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BackgroundThe brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer’s disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals.MethodsSeventy-two cognitively unimpaired older individuals aged 50–85 years (mean age = 65.2 ± 8.2 years, 37 women, 21APOEε4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau181, Aβ40, and Aβ42were measured using single-molecule array technology.ResultsIntensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t70= −5.12,p< 0.0001). After correction for age, sex, depression, andAPOEstatus, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F1,63= 6.73,pFDR= 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F1,61= 4.26,p= 0.04).ConclusionOur findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions.

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), beta-amyloid (A beta), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of A beta deposition below a threshold indicative of A beta positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of A beta and its convergence and divergence with in vivo A beta imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into A beta accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of A beta, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions.

Background Cognitive impairment is a common non-motor symptom in Parkinson's disease. So far, the underlying pathophysiology remains unclear. Several alterations in functional network connectivity have been described in Parkinson's disease patients with cognitive impairment which are probably the result of the heterogenous pathophysiology underlying this cognitive decline, including dopaminergic and cholinergic deficits. Accordingly, the reported resting-state connectivity patterns vary greatly among studies. Objective To evaluate the localization and magnitude of functional connectivity patterns in resting-state brain networks in Parkinson's disease patients with cognitive impairment by pooling data from available studies. Methods We searched PubMed, the Cochrane Library, MEDLINE, Embase and PsycINFO to identify functional MRI studies in Parkinson's disease patients with cognitive impairment. A voxel-based meta-analysis combined with quality statistics was performed, using the anisotropic effect-size version of the signed differential mapping method. Results Seventeen studies with cognitively impaired Parkinson's disease patients were included consisting of 222 Parkinson's disease patients with mild cognitive impairment, 68 patients with Parkinson's disease dementia, 289 cognitively unimpaired Parkinson's disease patients and 353 healthy controls. Parkinson's disease patients with cognitive impairment predominantly showed a reduced connectivity in specific brain regions that are part of the default mode network. Conclusion Cognitive impairment in Parkinson's disease is associated with reduced connectivity in networks relevant to cognition, most prominently the default mode network. Specific alterations in functional connectivity may contribute to cognitive decline in Parkinson patients and may be a promising future biomarker.

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods— Eleven CAA cases (median [IQR] age=69 years [65–79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68–92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results— Our results demonstrated increased IgG positivity in the frontotemporal ( P =0.044) and parietooccipital ( P =0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P =0.005 and P =0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β–positive vessels (Spearman ρ=0.71, P =0.015 and Spearman ρ=0.73, P =0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β–positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P =0.005 and Spearman ρ=0.70, P =0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions— Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.

Selective attention has been found to decline with aging, possibly depending on the sensory modality through which targets and distractors are presented. We investigated the capacity of older adults to improve performance on visual and auditory selective attention tasks. 31 younger (mean age = 22.8 years, SD = 2.1) and 29 older participants (mean age = 69.5 years, SD = 5.8) performed visual and auditory tasks with and without unimodal and cross-modal distraction across five practice sessions. Reaction time decreased with practice in both age groups. Strikingly, this performance improvement was similar across the age groups. Moreover, distractor modality did not affect performance gains in either age group. Older adults were disproportionally affected by cross-modal visual distraction, however, corroborating previous studies. This age-related effect was mitigated during the practice sessions. Finally, there was no transfer of practice to neuropsychological test performance. These results suggest a high capacity of older individuals to improve selective attention functions within and across sensory modalities.

Background: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load.Objective: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects.Methods: Thirty cognitively healthy individuals aged 40-70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance.RESULTS: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners.Conclusion: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline.

