Barcelonabeta

BackgroundRegional homogeneity (ReHo) is a widely used measure in resting‐state functional magnetic resonance imaging (rs‐fMRI) for assessing the coherence of blood oxygen level‐dependent (BOLD) fMRI timeseries among contiguous brain regions. ReHo serves as a proxy of oxygen consumption and captures similar aspects of brain function as fluorodeoxyglucose positron emission tomography (FDG‐PET). However, the clinical potential of ReHo remains unexplored. This study aimed to evaluate the feasibility of predicting changes in amyloid deposition using ReHo measures in middle to late‐aged participants at the earliest Alzheimer's inception and compare this technique's performance with FDG‐PET.MethodWe examined 330 cognitively unimpaired individuals (mean age=61.0, SD=4.7) with available CSF Aβ42/40, p‐tau181, rs‐fMRI, FDG‐PET and Aβ‐PET data (Table 1). Average follow‐up time was 3.3 years (SD=0.3). CSF Aβ42 and Aβ40 were assessed with the NeuroToolKit, a panel of exploratory robust prototype assays, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd., Switzerland). rs‐fMRI data was preprocessed using fMRIPrep and XCP‐D, and ReHo maps were subsequently extracted. Mean FDG and mean ReHo were computed across regions of the Landau and Centiloid masks, respectively. We examined associations of mean FDG and ReHo at baseline with amyloid load at baseline, as well as with changes in amyloid load (follow‐up minus baseline, divided by follow‐up period), as assessed with CSF Aβ42/40 and PET Centiloid. Statistical models were adjusted by age, sex, APOE status, years of education and p‐tau181.ResultCross‐sectional analysis revealed that lower ReHo levels were associated with lower CSF Aβ42/40 levels (p = 0.042), but not with PET Centiloids. FDG levels showed no significant association with either CSF Aβ42/40 or PET Centiloids (Figure 1). Longitudinally, lower baseline FDG levels were associated with increased PET amyloid burden over time (p = 0.008), while higher baseline ReHo levels were linked to decreases in CSF Aβ42/40 levels (p = 0.021) (Figure 2).ConclusionThe findings indicate that baseline ReHo and FDG provide complementary insights into amyloid dynamics in the preclinical phase of Alzheimer's disease. Specifically, ReHo shows potential as a predictive biomarker for early changes in soluble Aβ changes, warranting further investigation into its clinical utility alongside FDG‐PET.

Abstract BackgroundThe prevention of symptomatic Alzheimer’s disease (AD) is a major endeavor currently in the field, with the prevalence of subjects on the AD continuum (i.e. presence of amyloid‐ß [Aß] pathology) being much higher than previously estimated. However, the extent to which Aß pathology and its interaction with common risk factors in the aging population relates to disease progression is still limited. The AMYPAD Prognostic and Natural History Study (PNHS) aims to evaluate the value of amyloid‐PET for predicting AD‐related disease progression.MethodA total of 1423 non‐demented subjects were included from the AMYPAD‐PNHS pan‐European cohort (17 sites across 10 Parent Cohorts), for who a baseline [18F]flutemetamol or [18F]florbetaben amyloid‐PET scans that passed quality control was available (Table‐1). Amyloid burden was assessed using the Centiloid (CL) method (whole cerebellum reference region). Independent linear mixed‐effect models were used to assess the predictive value of continuous CL, and its interaction with time, across cognitive domains: mini‐mental state examination (MMSE), memory, attention, language fluency, visuospatial, and executive functions. Years from baseline, age, sex, years of education, cognitive dementia rating (CDR), and APOE‐e4 were used as independent variables. Clinical follow‐up was 3.4 ± 1.8 years (up to ±10 years) on average.ResultAt baseline, 90% of the subjects were classified as cognitively unimpaired (CDR = 0). Based on CL, most subjects were categorized as amyloid‐negative (59%, 0±9CL), followed by grey‐zone (24%, 25±11CL), and amyloid‐positive (17%, 82±21CL). Baseline CL and its interaction with time were predictive of MMSE scores, memory, attention, and language fluency. Baseline CL, but not its interaction with time, was predictive of executive function. Finally, the interaction of baseline CL with time, but not its main effect, was predictive of visuospatial functioning (Figure‐1). Age and sex were significant contributors to nearly all models.ConclusionHigher baseline CL was associated with lower cognitive performance in all explored domains, suggesting that emerging cerebral amyloid accumulation in non‐demented individuals is predictive of overall cognitive function. Also, higher CL values were predictive of decline across cognitive domains, except for executive function. Further analysis is ongoing, including different confounding factors, longitudinal PET outcomes, and other biomarkers of the disease.

