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Contains fulltext : 248857.pdf (Publisher’s version ) (Open Access) Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

Contains fulltext : 292515.pdf (Publisher’s version ) (Open Access) It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure.Significance statementAccording to consensus recommendations, adults should sleep between 7 and 9 hours to optimize their health. We found that sleeping less than the recommended amount was associated with greater regional brain volumes relative to intracranial volume, and very short sleep was only weakly related to smaller volumes. Genetic analyses did not show causal effects of sleep duration on brain structure. Taken together, the results suggest that habitual short sleep is not an important contributor to lower brain volumes in adults on a group level, and that large individual dfferences in sleep need likely exist.

Contains fulltext : 235500.pdf (Publisher’s version ) (Open Access) Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization. 22 p.

Contains fulltext : 228447.pdf (Publisher’s version ) (Open Access) We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults. 17 p.

The combination of transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) can provide original data to investigate age-related brain changes. We examined neural activity modulations induced by two multifocal tDCS procedures based on two distinct montages fitting two N-back task-based fMRI patterns ("compensatory" and "maintenance") related to high working memory (WM) in a previous publication (Fernández-Cabello et al. Neurobiol Aging (2016);48:23-33). We included 24 participants classified as stable or decliners according to their 4-year WM trajectories following a retrospective longitudinal approach. Then, we studied longitudinal fMRI differences between groups (stable and decliners) and across multifocal tDCS montages ("compensatory" and "maintenance") applied using a single-blind sham-controlled cross-over design. Decliners evidenced over-activation of non-related WM areas after 4 years of follow-up. Focusing on tDCS effects, among the decliner group, the "compensatory"-tDCS montage reduced the activity over the posterior regions where these subjects showed longitudinal hyperactivation. These results reinforce the notion that tDCS effects are characterized by an activity reduction and might be more noticeable in compromised systems. Importantly, the data provide novel evidence that cognitive trajectories predict tDCS effects in older adults.

Background and Objectives A healthy brain is central to physical and mental well-being. In this multi-site, qualitative study, we investigated views and attitudes of adult participants in brain research studies on the brain and personalized brain health as well as interest in maintaining a healthy brain. Design and Methods We conducted individual interviews with 44 adult participants in brain research cohorts of the Lifebrain consortium in Spain, Norway, Germany, and the United Kingdom. The interviews were audio recorded, transcribed, and coded using a cross-country codebook. The interview data were analyzed using qualitative content analysis. Results Most participants did not focus on their own brain health and expressed uncertainty regarding how to maintain it. Those actively focusing on brain health often picked one specific strategy like diet or memory training. The participants were interested in taking brain health tests to learn about their individual risk of developing brain diseases, and were willing to take measures to maintain their brain health if personalized follow-up was provided and the measures had proven impact. The participants were interested in more information on brain health. No differences in responses were identified between age groups, sex, or countries. Discussion and Implications Concise, practical, personalized, and evidence-based information about the brain may promote brain health. Based on our findings, we have launched an ongoing global brain health survey to acquire more extensive, quantitative, and representative data on public perception of personalized brain health.

While development and aging of the cerebral cortex show a similar topographic organization and are mainly governed by the same genes, it is unclear whether the same is true for subcortical structures, which follow fundamentally different ontogenetic and phylogenetic principles than the cerebral cortex. To test the hypothesis that genetically governed neurodevelopmental processes can be traced in subcortical structures throughout life, we analyzed a longitudinal magnetic resonance imaging dataset (n = 974, age 4-89 years), identifying five clusters of longitudinal change in development. With some exceptions, these clusters followed placement along the cranial axis in embryonic brain development, suggesting continuity in the pattern of change from prenatal stages. Developmental change patterns were conserved through the lifespan and predicted general cognitive function in an age-invariant manner. The results were replicated in longitudinal data from the Lifebrain consortium (n = 756, age 19-83 years). Genetic contributions to longitudinal brain changes were calculated from the Vietnam Era Twin Study of Aging (n = 331 male twins, age 51-60 years), revealing that distinct sets of genes tended to govern change for each developmental cluster. This finding was confirmed with single nucleotide polymorphisms and cross-sectional MRI data from the UK Biobank (n = 20,588, age 40-69), demonstrating significantly higher co-heritability among structures belonging to the same developmental clusters. Together, these results suggest that coordination of subcortical change adheres to fundamental principles of lifespan continuity, genetic organization and age-invariant relationships to cognitive function.Significance statementHere we show that subcortical change during childhood development is organized in clusters. These clusters tend to follow the main gradient of embryonic brain development, and are stable across life. This means that subcortical regions changing together in childhood also change together throughout the rest of life, in accordance with a lifespan perspective on brain development and aging. Twin and single nucleotide polymorphism-based heritability analyses in middle-aged and older adults showed that volume and volume change of regions within each developmental cluster tended to be governed by the same sets of genes. Thus, volumetric changes across subcortical regions are tightly organized, and the coordinated change can be described in a lifespan perspective according to ontogenetic and genetic influences.