Introduction Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age‐related trajectory of cortical thickness across the lifespan (9‐59 years) in a Colombian kindred with autosomal dominant AD (ADAD). Methods Two hundred eleven participants (105 presenilin‐1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non‐carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change‐points in the age‐related trajectory of cortical thickness in carriers and non‐carriers. Results Unimpaired carriers exhibited elevated cortical thickness compared to non‐carriers, and thickness more negatively correlated with age and cognition in carriers relative to non‐carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non‐carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. Discussion Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early‐life increased thickness to atrophy proximal to clinical onset.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-beta (A beta) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before A beta in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, A beta burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked A beta-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global A beta burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

BackgroundNeuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.MethodsFourteen ADAD mutation carriers (Presenilin-1E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2–3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2–4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.ResultsLongitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.ConclusionsOur results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.

Background and purpose Primitive reflexes may reoccur in various neurodegenerative diseases. However, little is known about their structural and functional correlates in the human brain. Notably, the neural mechanisms underlying a positive palmomental reflex (PMR) are poorly understood. As recent studies link Alzheimer's disease (AD)-related primitive reflexes to a dysfunction of the corticostriatal motor circuit (CMC), we conducted the present study to investigate functional and structural correlates of a positive PMR. We hypothesized an involvement of frontostriatal structures and an impairment of the CMC. Methods Using whole-brain resting-state functional connectivity (FC), hypothesis and FC result-based probabilistic tractography, and voxel-based morphometry analyses, we compared two groups of AD patients with either positive (n = 12) or negative PMR (n = 12). Results No significant differences in grey matter volume or structural connectivity (SC) could be observed between the PMR-positive and PMR-negative groups. In contrast, the PMR-positive group showed a decreased seed-to-voxel FC between the bilateral supplementary motor area and parts of the right-hemispherical caudate nucleus and thalamus and a decreased region of interest (ROI)-to-ROI FC between the left putamen and the left superior frontal gyrus. Conclusion Data suggest that dysfunction of the CMC reflected by decreased FC underlies a positive PMR in patients with AD. The lack of significant grey matter or SC differences might reflect that changes in FC appear before changes in SC in the structures of the CMC and brain atrophy.

Neurofibrillary tau tangles are a hallmark pathology of Alzheimer's disease (AD) and are more closely associated with AD-related cortical atrophy and symptom severity than amyloid-beta (A beta). However, studies regarding the effect of tau on longitudinal cortical thinning, particularly in healthy aging and preclinical AD, have been limited in number due to the relatively recent introduction of in vivo PET tracers for imaging tau pathology. Here, we investigate [18H-flortaucipir (FTP, a marker of paired helical filament tau) PET as a predictor of atrophy in healthy aging and preclinical AD. We examine longitudinal structural MRI brain imaging data, retrospectively and prospectively relative to FTP imaging, using piecewise linear mixed-effect models with time centered a each participant's FTP-PET session. Participants include 111 individuals from the Harvard Aging Brain Study who underwent at least three MRI sessions over an average of 4.46 years and one FTP-PET at the approximate midpoint of the observation period. Our primary analyses focus on inferior temporal (IT) FTP standardized uptake value ratios and longitudinal FreeSurfer defined cortical regions of interest. Relationships were also explored using other regional FTP measures (entorhinal, composite, and local), within high and low Pittsburgh compound-B (PiB) PET groups, and with longitudinal subcortical volume. Strong associations between IT FTP and cortical thinning were found, most notably in temporal, midline, and prefrontal regions, with stronger effects generally observed in the prospective as compared to retrospective time frame. Significant differences between prospective and retrospective rates of thinning were found in the inferior and middle temporal gyri, cingulate areas, as well as pars orbitalis such that higher IT FTP was associated with greater prospective rates of thinning. Within the high PiB group, significant differences between prospective and retrospective rates of thinning were similarly observed. However, no consistent pattern of tau-related change in cortical thickness within the low PiB group was discerned. These results provide support for the hypothesis that tau pathology is a driver of future atrophy as well as provide additional evidence for tau-PET as an effective AD biomarker for interventional clinical trials.