Abstract BackgroundObesity is associated with higher risk of Alzheimer’s disease (AD) and other dementias. This association could be mediated by a pro‐inflammatory effect of abdominal adiposity. Here, we used the waist‐to‐hip ratio (WHR) as a proxy for central adiposity to explore its association with AD and neuroinflammation biomarkers, as well as its interaction with sex in cognitively unimpaired adults from the ALFA+ cohort.MethodWe analyzed data from 353 participants (61.2% females; 64.3% β‐amyloid [Aβ]+; 61.04 ± 4.77 years on average). We measured CSF p‐tau and t‐tau with the Elecsys® immunoassays and CSF Aβ42, Aβ40 and neuroinflammation biomarkers (sTREM2, GFAP, YKL40, S100 and IL‐6) with the exploratory Roche NeuroToolKit robust prototype assays. We used separated linear regression models to analyze associations of WHR with CSF AD and neuroinflammation biomarkers while adjusting by age, sex, APOE status, education years, mean blood pressure and triglycerides. We ran interaction analyses between WHR and sex.ResultWe did not find significant main effects of WHR on CSF AD or neuroinflammation biomarkers. We found a significant interaction between WHR and sex on IL‐6 (p = 0.008; correcting by multiple hypotheses, p_adjusted = 0.067). After stratifying by sex, WHR was associated with IL‐6 in the male group (p = 0.032; p_adjusted = 0.242), but not in the female group (p = 0.596).ConclusionWHR is positively associated with IL‐6 levels in males. The effect of sex, and the role of neuroinflammation as a potential mediator in the association between obesity and dementia risk warrant further research.

Abstract BackgroundSex‐specific vulnerability and resilience along the amyloid cascade may be partly explained by neuroinflammatory processes. Microglial activation may play a more important role in the development of Alzheimer’s disease (AD) in women than in men. We investigated the effect of sex and biomarkers of microglia and astrocytic activation on amyloid (A) and tau (T) burden, and neurodegeneration (N) in cognitively unimpaired (CU) older adults at increased AD risk.MethodWe included 397 CU participants (49‐73 years, 61.5% women) with the following available CSF biomarker data: Aβ42/40, p‐tau181, sTREM2, GFAP, and YKL40 measured with Roche NeuroToolKit or Elecsys® immunoassays. A subsample (n = 299) also had MRI‐based hippocampal volume data (ASHS segmentation). The outcomes of interest were A: Aβ42/40, T: p‐tau181, and N: hippocampal volume. Predictors included demographics and neuroinflammation markers. First, we tested the effect of sex and neuroinflammation markers on A, T, and N in the whole sample. Then, we tested the neuroinflammation*Aβ42/40 and neuroinflammation*p‐tau interactions on p‐tau and hippocampal volume, respectively. Finally, we looked at sex‐stratified models.ResultMen were older, more often APOE‐ε4 carriers and showed higher GFAP levels (men>women). In the whole sample, neither sex nor neuroinflammation markers were associated with Aβ42/40. However, sex (women>men), higher sTREM2 and higher YKL40 were associated with higher p‐tau181 levels, and sex (women<men), lower sTREM2, and higher YKL40 were associated with lower hippocampal volume. Models including interaction terms showed a sex‐independent interaction of GFAP with Aβ42/40 and p‐tau181 on p‐tau181 and hippocampal volume, respectively, suggesting a role of astrocytic activation along the ATN pathway. Sex‐stratified analyses showed (1) in women only, a YKL40*Aβ42/40 interaction on p‐tau181 and an association of higher sTREM2 levels with greater hippocampal volume (p = .030), suggesting a protective effect, and (2) in men only, a p‐tau181*sTREM2 and p‐tau181*YKL40 interaction on hippocampal volume. Statistics are provided in Table 1.ConclusionPending replication with longitudinal measurements, our results suggest that microglial and astrocytic activation may play a sex‐specific role in downstream amyloid. While astrocytic activation moderates the associations between A, T and N in men and women, microglial activation might provide resilience to neurodegeneration only in women (Figure 1).