BackgroundAdvancing age affects the brain’s resting-state functional networks. Combining non-invasive brain stimulation (NIBS) with neuroimaging is a promising approach to modulate activity across resting-state functional systems and explore their true contribution to cognitive function in aging. However, substantial individual variability in the response to NIBS has been reported and, hence, identifying the individual predictors of NIBS-induced modulatory effects is crucial if we are to harness their potential.MethodsThirty-one cognitively healthy older adults (71.68 ± 2.5 years; 19 females) underwent two different multifocal real tDCS conditions (C1 and C2) and a sham condition in a crossover design during a resting-state functional magnetic resonance imaging (rs-fMRI) acquisition. The real tDCS conditions were designed to induce two distinct electric field distribution patterns either targeting generalized cortical overactivity or a dissociation between the frontal areas and the posteromedial cortex. Stimulation was delivered through an MRI-compatible device using 8 small circular electrodes. Each individuals’ anatomical T1-weighted MRI was used to generate a finite element model to define the individual electric field generated by each tDCS condition.ResultsThe two tDCS conditions modulated resting-state connectivity differently. C1 increased the coactivation of numerous functional couplings as compared to sham, however, a smaller amount of connections increased in C1 as compared to C2, while no differences between C2 and sham were appreciated. At the group level, C1-induced modulations primarily included temporo-occipital areas and distinct cerebellar regions. This functional pattern was anatomically consistent with the estimated distribution of the induced electric field in the C1 condition. Finally, at the individual level, the extent of tDCS-induced rs-fMRI modulation in C1 was predicted by baseline resting-state connectivity and simulation-based electric field magnitude.DiscussionOur results highlighted that multifocal tDCS procedures can effectively change neural dynamics in the elderly consistently with the spatial distribution of the estimated electric fields on the brain. Furthermore, we showed that specific brain factors that have been revealed to explain part of the individual variability to NIBS in young samples are also relevant in older adults. In accordance, designing multifocal tDCS configurations based on specific fMRI patterns appears to be a valuable approach to precisely adjust those complex neural dynamics sustaining cognition that are affected as a function of age. Furthermore, these innovative NIBS-based interventions should be individually-tailored based on subject-specific structural and functional data to ultimately boost their potential in aged populations.

BackgroundTo test the hypothesis that worse self-reported sleep relates to memory decay and reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that the relations are stronger in the presence of β-amyloid (Aβ) accumulation, a marker of Alzheimer’s disease (AD) pathology.MethodsTwo-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity. We measured memory decay using delayed recall from the California Verbal Learning Test. 18F-Flutemetamol positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled controlling for APOE ε4 status, and polygenic scores for sleep efficiency and AD.ResultsWorse global sleep quality and sleep efficiency related to more rapid reduction in hippocampal microstructural integrity over time. Focusing on sleep efficiency, the relation was stronger in presence of Aβ accumulation. Sleep efficiency related to memory decay indirectly via hippocampal integrity decline. The results were not explained by genetic risk for sleep efficiency and AD.ConclusionsPoor self-reported sleep efficiency related to decline in hippocampal integrity, especially in the presence of Aβ accumulation. Poor sleep and hippocampal microstructural decline may partly explain memory decline in older adults with Aβ pathology. The relationships were not explained by genetic risk. Poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations remain unknown.

BackgroundOlder persons with poor sleep are more likely to develop neurodegenerative disease, but the causality underlying this association is unclear. To move towards explanation, we examine whether sleep quality and quantity are similarly associated with brain changes across the adult lifespan.MethodsAssociations between self-reported sleep parameters (Pittsburgh Sleep Quality Index;PSQI) and longitudinal cortical change were tested using five samples from theLifebrainconsortium (n=2205, 4363 MRIs, 18-92 years). Analyses were augmented by considering episodic memory change, gene expression from the Allen Human Brain Atlas, and amyloid-beta (Aβ) accumulation (n=1980).ResultsPSQI components sleep problems and low sleep quality were related to thinning of the right lateral temporal cortex. The association with sleep problems emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. BMI and symptoms of depression had negligible effects. Sleep problems were neither related to longitudinal change in episodic memory function nor to Aβ accumulation, suggesting that sleep-related cortical changes were independent of AD neuropathology and cognitive decline.ConclusionWorse self-reported sleep in later adulthood was associated with more cortical thinning in regions of high expression of genes related to oligodendrocytes and S1 pyramidal neurons, but not to Aβ accumulation or memory decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes, except for a few restricted regions, indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