A body of animal and human evidence points to the norepinephrine (NE) locus coeruleus (LC) system in modulating memory for arousing experiences, but whether the LC would recast its role along memory stages remains unknown. Sedation precluded examination of LC dynamics during memory processing in animals. Here, we addressed the contribution of the LC during arousal-associated memory processing through a unique combination of dedicated ultra-high-field LC-imaging methods, a well-established emotional memory task, online physiological and saliva alpha-amylase measurements in young adults. Arousal-related LC activation followed amygdala engagement during encoding. During consolidation and recollection, activation transitioned to hippocampal involvement, reflecting learning and model updating. NE-LC activation is dynamic, plays an arousal-controlling role, and is not sufficient but requires interactions with the amygdala to form adaptive memories of emotional experiences. These findings have implications for understanding contributions of LC dysregulation to disruptions in emotional memory formation, observed in psychiatric and neurocognitive disorders.

Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20–70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40–50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.

Tau tangles are a pathophysiological hallmark of Alzheimer's disease (AD) and exhibit a stereotypical pattern of spatiotemporal spread which has strong links to disease progression and cognitive decline. Preclinical evidence suggests that tau spread depends on neuronal connectivity rather than physical proximity between different brain regions. Here, we present a novel physics-informed geometric learning model for predicting tau buildup and spread that learns patterns directly from longitudinal tau imaging data while receiving guidance from governing physical principles. Implemented as a graph neural network with physics-based regularization in latent space, the model enables effective training with smaller data sizes. For training and validation of the model, we used longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI) from the Harvard Aging Brain Study. The model led to higher peak signal-to-noise ratio and lower mean squared error levels than both an unregularized graph neural network and a differential equation solver. The method was validated using both two-timepoint and three-timepoint tau PET measures. The effectiveness of the approach was further confirmed by a cross-validation study.

Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p

Judgments of learning (JOL) pertain to introspective metamemory processes evaluating how well information is learned. Using a functional magnetic resonance imaging (fMRI) task, we investigated the neural substrates of JOL predictions in a group of 105 cognitively unimpaired older adults from the Harvard Aging Brain Study. Associations of JOL performance and its neural correlates with amyloid-β (Aβ) and tau pathology, two proteinopathies associated with Alzheimer’s disease (AD) and aging, were also examined. We found that trials judged as learned well relative to trials judged as learned less well (high JOL > low JOL) engaged the ventromedial prefrontal cortex and precuneus, among other midline regions, in addition to bilateral hippocampi. In this cohort of older adults, greater levels of entorhinal tau deposition were associated with overestimation of memory performance and with lower fMRI signal in midline regions during predicted memory success. No associations with Aβ were found. The findings suggest that tau pathology in unimpaired older adults may play a role in altered metamemory processes. We discuss our findings in light of the hypothesis that JOLs are partially dependent on a process involving attempts to retrieve a correct answer from memory, as well as implications for clinical research investigating unawareness of memory performance (i.e., anosognosia) in patients with AD dementia.

Highlights • Low baseline default-mode integrity and high amyloid presage future network atrophy. • The high amyloid group drives the within-network atrophy effect. • Alzheimer’s disease-related biomarkers didn’t explain the high amyloid group’s effect. • Results support links between functional and cortical integrity and connectivity as a protective factor., Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer’s disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aβ), in clinically-normal older adults. The default-mode network (DMN), a prominent intrinsic network, is heavily implicated in AD due to its spatial overlap with AD atrophy patterns and tau deposition. We investigated the influence of baseline Aβ positron emission tomography (PET) signal and intrinsic DMN connectivity on DMN-specific cortical thinning in 120 clinically-normal older adults from the Harvard Aging Brain Study (73 ± 6 years, 58% Female, CDR = 0). Participants underwent 11C Pittsburgh Compound-B (PiB) PET, 18F flortaucipir (FTP) PET, and resting-state MRI scans at baseline and longitudinal MRI (3.6 ± 0.96 scans; 5.04 ± 0.8 years). Linear mixed models tested relationships between baseline PiB and DMN connectivity on cortical thinning in a composite of DMN regions. Lower DMN connectivity was associated with faster cortical thinning, but only in those with elevated baseline PiB-PET signal. This relationship was network specific, in that the frontoparietal control network did not account for the observed association. Additionally, the relationship was independent of inferior temporal lobe FTP-PET signal. Our findings provide evidence that compromised DMN connectivity, in the context of preclinical AD, foreshadows neurodegeneration in DMN regions.