BackgroundRecent evidence suggests that the failure of the glymphatic system – the brain’s waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer’s Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD.Case reportThis report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD.ConclusionThe findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

Abstract BackgroundStress is associated with adverse health outcomes, but the pathways through which stressful life events affect brain health, and the age periods most vulnerable to these effects, are unknown. We investigated these questions in relation to Alzheimer’s disease (AD) pathophysiology and brain integrity in cognitively unimpaired participants at risk for AD.MethodIn this cross‐sectional cohort study, 1168 participants completed the 18‐item Elder’s Life Stress Inventory measuring the occurrence (and age at occurrence) of stressful life events. Of these, 393 participants had data available on AD biomarkers (cerebrospinal fluid [CSF] phosphorylated‐tau and amyloid‐beta1−42/amyloid‐beta1−40 ratio measured with Elecsys® assays and NeuroToolKit panel of robust prototype assays [Roche Diagnostics International Ltd, Rotkreuz, Switzerland], respectively) and neuroinflammation markers (CSF interleukin 6 [IL‐6], soluble TREM‐2 and glial fibrillary acidic protein measured with NeuroToolKit). In total, 830 had structural magnetic resonance imaging data available for amygdala and hippocampal volume, and grey matter volume/thickness for areas of the prefrontal cortex. The association of stressful events with AD biomarkers, neuroinflammation and brain integrity (adjusting for total intracranial volume) was examined using multiple regression analyses adjusting for sex, age and education. Associations of stressful events during early life (ages 0−25), early adulthood (26−40), middle adulthood (41−55) and late adulthood (≥56) were also examined. Analyses were stratified by sex and Apolipoprotein ε4 (APOE ε4)‐status.ResultParticipants’ age ranged between 47−76 and 62.5% were women. A higher number of stressful events during life‐course was associated with an increase in IL‐6 levels among APOE ε4‐carriers; with a decreased amyloid‐beta ratio among APOE ε4‐noncarriers; and with a reduction in caudal anterior cingulate cortex volume among women. A higher number of events during early adulthood was associated with higher phosphorylated‐tau levels and prefrontal brain integrity, and during middle adulthood was associated with decreased prefrontal brain integrity (Table 1. & 2.).ConclusionStress may affect later‐life brain health through multiple pathways, including neuroinflammation, amyloid‐beta and brain integrity, depending on APOE ε4‐carrier status and sex. Stressful events during early adulthood may promote phosphorylated‐tau in later‐life, while events during early/middle adulthood may have differential effects on brain integrity, suggesting potential windows for stress‐prevention strategies.

BackgroundSubjective cognitive decline (SCD) is often related to affective symptoms and both predict cognitive decline. We investigated whether SCD status predicted higher anxiety/depression during the Covid19‐related confinement, along with amyloid positivity in cognitively unimpaired older adults.MethodWe included 205 participants from the ALFA+ study (Table 1). During the confinement, anxiety and depression (Hospital Depression and Anxiety scale, HADS), perceived stress (Perceived Stress Scale) and stress resilience (Brief Resilience Scale) were measured. Participants completed HADS, SCD‐Questionnaire, and underwent a [18F]flutemetamol‐PET scan on average 2.4 years before confinement (baseline). We ran linear analyses with (i) cross‐sectional HADS scores during the confinement as well as (ii) change from baseline to confinement (delta scores) as dependent variables. SCD and amyloid status (+/‐, defined with a Centiloid threshold of 12) and their interaction were considered as predictors, and demographics, APOE‐ε4 status, and baseline HADS (for longitudinal analyses) as covariates. In a second step, perceived stress and stress resilience were considered in the models among covariates.ResultTwenty‐seven percent (n=56) of the participants were classified as SCD and 12.7% as amyloid positive. When main effects were tested, both SCD (p=0.03) and amyloid positivity (p=0.003) were associated with higher HADS scores during confinement (Table 2a). Further, a significant SCD*amyloid interaction was observed (p=0.001) such that only SCD participants with an amyloid positive scan showed higher HADS scores (p=0.001). SCD participants showed higher perceived stress than non‐SCD participants (p=.044), but no differences were found in stress resilience (p=0.6). The inclusion of perceived stress and stress resilience as covariates reduced the SCD effect to a trend (p=0.06) but not the effect of amyloid (p=0.003). Longitudinal analyses with delta scores showed similar results for amyloid but not for SCD main effects (Table 2b). The amyloid*SCD interaction was also significant in longitudinal analyses (p=0.002) with amyloid status predicting an increase in HADS scores only in participants with SCD (p=0.003) (Fig. 1).ConclusionHaving SCD and being amyloid positive is synergistically related to increased anxiety/depression during the Covid19‐related confinement. Longitudinal studies are warranted to investigate the impact of higher confinement related anxiety/depression in the clinical prognosis of the SCD population.

