A microRNA signature that correlates with cognition and is a target against cognitive decline.

While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

Resting-State Network Alterations Differ between Alzheimer's Disease Atrophy Subtypes.

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline.

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.

Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status.

BACKGROUND: Amyloid-ß accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer's continuum in the 2018 NIA-AA research framework. OBJECTIVE: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. METHODS: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAß+) and amyloidnegative SCD (SCDß-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB). RESULTS: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAß+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAß+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAß+) and precuneus SUVRFBB (both groups). CONCLUSION: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAß+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-ß load, highlighting incipient pathology in stage 2 of the AD continuum.

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum.

BACKGROUND: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. METHODS: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aß42/40 biomarker data, which was available in a subset of participants. RESULTS: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aß42/40 stratified analyses largely matched these results. CONCLUSIONS: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.

Dopamine replacement modulates oscillatory coupling between premotor and motor cortical areas in Parkinson's disease.

Efficient neural communication between premotor and motor cortical areas is critical for manual motor control. Here, we used high-density electroencephalography to study cortical connectivity in patients with Parkinson's disease (PD) and age-matched healthy controls while they performed repetitive movements of the right index finger at maximal repetition rate. Multiple source beamformer analysis and dynamic causal modeling were used to assess oscillatory coupling between the lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1) in the contralateral hemisphere. Elderly healthy controls showed task-related modulation in connections from lPM to SMA and M1, mainly within the γ-band (>30 Hz). Nonmedicated PD patients also showed task-related γ-γ coupling from lPM to M1, but γ coupling from lPM to SMA was absent. Levodopa reinstated physiological γ-γ coupling from lPM to SMA and significantly strengthened coupling in the feedback connection from M1 to lPM expressed as ß-ß as well as θ-ß coupling. Enhancement in cross-frequency θ-ß coupling from M1 to lPM was correlated with levodopa-induced improvement in motor function. The results show that PD is associated with an altered neural communication between premotor and motor cortical areas, which can be modulated by dopamine replacement.