Multimodal neuroimaging correlates of spectral power in NREM sleep delta sub-bands in cognitively unimpaired older adults.

STUDY OBJECTIVES: In aging, reduced delta power (0.5-4 Hz) during N2 and N3 sleep has been associated with gray matter (GM) atrophy and hypometabolism within frontal regions. Some studies have also reported associations between N2 and N3 sleep delta power in specific sub-bands and amyloid pathology. Our objective was to better understand the relationships between spectral power in delta sub-bands during N2-N3 sleep and brain integrity using multimodal neuroimaging. METHODS: In-home polysomnography was performed in 127 cognitively unimpaired older adults (mean age ±â€…SD: 69.0 ±â€…3.8 years). N2-N3 sleep EEG power was calculated in delta (0.5-4 Hz), slow delta (0.5-1 Hz), and fast delta (1-4 Hz) frequency bands. Participants also underwent magnetic resonance imaging and Florbetapir-PET (early and late acquisitions) scans to assess GM volume, brain perfusion, and amyloid burden. Amyloid accumulation over ~21 months was also quantified. RESULTS: Higher delta power was associated with higher GM volume mainly in fronto-cingular regions. Specifically, slow delta power was positively correlated with GM volume and perfusion in these regions, while the inverse association was observed with fast delta power. Delta power was neither associated with amyloid burden at baseline nor its accumulation over time, whatever the frequency band considered. CONCLUSIONS: Our results show that slow delta is particularly associated with preserved brain structure, and highlight the importance of analyzing delta power sub-bands to better understand the associations between delta power and brain integrity. Further longitudinal investigations with long follow-ups are needed to disentangle the associations among sleep, amyloid pathology, and dementia risk in older populations. CLINICAL TRIAL INFORMATION: Name: Study in Cognitively Intact Seniors Aiming to Assess the Effects of Meditation Training (Age-Well). URL: https://clinicaltrials.gov/ct2/show/NCT02977819?term=Age-Well&draw=2&rank=1. See STROBE_statement_AGEWELL in supplemental materials. REGISTRATION: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

Respective influence of beta-amyloid and APOE ε4 genotype on medial temporal lobe subregions in cognitively unimpaired older adults.

Medial temporal lobe (MTL) subregions are differentially affected in Alzheimer's disease (AD), with a specific involvement of the entorhinal cortex (ERC), perirhinal cortex and hippocampal cornu ammonis (CA)1. While amyloid (Aß) and APOEε4 are respectively the first molecular change and the main genetic risk factor in AD, their links with MTL atrophy remain relatively unclear. Our aim was to uncover these effects using baseline data from 130 participants included in the Age-Well study, for whom ultra-high-resolution structural MRI, amyloid-PET and APOEε4 genotype were available. No volume differences were observed between Aß + (n = 24) and Aß- (n = 103), nor between APOE4+ (n = 35) and APOE4- (n = 95) participants. However, our analyses showed that both Aß and APOEε4 status interacted with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOEε4 status moderated the effects of age on other subregions (subiculum, ERC), suggesting a more important contribution of APOEε4 than Aß to MTL atrophy in cognitively unimpaired population. These results are crucial to develop MRI-based biomarkers to detect early AD.

Rapid Eye Movement Sleep, Neurodegeneration, and Amyloid Deposition in Aging.

OBJECTIVE: Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging. METHODS: We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 ± 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro- and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxel-wise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status. RESULTS: Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas. INTERPRETATION: These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum. ANN NEUROL 2023;93:979-990.

Depressive symptoms in cognitively unimpaired older adults are associated with lower structural and functional integrity in a frontolimbic network.

Subclinical depressive symptoms are associated with increased risk of Alzheimer's disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.

Importance: No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk. Objective: To investigate the effects of meditation training on brain integrity in older adults. Design, Setting, and Participants: Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021. Interventions: Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices. Main Outcomes and Measures: Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores. Results: Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002). Conclusions and Relevance: The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Relationships between diabetes-related vascular risk factors and neurodegeneration biomarkers in healthy aging and Alzheimer's disease.