Abstract BackgroundIn the absence of effective treatments to reverse cognitive deterioration related to Alzheimer's disease (AD), nonpharmacological secondary prevention interventions at early preclinical stages have been found to be a promising strategy to prevent cognitive decline. In this context, the PENSA study, framed within the WW‐FINGERS consortium, is a randomized clinical trial involving cognitively normal elderly individuals with an increased risk of developing AD (meeting subjective cognitive decline, SCD‐plus criteria and being APOE‐ɛ4 carriers). The aim of the study is to evaluate the efficacy of a multimodal personalized lifestyle intervention (dietary and physical activity counseling and cognitive training) combined with a dietary supplement, epigallocatechin gallate (EGCG) in slowing down cognitive decline.MethodIn this work we present the baseline sociodemographic, mood and cognitive characteristics of the already enrolled sample. Cognitive function was measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC) and adding to this original version the interference score from the Stroop Color and Word Test and the Five Digit Test (ADCS‐PACC‐Plus‐exe). Additionally, the Digit Span, the Boston Naming Test and the Animal Fluency Test were administered. Psychological distress was measured with the Hospital Anxiety and Depression Scale.ResultOn January 2021 the study had enrolled 68 individuals (62% women) with a mean (SD) age of 67.4 (4.6) years and the following APOE genotype: 83% ɛ3/ɛ4, 13% ɛ4/ɛ4 and 4% ɛ2/ɛ4. Most had higher education (66.2%) and 84% were retired (Table 1). Mild and moderate symptoms of psychological distress were present in 14.7% and 23.5% of participants, respectively. The mean (SD) number of cognitive domains affected (memory, concentration, language, visuospatial skills), measured by an ad‐hoc SCD questionnaire, were 2.54 (±0.9). 77.3% of participants referred memory centered complaints. Considering the different domains, participants reported alterations on memory (97.1%), concentration (73.5%), language (67.6%) and visuospatial skills (11.8%). SCD profiles are shown in Figure 1. Table 2 shows the ADCS‐PACC‐Plus‐exe scores.ConclusionThe PENSA study will provide valuable information on the effect of a lifestyle intervention supplemented with EGCG to prevent cognitive decline and will aid to share light on the benefit of these strategies in people at‐risk of developing AD.

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence suggests that, in higher-income countries, dementia incidence is decreasing as a result of healthier lifestyles. This observation supports the notion that preventing dementia is possible and that a certain degree of prevention is already in action. Further reduction of dementia incidence through deliberate prevention plans is needed to counteract its growing prevalence due to increasing life expectancy.An increasing number of individuals with normal cognitive performance seek help in the current memory clinics asking an evaluation of their dementia risk, preventive interventions, or interventions to ameliorate their cognitive performance. Consistent evidence suggests that some of these individuals are indeed at increased risk of dementia. This new health demand asks for a shift of target population, from patients with cognitive impairment to worried but cognitively unimpaired individuals. However, current memory clinics do not have the programs and protocols in place to deal with this new population.We envision the development of new services, henceforth called Brain Health Services, devoted to respond to demands from cognitively unimpaired individuals concerned about their risk of dementia. The missions of Brain Health Services will be (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction, and (iv) cognitive enhancement. In this paper, we present the organizational and structural challenges associated with the set-up of Brain Health Services.