Search

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time‐encoded arterial spin labeling (te‐ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te‐ASL with single‐postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aβ) negative (−), CU Aβ positive (+), and CI Aβ+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te‐ASL was more sensitive at detecting CBF reduction in the CU Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te‐ASL is more sensitive than single‐PLD ASL at detecting CBF changes in AD. Highlights: Lower CBF can be detected in CU subjects in the early AD continuum.te‐ASL is more sensitive than single‐PLD ASL at detecting CBF alterations in AD.CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration. [ABSTRACT FROM AUTHOR]

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle‐aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non‐carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross‐sectional study, we investigated textural properties of T1‐weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT‐Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel‐based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non‐carriers. Textural maps were generated and were subsequently harmonised using voxel‐wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non‐carriers at midlife and have established associations of textural features with ageing and sex. [ABSTRACT FROM AUTHOR]

Single-photon emission computed tomography (SPECT) systems with pinhole collimators are becoming increasingly important in clinical and preclinical nuclear medicine investigations as they can provide a superior resolution-sensitivity tradeoff compared to conventional parallel-hole and fanbeam collimators. Previously, open-source software did not exist for reconstructing tomographic images from pinhole-SPECT datasets. A 3D SPECT system matrix modelling library specific for pinhole collimators has recently been integrated into STIR, an open-source software package for tomographic image reconstruction. The pinhole-SPECT library enables corrections for attenuation and the spatially variant collimator-detector response by incorporating their effects into the system matrix. Attenuation correction can be calculated with a simple single line of response or a full model. The spatially variant collimator-detector response can be modelled with a point spread function and depth of interaction corrections for increased system matrix accuracy. In addition, improvements to computational speed and memory requirements can be made with image masking. This work demonstrates the flexibility and accuracy of STIR's support for pinhole-SPECT datasets using measured and simulated single-pinhole SPECT data from which reconstructed images were analysed quantitatively and qualitatively. The extension of the opensource STIR project with advanced pinhole-SPECT modelling will enable the research community to study the impact of pinhole collimators in several SPECT imaging scenarios and with different scanners. [ABSTRACT FROM AUTHOR]

Objective: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. Methods: This cross‐sectional cohort study included 1,290 CU participants (aged 48–77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)‐tau181 and Aβ1–42/1–40 ratio, (2) interleukin 6 (IL‐6), and (3) GM volumes voxel‐wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. Results: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p‐tau181 and IL‐6. Participants with history of psychiatric disease and men, showed lower Aβ1–42/1–40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. Interpretation: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058–1068 [ABSTRACT FROM AUTHOR]

Background: In this study, we evaluated the association between tau PET and fluid biomarkers and explored biological mechanisms associated with elevated tau in cognitively unimpaired(CU) individuals. Method: Seventy‐nine CU individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted MRI, CSF and plasma biomarkers. Longitudinal changes in cognition were measured using cognition composites(Table1). Participants were categorized into AT stages using CSF biomarkers and pre‐established cut‐offs(Table 1). [18F]RO‐948 SUVR was measured in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference. Regional positivity thresholds per Braak region were calculated as mean+2SD of the A‐T‐ group. [18F]flutemetamol PET scans were quantified in Centiloids(CL). Associations between [18F]RO‐948 SUVRs and AD biomarkers (Figure1) were assessed using Pearson correlations. Receiver Operating Curve(ROC) analyses were conducted to determine the capacity of biomarkers to predict BraakI/II positivity. In those with CL>cut‐off for tau‐PET positivity, differences in non‐core AD fluid biomarkers(Figure2) and longitudinal cognition were sought between tau BraakI/II positive and negative individuals. The mediating effect of non‐core AD biomarkers on the AD pathophysiological cascade were sought. FDR‐corrected p‐values<0.05 were considered significant. Result: Nine cases(11.4%) were positive in BraakI/II. Following a hierarchical pattern, four of them were also positive for BraakIII/IV and one for BraakV/VI. Fluid biomarkers presented correlations with tau PET SUVR in all Braak stages (Figure1) and predictive capacity for tau‐PET positivity in BraakI/II(Table2). In individuals with CL>32.53, BraakI/II positives had higher levels of CSF‐GFAP(p<0.01) and CSF‐NFL(p = 0.03), and presented declines in PACC and in visual, attention, and memory composites (Figure1). CSF‐GFAP partially mediated the association between CL and tau‐PET (16%) and between tau‐PET and CSF‐NfL (30%). Conclusion: Early in the AD continuum, [18F]RO‐948 PET conformed to the Braak hierarchical model. CSF and plasma biomarkers showed moderate associations with tau PET SUVR but good capacity to predict tau PET positivity in BraakI/II. Tau‐PET positivity in this region was associated with higher astrogliosis, neurodegeneration and cognitive decline as compared to tau‐PET negatives with similar levels of amyloid deposition. Astrogliosis partially explained the observed associations between amyloid deposition and the presence of tau tangles in medial temporal regions and, even strongly, between the latter and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies show that multiparity (≥3 children) is associated with a higher risk of clincal AD in cognitively unimpaired (CU) women. However, studies exploring the impact of parity on AD biomarkers are scarce. We explored the association between number of children and imaging and fluid AD biomarkers, and the related interaction with neurodegeneration and cognition. Method: We included 210 CU parous women from the ALFA+ cohort with 34 nulliparous women and 152 men with children as controls. The number of children was dichotomized as <3 children vs ≥3 children. All CSF biomarkers were measured using the Roche NeuroToolKit and Elecsys® immunoassays (both Roche Diagnostics International Ltd), except p‐tau231 and GAP‐43 (ELISA). All plasma biomarkers were measured using the Simoa HD‐X (Quanterix Corp) except sICAM1 (MSD). Jack's cortical thickness AD signature was used as a marker of neurodegeneration. Cognitive change (3‐year follow‐up) was measured with a PACC‐like composite as well as for individual cognitive domains. Biomarkers differences between parity groups were analyzed with ANCOVA adjusted by age. Independent linear models with biomarkers, AD signature and cognitive change as dependent variable were constructed. The number of children was set as predictor, and age, APOE‐ε4, and age at first birth as covariates in all models. Interaction terms between number of children and biomarkers were modeled. p‐values <0.05 were considered as significant. Result: Several biomarkers were significantly higher in grand multiparours women (Table 1). Linear regression results (Table 2, Fig. 1A) showed that multiparity was associated with higher CSF p‐tau181 levels. Moreover, multiparity interacted with CSF p‐tau181 to predict thinner cortical thickness in AD‐sensitive regions and a steeper decline in executive function (Table 2, Fig. 1B & 1C). No significant associations in men and nulliparous women were found. Conclusion: Having ≥3 children increases the risk of higher CSF p‐tau181 levels in CU middle‐aged women, with CSF p‐tau181 having a more deleterious effect on cortical thickness and change on executive function performance. These findings contribute to our understanding of the higher risk for AD observed in CU multiparous women, who show higher susceptibility and more adverse downstream consequences to tau pathology. [ABSTRACT FROM AUTHOR]