Vascular risk factors such as hyperglycemia and platelet hyperactivation play a significant role in type 2 diabetes (T2D), a risk factor for AD. We investigated the relationships between glycemia levels, platelet indices (platelet count; mean platelet volume (MPV)) and AD neuroimaging markers in 105 cognitively unimpaired adults, including 21 amyloid-negative older adults (Aß-neg controls), and 45 amyloid-positive patients with mild cognitive impairment or dementia (Aß-pos patients). We assessed between-group differences on the two T2D-related vascular risk factors, then the association between blood parameters and multimodal neuroimaging (structural MRI, 18F-fluorodeoxyglucose, and 18F-florbetapir-PET) in cognitively unimpaired adults and Aß-pos patients using multiple regressions. Compared to Aß-neg controls, Aß-pos patients showed lower platelet count and higher MPV. In cognitively unimpaired adults, increased glycemia levels were associated with atrophy and hypometabolism in AD-sensitive regions. In Aß-pos patients, increased MPV was associated with entorhinal and perirhinal cortex atrophy. Subclinical but high glycemia levels in healthy individuals and MPV in AD patients are associated with neurodegeneration in AD-sensitive brain regions but not with amyloid deposition.

Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimer's Disease: Links With Cognition, Brain Structure, Brain Function and Amyloid Burden.

Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes; including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimer's disease (ALZ). A positive correlation was found between tPA and age in CUA (p < 0.001), with males showing higher tPA than females (p = 0.05). No significant difference was found between ALZ patients and cognitively unimpaired elders (CUE). Plasma tPA in CUA negatively correlated with global brain volume. No correlation was found with brain FDG metabolism or amyloid deposition. Age-related tPA changes were associated to changes in blood pressure, glycemia and body mass index. Within the ALZ patients, tPA didn't correlate with any cognitive or neuroimaging measures, but only with physiological measures. Altogether our study suggests that increased tPA plasma concentration with age is related to neuronal alterations and cardiovascular risk factors.

Vascular Health Is Associated With Functional Connectivity Decline in Higher-Order Networks of Older Adults.

Background: Poor vascular health may impede brain functioning in older adults, thus possibly increasing the risk of cognitive decline and Alzheimer's disease (AD). The emerging link between vascular risk factors (VRF) and longitudinal decline in resting-state functional connectivity (RSFC) within functional brain networks needs replication and further research in independent cohorts. Method: We examined 95 non-demented older adults using the IMAP+ cohort (Caen, France). VRF were assessed at baseline through systolic and diastolic blood pressure, body-mass-index, and glycated hemoglobin (HbA1c) levels. Brain pathological burden was measured using white matter hyperintensity (WMH) volumes, derived from FLAIR images, and cortical ß-Amyloid (Aß) deposition, derived from florbetapir-PET imaging. RSFC was estimated from functional MRI scans within canonical brain networks at baseline and up to 3 years of follow-up. Linear mixed-effects models evaluated the independent predictive value of VRF on longitudinal changes in network-specific and global RSFC as well as a potential association between these RSFC changes and cognitive decline. Results: We replicate that RSFC increased over time in global RSFC and in the default-mode, salience/ventral-attention and fronto-parietal networks. In contrast, higher diastolic blood pressure levels were independently associated with a decrease of RSFC over time in the default-mode, salience/ventral-attention, and fronto-parietal networks. Moreover, higher HbA1c levels were independently associated with a reduction of the observed RSFC increase over time in the salience/ventral-attention network. Both of these associations were independent of brain pathology related to Aß load and WMH volumes. The VRF-related changes in RSFC over time were not significantly associated with longitudinal changes in cognitive performance. Conclusion: Our longitudinal findings corroborate that VRF promote RSFC alterations over time within higher-order brain networks, irrespective of pathological brain burden. Altered RSFC in large-scale cognitive networks may eventually increase the vulnerability to aging and AD.

Dynamic functional connectivity patterns associated with dementia risk.

