the Mini-Mental score was observed.

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

Background: There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD). Objectives: To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts. Methods: The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157). Results: When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]). Conclusions: DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

An update on mobile applications collecting data among subjects with or at risk of Alzheimer's disease.

Smart mobile phone use is increasing worldwide, as is the ability of mobile devices to monitor daily routines, behaviors, and even cognitive changes. There is a growing opportunity for users to share the data collected with their medical providers which may serve as an accessible cognitive impairment screening tool. Data logged or tracked in an app and analyzed with machine learning (ML) could identify subtle cognitive changes and lead to more timely diagnoses on an individual and population level. This review comments on existing evidence of mobile device applications designed to passively and/or actively collect data on cognition relevant for early detection and diagnosis of Alzheimer's disease (AD). The PubMed database was searched to identify existing literature on apps related to dementia and cognitive health data collection. The initial search deadline was December 1, 2022. Additional literature published in 2023 was accounted for with a follow-up search prior to publication. Criteria for inclusion was limited to articles in English which referenced data collection via mobile app from adults 50+ concerned, at risk of, or diagnosed with AD dementia. We identified relevant literature (n = 25) which fit our criteria. Many publications were excluded because they focused on apps which fail to collect data and simply provide users with cognitive health information. We found that although data collecting cognition-related apps have existed for years, the use of these apps as screening tools remains underdeveloped; however, it may serve as proof of concept and feasibility as there is much supporting evidence on their predictive utility. Concerns about the validity of mobile apps for cognitive screening and privacy issues remain prevalent. Mobile applications and use of ML is widely considered a financially and socially viable method of compiling symptomatic data but currently this large potential dataset, screening tool, and research resource is still largely untapped.

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Reconfiguration of brain network dynamics underlying spatial deficits in subjective cognitive decline.

Brain dynamics and the associations with spatial navigation in individuals with subjective cognitive decline (SCD) remain unknown. In this study, a hidden Markov model (HMM) was inferred from resting-state functional magnetic resonance imaging data in a cohort of 80 SCD and 77 normal control (NC) participants. By HMM, 12 states with distinct brain activity were identified. The SCD group showed increased fractional occupancy in the states with less activated ventral default mode, posterior salience, and visuospatial networks, while decreased fractional occupancy in the state with general network activation. The SCD group also showed decreased probabilities of transition into and out of the state with general network activation, suggesting an inability to dynamically upregulate and downregulate brain network activity. Significant correlations between brain dynamics and spatial navigation were observed. The combined features of spatial navigation and brain dynamics showed an area under the curve of 0.854 in distinguishing between SCD and NC. The findings may provide exploratory evidence of the reconfiguration of brain network dynamics underlying spatial deficits in SCD.

Spatial navigation is associated with subcortical alterations and progression risk in subjective cognitive decline.

BACKGROUND: Subjective cognitive decline (SCD) may serve as a symptomatic indicator for preclinical Alzheimer's disease; however, SCD is a heterogeneous entity regarding clinical progression. We aimed to investigate whether spatial navigation could reveal subcortical structural alterations and the risk of progression to objective cognitive impairment in SCD individuals. METHODS: One hundred and eighty participants were enrolled: those with SCD (n = 80), normal controls (NCs, n = 77), and mild cognitive impairment (MCI, n = 23). SCD participants were further divided into the SCD-good (G-SCD, n = 40) group and the SCD-bad (B-SCD, n = 40) group according to their spatial navigation performance. Volumes of subcortical structures were calculated and compared among the four groups, including basal forebrain, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. Topological properties of the subcortical structural covariance network were also calculated. With an interval of 1.5 years ± 12 months of follow-up, the progression rate to MCI was compared between the G-SCD and B-SCD groups. RESULTS: Volumes of the basal forebrain, the right hippocampus, and their respective subfields differed significantly among the four groups (p < 0.05, false discovery rate corrected). The B-SCD group showed lower volumes in the basal forebrain than the G-SCD group, especially in the Ch4p and Ch4a-i subfields. Furthermore, the structural covariance network of the basal forebrain and right hippocampal subfields showed that the B-SCD group had a larger Lambda than the G-SCD group, which suggested weakened network integration in the B-SCD group. At follow-up, the B-SCD group had a significantly higher conversion rate to MCI than the G-SCD group. CONCLUSION: Compared to SCD participants with good spatial navigation performance, SCD participants with bad performance showed lower volumes in the basal forebrain, a reorganized structural covariance network of subcortical nuclei, and an increased risk of progression to MCI. Our findings indicated that spatial navigation may have great potential to identify SCD subjects at higher risk of clinical progression, which may contribute to making more precise clinical decisions for SCD individuals who seek medical help.

Ginkgo biloba Extract EGb 761 in the Treatment of Patients with Mild Neurocognitive Impairment: A Systematic Review.