Introduction The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic‐memory decline in non‐demented individuals remains unclear. Methods We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)–derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European Lifebrain consortium. Results The change‐change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non‐carriers: N = 467, r = 0.073, P = .117). The linear relationship was significantly steeper for the carriers [t(629) = 2.4, P = .013]. A similar trend toward a stronger change‐change relation for carriers was seen in a subsample with more than two assessments. Discussion These findings provide evidence for a difference in hippocampus‐memory association between ε4 carriers and non‐carriers, thus highlighting how genetic factors modulate the translation of the AD‐related pathophysiological cascade into cognitive deficits.

Adults with psychotic disorders have abnormal connectivity of fronto-temporal networks. However, whether these abnormalities are present in adolescents with early psychosis has not been fully assessed. One-hundred and thirty-nine adolescents aged 12-18 underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging. Following motion correction, data were available for 44 participants with a psychosis risk syndrome, 34 patients with a first episode psychosis (FEP) and 35 healthy controls. Independent component analysis was performed to assess functional networks showing a fronto-temporal scope; this identified a language and a salience network. Mean fractional anisotropy was measured in clusters showing between-group differences in intrinsic functional connectivity (iFC). For the language network, there was a group effect within the right middle/inferior frontal gyrus, explained by reduced iFC in patients with an FEP relative to healthy controls, while in participants with a psychosis risk syndrome values of iFC were intermediate. In this region, values of iFC were positively correlated with mean fractional anisotropy in patients with an FEP. No group differences were observed in the salience network. Reduced iFC of the language network, in association with disrupted white matter microstructure, may characterize FEP during adolescence.

BackgroundPoor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan.MethodsSelf-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants, covering up to 11 years. Cross-sectional analyses were repeated in a sample of 21390 participants from the UK Biobank.ResultsThe relationship between self-reported sleep and age differed across sleep items. Sleep duration, efficiency, problems, and use of medication worsened monotonously with age, whereas subjective sleep quality, sleep latency, and daytime tiredness improved. Women reported worse sleep in general than men, but the relationship to age was similar. No cross-sectional sleep – hippocampal volume relationships was found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing on average 0.22% greater annual loss than low scorers. Simulations showed that longitudinal effects were too small to be detected as age-interactions in cross-sectional analyses.ConclusionsWorse self-reported sleep is associated with higher rates of hippocampal decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.

Highlights • We assessed intrinsic connectivity of networks underlying cognition in youth. • Evidence of age effects on intrinsic connectivity was found across all networks. • Intrinsic connectivity showed no effect of sex, nor age by sex interactions., There is limited evidence on the effects of age and sex on intrinsic connectivity of networks underlying cognition during childhood and adolescence. Independent component analysis was conducted in 113 subjects aged 7–18; the default mode, executive control, anterior salience, basal ganglia, language and visuospatial networks were identified. The effect of age was examined with multiple regression, while sex and ‘age × sex’ interactions were assessed by dividing the sample according to age (7–12 and 13–18 years). As age increased, connectivity in the dorsal and ventral default mode network became more anterior and posterior, respectively, while in the executive control network, connectivity increased within frontoparietal regions. The basal ganglia network showed increased engagement of striatum, thalami and precuneus. The anterior salience network showed greater connectivity in frontal areas and anterior cingulate, and less connectivity of orbitofrontal, middle cingulate and temporoparietal regions. The language network presented increased connectivity of inferior frontal and decreased connectivity within the right middle frontal and left inferior parietal cortices. The visuospatial network showed greater engagement of inferior parietal and frontal cortices. No effect of sex, nor age by sex interactions was observed. These findings provide evidence of strengthening of cortico-cortical and cortico-subcortical networks across childhood and adolescence.