BACKGROUND: This study assesses the relationships between dynamic functional network connectivity (DFNC) and dementia risk. METHODS: DFNC of the default mode (DMN), salience (SN), and executive control networks was assessed in 127 cognitively unimpaired older adults. Stepwise regressions were performed with dementia risk and protective factors and biomarkers as predictors of DFNC. RESULTS: Associations were found between times spent in (i) a "weakly connected" state and lower self-reported engagement in early- and mid-life cognitive activity and higher LDL cholesterol; (ii) a "SN-negatively connected" state and higher blood pressure, higher depression score, and lower body mass index (BMI); (iii) a "strongly connected" state and higher self-reported engagement in early-life cognitive activity, Preclinical Alzheimer's cognitive composite-5 score, and BMI; and (iv) a "DMN-negatively connected" state and higher self-reported engagement in early- and mid-life stimulating activities and lower LDL cholesterol and blood pressure. The lower number of state transitions was associated with lower brain perfusion. CONCLUSION: DFNC states are differentially associated with dementia risk and could underlie reserve.

Role of Cardiovascular Risk Factors on the Association Between Physical Activity and Brain Integrity Markers in Older Adults.

BACKGROUND AND OBJECTIVES: Physical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults. METHODS: At baseline, participants from the Age-Well study completed a physical activity questionnaire and underwent cardiovascular risk factors collection (systolic blood pressure, body mass index [BMI], current smoker status, and high-density lipoprotein cholesterol, total cholesterol, and insulin levels) and multimodal neuroimaging (structural MRI, diffusion MRI, FDG-PET, and florbetapir PET). Multiple regressions were conducted to assess the association among physical activity, cardiovascular risk factors, and neuroimaging. Mediation analyses were performed to test whether cardiovascular risk factors mediated the associations between physical activity and neuroimaging. RESULTS: A total of 134 cognitively unimpaired older adults (≥65 years) were included. Higher physical activity was associated with higher gray matter (GM) volume (ß = 0.174, p = 0.030) and cerebral glucose metabolism (ß = 0.247, p = 0.019) but not with amyloid deposition or white matter integrity. Higher physical activity was associated with lower insulin level and BMI but not with the other cardiovascular risk factors. Lower insulin level and BMI were related to higher GM volume but not to cerebral glucose metabolism. When controlling for insulin level and BMI, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with GM volume was lost. When insulin level and BMI were entered in the same model, only BMI remained a significant predictor of GM volume. Mediation analyses confirmed that insulin level and BMI mediated the association between physical activity and GM volume. Analyses were replicated within Alzheimer disease-sensitive regions and results remained overall similar. DISCUSSION: The association between physical activity and GM volume is mediated by changes in insulin level and BMI. In contrast, the association with cerebral glucose metabolism seems to be independent from cardiovascular risk factors. Older adults engaging in physical activity experience cardiovascular benefits through the maintenance of a lower BMI and insulin level, resulting in greater structural brain integrity. This study has implications for understanding how physical activity affects brain health and may help in developing strategies to prevent or delay age-related decline. TRIAL REGISTRATION INFORMATION: EudraCT: 2016-002,441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

White matter hyperintensity topography in Alzheimer's disease and links to cognition.

INTRODUCTION: White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. METHODS: Regional WMH were estimated in 54 cognitively impaired amyloid beta-positive AD (Aßpos-AD), compared to 40 cognitively unimpaired amyloid beta-negative older controls (Aßneg-controls) matched for vascular risk factors. The cross-sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. RESULTS: WMH volume was larger in Aßpos-AD compared to Aßneg-controls in all regions, with the greatest changes in the splenium of the corpus callosum (S-CC). In Aßpos-AD patients, larger total and regional WMH volume, especially in the S-CC, was strongly associated with decreased cognition. DISCUSSION: WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S-CC WMH.

Sex-specificities in anxiety and depressive symptoms across the lifespan and their links with multimodal neuroimaging.