Background: Many clinical trials testing Ginkgo biloba extract EGb 761 in patients with mild forms of cognitive impairment were conducted before widely accepted terms and diagnostic criteria for such conditions were available. This makes it difficult to compare any results from earlier and more recent trials. The objective of this systematic review was to provide a descriptive overview of clinical trials of EGb 761 in patients who met the diagnostic criteria for mild neurocognitive disorder (mild NCD) according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). Methods: MEDLINE, PubMed and EMBASE were searched for randomized, placebo-controlled double-blind trials of EGb 761 in mild impairment of cognitive functioning. All trials involving patients who met retrospectively applied diagnostic criteria for mild NCD were included. Trials of primary prevention of dementia and trials of combinations of medical treatments were excluded. Results: Among 298 records found in databases and 76 further records related to EGb 761 in references of systematic reviews, 9 reports on clinical trials involving 946 patients met the pre-specified criteria for inclusion. Beneficial effects of EGb 761 were seen in neuropsychological tests (8 of 9 studies), scales for neuropsychiatric symptoms (3 of 3 studies), geriatric rating scales (1 of 2 studies) and global ratings of change (1 of 1 study). Significant effects were found in several domains of cognition (memory, speed of processing, attention and executive functioning). Among the neuropsychiatric symptoms, depression (2 of 3 studies) and anxiety (1 of 1 study) were significantly improved. No differences between EGb 761 treatment and placebo were seen with regard to the rates of adverse events. Discussion: The included studies demonstrate treatment benefits of Ginkgo biloba extract EGb 761, mainly on cognitive deficits and neuropsychiatric symptoms, in patients with mild NCD. The drug was safe and well tolerated.

Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status.

Introduction: Choroid plexus (CP)-related mechanisms have been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. In this pilot study, we aimed to elucidate the association between longitudinal changes in CP volume, sex and cognitive impairment. Methods: We assessed longitudinal changes in CP volume in a cohort of n = 613 subjects across n = 2,334 datapoints from ADNI 2 and ADNI-GO, belonging to cognitively unimpaired (CN), stable mild cognitive impairment (MCI), clinically diagnosed Alzheimer's disease dementia (AD) or convertor (to either AD or MCI) subgroups. CP volume was automatically segmented and used as a response variable in linear mixed effect models with random intercept clustered by patient identity. Temporal effects of select variables were assessed by interactions and subgroup analyses. Results: We found an overall significant increase of CP volume in time (14.92 mm3 per year, 95% confidence interval, CI (11.05, 18.77), p < 0.001). Sex-disaggregated results showed an annual rate of increase 9.48 mm3 in males [95% CI (4.08, 14.87), p < 0.001], and 20.43 mm3 in females [95% CI (14.91, 25.93), p < 0.001], indicating more than double the rate of increase in females, which appeared independent of other temporal variables. The only diagnostic group with a significant CP increase as compared to CN was the convertors group, with an increase of 24.88 mm3/year [95% CI (14, 35.82), p < 0.001]. ApoE exhibited a significant temporal effect, with the E4 homozygote group's CP increasing at more than triple the rate of non-carrier or heterozygote groups [40.72, 95% CI (25.97, 55.46), p < 0.001 vs. 12.52, 95% CI (8.02, 17.02), p < 0.001 for ApoE E4 homozygotes and E4 non-carriers, respectively], and may have modified the diagnostic group relationship. Conclusion: Our results contribute to potential mechanisms for sex differences in cognitive impairment with a novel finding of twice the annual choroid plexus enlargement in females and provide putative support for CP-related mechanisms of cognitive deterioration and its relationship to ApoE E4.

Missorting of plasma miRNAs in aging and Alzheimer's disease.

The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.

Sex differences in grey matter networks in dementia with Lewy bodies.

Objectives: Sex differences permeate many aspects of dementia with Lewy bodies (DLB), including epidemiology, pathogenesis, disease progression, and symptom manifestation. However, less is known about potential sex differences in patterns of neurodegeneration in DLB. Here, we test whether grey matter networks also differ between female and male DLB patients. To assess the specificity of these sex differences to DLB, we additionally investigate sex differences in healthy controls (HCs). Methods: A total of 119 (68.7 ± 8.4 years) male and 45 female (69.9 ± 9.1 years) DLB patients from three European centres and the Mayo Clinic were included in this study. Additionally, we included 119 male and 45 female age-matched HCs from the Mayo Clinic. Grey matter volumes of 58 cortical, subcortical, cerebellar, and pontine brain regions derived from structural magnetic resonance images were corrected for age, intracranial volume, and centre. Sex-specific grey matter networks for DLB patients and HCs were constructed by correlating each pair of brain regions. Network properties of the correlation matrices were compared between sexes and groups. Additional analyses were conducted on W-scored data to identify DLB-specific findings. Results: Networks of male HCs and male DLB patients were characterised by a lower nodal strength compared to their respective female counterparts. In comparison to female HCs, the grey matter networks of male HCs showed a higher global efficiency, modularity, and a lower number of modules. None of the global and nodal network measures showed significant sex differences in DLB. Conclusions: The disappearance of sex differences in the structural grey matter networks of DLB patients compared to HCs may indicate a sex-dependent network vulnerability to the alpha-synuclein pathology in DLB. Future studies might investigate whether the differences in structural network measures are associated with differences in cognitive scores and clinical symptoms between the sexes.

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

Sex differences in brain atrophy in dementia with Lewy bodies.

Background and objectives: Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods: We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results: We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions: This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.