The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc.

Introduction: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. Methods: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. Results: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. Discussion: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

See Jacobs and Buckley (doi:10.1093/brain/awy243) for a scientific commentary on this article. Despite the prevalence of white matter alterations in Alzheimer's disease, their occurrence in the presymptomatic phase is poorly understood. Araque-Caballero et al. report that diffusivity alterations occur first within the anterior and posterior callosal fibres approximately 10 years before the onset of dementia symptoms in autosomal dominant Alzheimer's disease., White matter alterations are present in the majority of patients with Alzheimer’s disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer’s disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer’s disease. In early-onset autosomal-dominantly inherited Alzheimer’s disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres—many connecting default mode network regions—between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts’ projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer’s disease pathology and microglia activity in the brain.

Based on individual circadian cycles and associated cognitive rhythms, humans can be classified via standardised self-reports as being early (EC), late (LC) and intermediate (IC) chronotypes. Alterations in neural cortical structure underlying these chronotype differences have rarely been investigated and are the scope of this study. 16 healthy male ECs, 16 ICs and 16 LCs were measured with a 3 T MAGNETOM TIM TRIO (Siemens, Erlangen) scanner using a magnetization prepared rapid gradient echo sequence. Data were analysed by applying voxel-based morphometry (VBM) and vertex-wise cortical thickness (CTh) analysis. VBM analysis revealed that ECs showed significantly lower grey matter volumes bilateral in the lateral occipital cortex and the precuneus as compared to LCs, and in the right lingual gyrus, occipital fusiform gyrus and the occipital pole as compared to ICs. CTh findings showed lower grey matter volumes for ECs in the left anterior insula, precuneus, inferior parietal cortex, and right pars triangularis than for LCs, and in the right superior parietal gyrus than for ICs. These findings reveal that chronotype differences are associated with specific neural substrates of cortical thickness, surface areas, and folding. We conclude that this might be the basis for chronotype differences in behaviour and brain function. Furthermore, our results speak for the necessity of considering "chronotype" as a potentially modulating factor in all kinds of structural brain-imaging experiments.

Background Amyloid-beta (Aβ) has a dose-response relationship with cognition in healthy adults. Additionally, the levels of functional connectivity within and between brain networks have been associated with cognitive performance in healthy adults. Aiming to explore potential synergistic effects, we investigated the relationship of inter-network functional connectivity, Aβ burden, and memory decline among healthy individuals and individuals with preclinical, prodromal, or clinical Alzheimer’s disease. Methods In this longitudinal cohort study (ADNI2), participants (55–88 years) were followed for a maximum of 5 years. We included cognitively healthy participants and patients with mild cognitive impairment (with or without elevated Aβ) or Alzheimer’s disease. Associations between memory decline, Aβ burden, and connectivity between networks across the groups were investigated using linear and curvilinear mixed-effects models. Results We found a synergistic relationships between inter-network functional connectivity and Aβ burden on memory decline. Dose-response relationships between Aβ and memory decline varied as a function of directionality of inter-network connectivity across groups. When inter-network correlations were negative, the curvilinear mixed-effects models revealed that higher Aβ burden was associated with greater memory decline in cognitively normal participants, but when inter-network correlations were positive, there was no association between the magnitude of Aβ burden and memory decline. Opposite patterns were observed in patients with mild cognitive impairment. Combining negative inter-network correlations with Aβ burden can reduce the required sample size by 88% for clinical trials aiming to slow down memory decline. Conclusions The direction of inter-network connectivity provides additional information about Aβ burden on the rate of expected memory decline, especially in the preclinical phase. These results may be valuable for optimizing patient selection and decreasing study times to assess efficacy in clinical trials. Electronic supplementary material The online version of this article (10.1186/s13195-018-0420-9) contains supplementary material, which is available to authorized users.