BACKGROUND: Anxiety and depressive symptoms are associated with impaired well-being, higher risk of developing psychoaffective disorders and are risk factors for Alzheimer's disease (AD). To further understand their relevance and the mechanisms underlying their link with AD, our aims were to assess how anxiety and depressive symptoms changed with age and related to AD neuroimaging biomarkers across the adult lifespan, while also exploring sex specificities. METHODS: 210 cognitively normal participants aged 19-86 years (101 men, 109 women) completed assessments of anxiety and depressive symptoms with the STAI-A and MADRS respectively, and neuroimaging measurements including structural MRI, FDG-PET and amyloid-PET. 167 of those were followed-up over 1.5-3 years. Multiple regressions were performed to assess the links between anxiety or depressive symptoms versus age, global cognition or each imaging modality, both cross-sectionally and longitudinally; and general linear models we used to test the interactive effect of sex on these associations. RESULTS: Depressive symptoms decreased with age, while anxiety symptoms increased only among women. Higher anxiety symptoms were associated with lower grey matter (GM) volume and glucose metabolism, with an interaction of sex, this relationship being significant only in women. Longitudinally, only low baseline GM volume predicted an increase in anxiety symptoms with time. LIMITATIONS: Only 43% of participants reported depressive symptoms. Despite additional analyses, the low variability in the measure might have prevented us from detecting subtle changes. CONCLUSIONS: This study emphasizes the need to consider anxiety symptoms in assessments for dementia risk, particularly in women.

Subjective cognitive decline: opposite links to neurodegeneration across the Alzheimer's continuum.

Subjective memory decline is associated with neurodegeneration and increased risk of cognitive decline in participants with no or subjective cognitive impairment, while in patients with mild cognitive impairment or Alzheimer's-type dementia, findings are inconsistent. Our aim was to provide a comprehensive overview of subjective memory decline changes, relative to objective memory performances, and of their relationships with neurodegeneration, across the clinical continuum of Alzheimer's disease. Two hundred participants from the Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce (IMAP+) primary cohort and 731 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) replication cohort were included. They were divided into four clinical groups (Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce/Alzheimer's Disease Neuroimaging Initiative): controls (n = 67/147, age: 60-84/60-90, female: 54/55%), patients with subjective cognitive decline (n = 30/84, age: 54-84/65-80, female: 44/63%), mild cognitive impairment (n = 50/369, age: 58-86/55-88, female: 45/44%) or Alzheimer's-type dementia (n = 36/121, age: 51-86/61-90, female: 41/41%). Subjective and objective memory scores, and their difference (i.e. delta score reflecting memory awareness), were compared between groups. Then, voxelwise relationships between subjective memory decline and neuroimaging measures of neurodegeneration [atrophy (T1-MRI) and hypometabolism (18F-fluorodeoxyglucose-PET)] were assessed across clinical groups and the interactive effect of the level of cognitive impairment within the entire sample was assessed. Analyses were adjusted for age, sex and education, and repeated including only the amyloid-positive participants. In Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce, the level of subjective memory decline was higher in all patient groups (all P < 0.001) relative to controls, but similar between patient groups. In contrast, objective memory deficits progressively worsened from the subjective cognitive decline to the dementia group (all P < 0.001). Accordingly, the delta score showed a progressive decline in memory awareness across clinical groups (all P < 0.001). Voxelwise analyses revealed opposite relationships between the subjective memory decline score and neurodegeneration across the clinical continuum. In the earliest stages (i.e. patients with subjective cognitive decline or Mini Mental State Examination > 28), greater subjective memory decline was associated with increased neurodegeneration, while in later stages (i.e. patients with mild cognitive impairment, dementia or Mini Mental State Examination < 27) a lower score was related to more neurodegeneration. Similar findings were recovered in the Alzheimer's Disease Neuroimaging Initiative replication cohort, with slight differences according to the clinical group, and in the amyloid-positive subsamples. Altogether, our findings suggest that the subjective memory decline score should be interpreted differently from normal cognition to dementia. Higher scores might reflect greater neurodegeneration in earliest stages, while in more advanced stages lower scores might reflect decreased memory awareness, i.e. more anosognosia associated with advanced neurodegeneration.

Longitudinal Changes in Hippocampal Network Connectivity in Alzheimer's Disease.