Background: Biochemical changes, which may precede morphological changes, could be of great relevance in profiling preclinical AD. We aimed to investigate metabolic changes using magnetic resonance spectroscopy (MRS) in three AD‐relevant regions: right hippocampus, right angular gyrus, and right precuneus, focusing on myoinositol due to its role in glial activity (osmoregulation‐neuroinflammation). Method: Three hundred sixty‐six participants from the ALFA+ cohort underwent three single‐voxel MRS (PRESS sequence, TR = 2000ms; TE = 100ms chosen to invert myoinositol peak for more precise quantitation; volume of interest (VOI): 20×20×20mm3 [25×20×16mm3 for hippocampus]). Figure 1 shows VOI location and MRS samples. Concentrations of N‐acetyl‐containing compounds (NAA) that is a neuronal marker, total creatine (Cr) related to brain energy, myoinositol (mI), choline‐containing compounds (Cho) related to cell proliferation, and glutamate/glutamine were calculated with LCModel in arbitrary units (using water reference) with the default settings and basis set adapted to the acquisition conditions. Concentrations were corrected for VOI CSF content. Remaining VOI gray matter percentage was used as a confounder in all analyses, jointly with age, sex, and APOE‐e4 status (carrier/non‐carrier). We investigated the correlation of MRS metabolite concentrations with CSF concentrations of Aβ42/40 and ptau‐181 as biomarkers for AD (Elecsys®; Roche Diagnostics). For completeness, we also checked the dependency of MRS metabolites on age. MRS not meeting QA criteria were discarded (Cramer‐Rao lower bounds >20 for any of the metabolites or imprecise VOI location). The statistical threshold was set to p<0.05 for all the analyses. Result: Table 1 shows characteristics of the subsamples with MRS in each location. Higher myoinositol levels in hippocampus and angular gyrus were associated with lower CSF Ab42/40, but not in the precuneus, where it was associated with higher Cr/Cho ratio. Higher Cr and NAA were positively associated with higher CSF p‐tau181 levels in the angular gyrus. NAA was negatively associated with age on cortical regions, as well as Cr on the angular gyrus. Table 2 summarizes the main results. Conclusion: MRS allowed determination of differential metabolite changes in AD‐related regions in preclinical AD. Further research is warranted to better characterize the nature of these metabolic changes and determine their impact on longitudinal outcomes of these participants. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self‐reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. METHODS: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel‐wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. RESULTS: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self‐reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. DISCUSSION: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD‐related neurodegeneration in areas involved in sleep–wake regulation may induce or worsen sleep disturbances. Highlights: Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology.Poor sleep exacerbates brain changes observed in preclinical AD.Sleep is an appealing therapeutic strategy for preventing AD. [ABSTRACT FROM AUTHOR]