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status.

Background: On target F-18-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. Objective: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. Methods: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. Results: B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p< 10(-14)), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. Conclusion: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.

Locus Coeruleus (LC) is a neuromelanin-rich brainstem structure that is the source of noradrenaline in the cortex and is thought to modulate attention and memory. LC imaging in vivo is commonly performed with a 2D T 1-weighted Turbo Spin Echo (TSE) MRI sequence, an approach that suffers from several drawbacks at 3T, including long acquisition times and highly anisotropic spatial resolution. In this study, we developed a high-resolution Magnetization Transfer (MT) sequence for LC imaging at both 7T and 3T and compared its performance to a TSE sequence. Results indicate that LC imaging can be achieved with an MT sequence at both 7 and 3T at higher spatial resolution than the 3T TSE. Furthermore, we investigated whether the currently disputed source of contrast in the LC region with a TSE sequence relates to MT effects or shortened T 1 and T 2* due to increased iron concentration. Our results suggest that the contrast in the LC area relates to MT effects. To conclude, in this study we managed to image the LC, for the first time, at 7T and at an increased resolution compared to the current state-of-the-art. Imaging the LC is highly relevant for clinical diagnostics as structural tissue properties of the LC may hold promise as a biomarker in neurodegenerative diseases.

Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease.

The cerebellum has long been regarded as essential only for the coordination of voluntary motor activity and motor learning. Anatomical, clinical and neuroimaging studies have led to a paradigm shift in the understanding of the cerebellar role in nervous system function, demonstrating that the cerebellum appears integral also to the modulation of cognition and emotion. The search to understand the cerebellar contribution to cognitive processing has increased interest in exploring the role of the cerebellum in neurodegenerative and neuropsychiatric disorders. Principal among these is Alzheimer's disease. Here we review an already sizeable existing literature on the neuropathological, structural and functional neuroimaging studies of the cerebellum in Alzheimer's disease. We consider these observations in the light of the cognitive deficits that characterize Alzheimer's disease and in so doing we introduce a new perspective on its pathophysiology and manifestations. We propose an integrative hypothesis that there is a cerebellar contribution to the cognitive and neuropsychiatric deficits in Alzheimer's disease. We draw on the dysmetria of thought theory to suggest that this cerebellar component manifests as deficits in modulation of the neurobehavioural deficits. We provide suggestions for future studies to investigate this hypothesis and, ultimately, to establish a comprehensive, causal clinicopathological disease model.

Memory slowly falters as we age. A new study by Dahl and colleagues tests the involvement of a tiny region hidden in the brainstem, the locus coeruleus, which enables cellular processes of learning. Better initial learning in older individuals was related to greater integrity of this region, particularly for the part that is connected to other memory regions in the brain.

SUMMARY: Pericortical enhancement on postcontrast FLAIR images is a marker for subtle leptomeningeal blood-brain barrier leakage. We explored the optimal FLAIR sequence parameters for the detection of low gadolinium concentrations within the CSF. On the basis of phantom experiments and human in vivo data, we showed that detection of subtle pericortical enhancement can be facilitated by using a relatively long TE. Future studies should choose their FLAIR sequence parameters carefully when assessing pericortical enhancement due to subtle blood-brain barrier leakage.