Objective Cortical surface area and thickness abnormalities have been observed in patients with schizophrenia and bipolar disorders; however, no study thus far has examined cortical morphologic measurements in children and adolescents at genetic risk for the disorders comparatively. Method One hundred thirty-seven participants, including 36 offspring of patients with schizophrenia (SzO), 54 offspring of patients with bipolar disorder (BpO), and 47 offspring of community controls (CcO), 6 to 17 years old, were assessed with clinical and neuroimaging methods. Sixty-nine percent of the sample was reassessed at a 27.6-month (mean) follow-up. Cortical surface reconstruction was applied to measure cortical area and thickness using FreeSurfer; mixed-effects models were used to investigate cross-sectional and longitudinal differences in global and lobar morphologic measurements. Results The SzO group exhibited a cross-sectional decrease in global, parietal, and occipital lobe surface area compared with the CcO group, and in the occipital lobe compared with the BpO group. In the SzO group, global and parietal surface area values were inversely associated with attenuated positive and negative prodromal symptom scores. No cross-sectional differences in cortical thickness were observed. Division of the sample by pubertal status showed group-by-time interactions in the pubertal and postpubertal SzO subgroup, with less longitudinal decrease in cortical surface area and thickness than in the CcO and BpO subgroups, respectively. Conclusion The SzO, but not the BpO, group was characterized by cross-sectional decreases in surface area, and this was associated with prodromal symptoms. Longitudinal changes in cortical morphology associated with risk for schizophrenia may be expressed differently according to developmental stage.

White matter (WM) damage has been reported in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in diffusion tensor imaging (DTI) studies. It is, however, unknown how the investigation of multiple tensor indexes in the same patients, can differentiate them from normal aging or relate to patients cognition. Forty-six individuals (15 healthy, 16 a-MCI and 15 AD) were included. Voxel-based tract based spatial-statistics (TBSS) was used to obtain whole-brain maps of main WM bundles for fractional anisotropy (FA), radial diffusivity (DR), axial diffusivity (DA) and mean diffusivity (MD). FA reductions were evidenced among AD patients with posterior predominance. A-MCI patients displayed reduced mean FA in these critical regions, compared to healthy elders. MD increases were widespread in both groups of patients. Interestingly, a-MCI patients exhibited DR increases in overlapping areas of FA shrinkages in AD, whereas DA increases were only observed in AD. Gray matter atrophy explained most DTI differences, except those regarding MD in both groups as well as DR increases in posterior associative pathways among a-MCI cases. FA values were the only DTI measure significantly related to memory performance among patients. Present findings suggest that most DTI-derived changes in AD and a-MCI are largely secondary to gray matter atrophy. Notably however, specific DR signal increases in posterior parts of the inferior fronto-occipital and longitudinal fasciculi may reflect early WM compromise in preclinical dementia, which is independent of atrophy. Finally, global measures of integrity, particularly orientation coherence (FA) of diffusion, appear to be more closely related to the cognitive profile of our patients than indexes reflecting water movement parallel (DA) and perpendicular (DR) to the primary diffusion direction.

Objective We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosed using the new research criteria in a clinical setting. In order to further characterize these patients, we also study the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging (MRI) findings. Methods/Patients 76 participants—24 controls (CTR), 20 amnesic patients, and 32 Alzheimer's disease (AD) patients—were included in the study. PrdAD was defined on the basis of an objective episodic memory deficit and an AD CSF profile. Structural MRI was performed in all participants. Results After FWE correction, voxel-based morphometry (VBM) analysis of PrdAD patients versus CTR showed significant clusters of decreased gray matter (GM) volume in the left hemisphere regions including the parahippocampal gyrus, uncus, precuneus, and middle frontal gyrus. We did not find differences in brain atrophy between PrdAD and mild AD patients. Some significant associations were found between CSF levels and episodic and semantic fluency tests in the PrdAD group. Correlations in the PrdAD group revealed that patients with higher scores on delayed free recall had significantly greater GM volume in the left superior temporal gyrus (t = 6.64, p

The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), t-tau, and p-tau and cognitive performance along the Alzheimer's disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ(1-42), t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ(1-42) levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = -0.483; p < 0.005) and p-tau levels (r = -0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = -0.420; p < 0.005) and p-tau levels (r = -0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ(1-42) levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ(1-42) levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage.

Introduction Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology in order to minimize clinical manifestations. Previous studies showed that CR modulates the patterns of brain activity in both healthy and clinical populations. In the present study we sought to determine whether reorganizations of functional brain resources linked to CR could already be observed in amnestic mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD) patients when performing a task corresponding to an unaffected cognitive domain. We further investigated if activity in regions showing task-induced deactivations, usually identified as pertaining to the default-mode network (DMN), was also influenced by CR. Methods Fifteen healthy elders, 15 a-MCI and 15 AD patients underwent functional magnetic resonance imaging (fMRI) during a speech comprehension task. Differences in the regression of slopes between CR proxies and blood-oxygen-level dependent (BOLD) signals across clinical groups were investigated for activation and deactivation areas. Correlations between significant fMRI results and a language comprehension test were also computed. Results Among a-MCI and AD we observed positive correlations between CR measures and BOLD signals in task-induced activation areas directly processing speech, as well as greater deactivations in regions of the DMN. These relationships were inverted in healthy elders. We found no evidence that these results were mediated by gray matter volumes. Increased activity in left frontal areas and decreased activity in the anterior cingulate were related to better language comprehension in clinical evaluations. Conclusions The present findings provide evidence that the neurofunctional reorganizations related to CR among a-MCI and AD patients can be seen even when considering a preserved cognitive domain, being independent of gray matter atrophy. Areas showing both task-induced activations and deactivations are modulated by CR in an opposite manner when considering healthy elders versus patients. Brain reorganizations facilitated by CR may reflect behavioral compensatory mechanisms.