OBJECTIVE: The hippocampus is connected to 2 distinct cortical brain networks, the posterior-medial and the anterior-temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these 2 networks, their changes over time, and links to cognition in Alzheimer's disease. METHODS: We assessed MTL connectivity in 53 amyloid-ß-positive patients with mild cognitive impairment and AD dementia and 68 healthy elderly controls, using resting-state functional magnetic resonance imaging, cross-sectionally and longitudinally. First, we compared the functional connectivity of the posterior-medial and anterior-temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18-month follow-up in patients. Third, we assessed the association in the connectivity changes between the 2 networks, and with cognitive performance. RESULTS: We found decreased connectivity in patients specifically between the hippocampus and the posterior-medial network, together with increased connectivity between several MTL subregions and the anterior-temporal network. Moreover, changes in the posterior-medial and anterior-temporal networks were interrelated such that decreased MTL-posterior-medial connectivity was associated with increased MTL-anterior-temporal connectivity. Finally, both MTL-posterior-medial decrease and MTL-anterior-temporal increase predicted cognitive decline. INTERPRETATION: Our findings demonstrate that longitudinal connectivity changes in the posterior-medial and anterior-temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer's disease. These results shed light on the critical role of the posterior-medial and anterior-temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. ANN NEUROL 2021;90:391-406.

Evaluation of the early-phase [18F]AV45 PET as an optimal surrogate of [18F]FDG PET in ageing and Alzheimer's clinical syndrome.

Dual-phase [18F]AV45 positron emission tomography (PET) is highly promising in the assessment of neurodegenerative diseases, allowing to obtain information on both neurodegeneration (early-phase; eAV45) and amyloid deposition (late-phase; lAV45) which are highly complementary; yet eAV45 needs further evaluation. This study aims at validating eAV45 as an optimal proxy of [18F]FDG PET in a large mixed-population of healthy ageing and Alzheimer's clinical syndrome participants (n = 191) who had [18F]FDG PET, eAV45 and lAV45 scans. We found early time frame 0-4 min to give maximal correlation with [18F]FDG PET and minimal correlation with lAV45. Moreover, maximal overlap of [18F]FDG PET versus eAV45 associations with clinical diagnosis and cognition was obtained with pons scaling. Across reference regions, classification performance between clinical subgroups was similar for both eAV45 and [18F]FDG PET. These findings highlight the optimal use of eAV45 to assess neurodegeneration as a validated proxy of [18F]FDG PET. On top of this purpose, this study showed that combined [18F]AV45 PET dual-biomarker even outperformed [18F]FDG PET or lAV45 alone.

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

BACKGROUND AND PURPOSE: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria 18F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aß deposition. METHODS: From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed P<0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values. RESULTS: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism (P range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared. CONCLUSIONS: Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.

Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults.

BACKGROUND: As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults. METHODS: One hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations. RESULTS: Only physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively. CONCLUSIONS: Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.

Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer's disease.

BACKGROUND: White matter hyperintensities (WMH) are frequently found in Alzheimer's disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aß) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aß burden, glucose hypometabolism, and gray matter volume reduction. METHODS: In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aß deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. RESULTS: There were no significant associations between global Aß burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aß deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. CONCLUSIONS: This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

Resting state functional atlas and cerebral networks in mouse lemur primates at 11.7 Tesla.

Measures of resting-state functional connectivity allow the description of neuronal networks in humans and provide a window on brain function in normal and pathological conditions. Characterizing neuronal networks in animals is complementary to studies in humans to understand how evolution has modelled network architecture. The mouse lemur (Microcebus murinus) is one of the smallest and more phylogenetically distant primates as compared to humans. Characterizing the functional organization of its brain is critical for scientists studying this primate as well as to add a link for comparative animal studies. Here, we created the first functional atlas of mouse lemur brain and describe for the first time its cerebral networks. They were classified as two primary cortical networks (somato-motor and visual), two high-level cortical networks (fronto-parietal and fronto-temporal) and two limbic networks (sensory-limbic and evaluative-limbic). Comparison of mouse lemur and human networks revealed similarities between mouse lemur high-level cortical networks and human networks as the dorsal attentional (DAN), executive control (ECN), and default-mode networks (DMN). These networks were however not homologous, possibly reflecting differential organization of high-level networks. Finally, cerebral hubs were evaluated. They were grouped along an antero-posterior axis in lemurs while they were split into parietal and frontal clusters in humans.

White matter hyperintensities across the adult lifespan: relation to age, Aß load, and cognition.

BACKGROUND: White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical ß-amyloid (Aß) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. METHODS: One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aß. The relationships of total and regional WMH to age, vascular risk factors, cortical Aß, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). RESULTS: WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aß, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aß load in the models did not alter the results, and there was no interaction between WMH and Aß on cognition. CONCLUSION: WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aß load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.