Key PointsQuestionIs cognitive decline associated with amyloid-beta or tau tangles accumulation? FindingsIn this cohort study that included 60 normal older adults with repeated positron emission tomography measures, the rate of tau accumulation in the inferior temporal neocortex was associated with the rate of cognitive decline. Amyloid accumulation was associated with subsequent tau accumulation, and this sequence of successive amyloid and tau changes in neocortex was found to mediate the association of initial amyloid with final cognition, measured 7 years later. MeaningAmyloid positron emission tomography is useful to detect early Alzheimer pathology; repeated tau positron emission tomography is useful to track disease progression.ImportancePositron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-beta (A beta) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. ObjectiveTo assess the associations among A beta, tau, and cognition, measured during different observation periods for 7 years. Design, Setting, and ParticipantsProspective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple A beta and tau PET observations available on October 31, 2017. Main Outcomes and MeasuresA median of 3 Pittsburgh compound B-PET (A beta, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in A beta and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. ResultsOf the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high A beta burden. An antecedent rise in A beta was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P=.02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P=.001), covarying baseline A beta and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n=6) than in those who did not (n=11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P=.001). A serial mediation model demonstrated that the association between initial A beta and final cognition, measured 7 years later, was mediated by successive changes in A beta and tau. Conclusions and RelevanceWe identified sequential changes in normal older adults, from A beta to tau to cognition, after which the participants with high A beta with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.This cohort study assesses the associations among amyloid-beta, tau, and cognition, measured during different observation periods for 7 years.

Highlights • Decreased meta-memory processing is related to tauopathy. • No association was found with amyloid pathology. • Decreased meta-memory may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase., The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase.

Graph convolutional neural networks (GCNNs) aim to extend the data representation and classification capabilities of convolutional neural networks, which are highly effective for signals defined on regular Euclidean domains, e.g. image and audio signals, to irregular, graph-structured data defined on non-Euclidean domains. Graph-theoretic tools that enable us to study the brain as a complex system are of great significance in brain connectivity studies. Particularly, in the context of Alzheimer's disease (AD), a neurodegenerative disorder associated with network dysfunction, graph-based tools are vital for disease classification and staging. Here, we implement and test a multi-class GCNN classifier for network-based classification of subjects on the AD spectrum into four categories: cognitively normal, early mild cognitive impairment, late mild cognitive impairment, and AD. We train and validate the network using structural connectivity graphs obtained from diffusion tensor imaging data. Using receiver operating characteristic curves, we show that the GCNN classifier outperforms a support vector machine classifier by margins that are reliant on disease category. Our findings indicate that the performance gap between the two methods increases with disease progression from CN to AD. We thus demonstrate that GCNN is a competitive tool for staging and classification of subjects on the AD spectrum.

We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56–89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ1–42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of Aβ1–42, sex, and APOEe4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal Aβ1–42 and APOEe4 but not with sex. Longitudinally, low baseline CSF Aβ1–42 levels, but not APOEe4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF Aβ1–42 and tau accumulation was strongest in APOEe4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF Aβ1–42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease.

IMPORTANCE Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) epsilon 4 status and beta-amyloid (A beta). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.OBJECTIVE To examine sex differences in the cross-sectional association between A beta and regional tau deposition as measured with positron emission tomography (PET).DESIGN, SETTING AND PARTICIPANTS This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and A beta PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F-18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET.MAIN OUTCOMES AND MEASURES A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global A beta as well as sex and APOE epsilon 4 on these regions after controlling for age were also examined.RESULTS The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE epsilon 4 carriers [31%]; 89 individuals [30%] with high A beta. There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: beta [male] = -0.11 [0.05]; 95% CI,-0.21 to -0.02; P=.02), which was associated with individuals with higher AB burden. A sex by APOE epsilon 4 interaction was not associated with regional tau (meta-analytic estimate: beta [male, APOE epsilon 4+] = -0.15 [0.09]; 95% Cl, -0.32 to 0.01; P=.07).CONCLUSIONS AND RELEVANCE Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.