Cognitive reserve (CR) is the brain's capacity to cope with cerebral damage to minimize clinical manifestations. The 'passive model' considers head or brain measures as anatomical substrates of CR, whereas the 'active model' emphasizes the use of brain networks effectively. Sixteen healthy subjects, 12 amnestic mild cognitive impairment (MCI) and 16 cases with mild Alzheimer's disease (AD) were included to investigate the relationships between proxies of CR and cerebral measures considered in the 'passive' and 'active' models. CR proxies were inferred premorbid IQ (WAIS Vocabulary test), 'education-occupation', a questionnaire of intellectual and social activities and a composite CR measure. MRI-derived whole-brain volumes and brain activity by functional MRI during a visual encoding task were obtained. Among healthy elders, higher CR was related to larger brains and reduced activity during cognitive processing, suggesting more effective use of cerebral networks. In contrast, higher CR was associated with reduced brain volumes in MCI and AD and increased brain function in the latter, indicating more advanced neuropathology but that active compensatory mechanisms are still at work in higher CR patients. The right superior temporal gyrus (BA 22) and the left superior parietal lobe (BA 7) showed greatest significant differences in direction of slope with CR and activation between controls and AD cases. Finally, a regression analysis revealed that fMRI patterns were more closely related to CR proxies than brain volumes. Overall, inverse relationships for healthy and pathological aging groups emerged between brain structure and function and CR variables.

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Despite the increasing aging population and the high prevalence of OSA in elderly adults, little is known about cognitive effects of OSA and the effectiveness of CPAP treatment. Therefore, this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment.This randomized, evaluator-blinded, parallel-group, single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome. Thirty-three patients were assigned to receive either conservative care (CC) or CPAP plus CC for 3 months. At baseline and 3 months after treatment, patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network (DMN) and of cortical thickness.Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline. By contrast, after CPAP treatment, patients showed a significant improvement in episodic (between-group difference in change, 7.60; 95% CI, 1.66-13.55; P = .014) and short-term memory (between-group difference in change, 1.06; 95% CI, 0.10-2.01; P = .032) and in executive function (speed of mental processing, 5.74; 95% CI, 1.69-9.79; P = .007; mental flexibility, -47.64; 95% CI, -81.83 to -13.45; P = .008), whereas no changes were observed in the CC group. Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group. No association was seen between cognition and brain functional connectivity changes within the DMN.Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment. Moreover, CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning.ClinicalTrials.gov; No.: NCT01826032; URL: www.clinicaltrials.gov.

Previous reports have suggested an association between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Normal pressure hydrocephalus (NPH) is considered to be an example of reversible dementia although the clinical improvement after shunting varies from subject to subject. An association has been suggested between vascular risk factors and the development of NPH. The ACE plays a major role in vascular pathology and physiology. In the present study we investigated the distribution of an ACE gene insertion/deletion polymorphism in 112 patients diagnosed with NPH and in 124 controls. We also evaluated the role of this genetic polymorphism in cognitive functioning before and following surgery in a subgroup of 72 patients. No differences in genetic or allele distributions were found between patients and healthy subjects, but among patients, carriers of D/D or D/I genotypes obtained less cognitive benefit following shunt surgery, especially on measures of memory and frontal function. Our data support previous findings in other conditions indicating that possession of at least one D allele is associated with poorer cognitive performance.

Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer's disease (AD) and is a high-risk condition for dementia. The endothelial nitric oxide synthase (NOS3) gene encodes endothelial NOS, an enzyme that regulates the production of the vasodilatory nitric oxide associated with the cerebral small vessel pathology observed in early AD. We studied the distribution of genotype and allele frequencies of the NOS3 Glu/Asp polymorphism in a sample of 62 MCI subjects and 136 controls. Though no association between NOS3 gene variation and MCI status was observed, MCI cases carrying the Asp variant (T+) performed worse in the Mini-Mental State Examination, Wechsler Memory Scale (Revised) long-term visual memory and the phonetic verbal fluency tests. These results suggest that the T allele is a genetic risk factor for cognitive impairment in the elderly.