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Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.

BackgroundImpaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates.MethodsWe examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z-scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog.ResultsPD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI.ConclusionsSimilar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

IMPORTANCE: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, and PARTICIPANTS: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03094546.

To investigate whether physical and cognitive fitness measured in late adolescence was associated with future risk of Parkinson’s disease (PD). The cohort included 1,259,485 Swedish men with physical fitness, body mass index (BMI), resting heart rate (RHR), blood pressure, intelligence quotient (IQ), and stress resilience measured at the age of 17–20 in relation to conscription. Incident cases of PD were ascertained from the Swedish Patient Register. Hazard ratios were estimated from Cox models, after controlling for multiple confounders. We further performed Mendelian randomization (MR) analyses to assess the causality of the associations, using GWAS summary statistics with > 800,000 individuals. During follow-up, we identified 1,034 cases of PD (mean age at diagnosis = 53). Men with an RHR > 100 beats per minute had a higher risk of PD compared to men with an RHR of 60–100 beats per minute (HR = 1.47; 95% CI = 1.08–1.99). Men with IQ above the highest tertile had a higher risk of PD compared to men with an IQ below the lowest tertile (HR = 1.46; 95% CI = 1.19–1.79). We found no association for physical fitness, BMI, blood pressure, or stress resilience. A causal relationship was suggested by the MR analysis between IQ and PD, but not between RHR and PD. RHR and IQ in late adolescence were associated with a higher risk of PD diagnosed at relatively young age. The association of IQ with PD is likely causal, whereas the association of RHR with PD suggests that altered cardiac autonomic function might start before 20 years of age in PD. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00730-y.

Human cognitive abilities decline with increasing chronological age, with decreased explicit memory performance being most strongly affected. However, some older adults show “successful aging,” that is, relatively preserved cognitive ability in old age. One explanation for this could be higher brain-structural integrity in these individuals. Alternatively, the brain might recruit existing resources more efficiently or employ compensatory cognitive strategies. Here, we approached this question by testing multiple candidate variables from structural and functional neuroimaging for their ability to predict chronological age and memory performance, respectively. Prediction was performed using support vector machine (SVM) classification and regression across and within two samples of young (N = 106) and older (N = 153) adults. The candidate variables were (1) behavioral response frequencies in an episodic memory test; (2) recently described functional magnetic resonance imaging (fMRI) scores reflecting preservation of functional memory networks; (3) whole-brain fMRI contrasts for novelty processing and subsequent memory; (4) resting-state fMRI maps quantifying voxel-wise signal fluctuation; and (5) gray matter volume estimated from structural MRIs. While age group could be reliably decoded from all variables, chronological age within young and older subjects was best predicted from gray matter volume. In contrast, memory performance was best predicted from task-based fMRI contrasts and particularly single-value fMRI scores, whereas gray matter volume has no predictive power with respect to memory performance in healthy adults. Our results suggest that superior memory performance in healthy older adults is better explained by efficient recruitment of memory networks rather than by preserved brain structure.

Seizure-related gene 6 (Sez6), Sez6-Like (Sez6L), and Sez6-Like 2 (Sez6L2) comprise a family of homologous proteins widely expressed throughout the brain that have been linked to neurodevelopmental and psychiatric disorders. Here, we use Sez6 triple knockout (TKO) mice, which lack all three Sez6 family proteins, to demonstrate that Sez6 family proteins regulate dendritic spine structure and cognitive functions, motor learning, and maintenance of motor functions across the lifespan. Compared to WT controls, we found that Sez6 TKO mice had impaired motor learning and their motor coordination was negatively affected from 6 weeks old and declined more rapidly as they aged. Sez6 TKO mice had reduced spine density in the hippocampus and dendritic spines were shifted to more immature morphologies in the somatosensory cortex. Cognitive testing revealed that they had enhanced stress responsiveness, impaired working, and spatial short-term memory but intact spatial long-term memory in the Morris water maze albeit accompanied by a reversal deficit. Our study demonstrates that the lack of Sez6 family proteins results in phenotypes commonly associated with neuropsychiatric disorders making it likely that Sez6 family proteins contribute to the complex etiologies of these disorders.

Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy. Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study. Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and 7), cognitive testing at examination cycle 7 (present study baseline: 1998–2001) and after a mean±SD of 6.6±1.1 years from baseline (n = 1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n = 1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses. Results: Higher MIND diet scores were associated with better global cognitive function (β±SE,+0.03SD±0.01; p = 0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, and SBIs) or cognitive decline. Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline.

Adult neurogenesis in the hippocampal dentate gyrus (DG) is an extraordinary form of plasticity fundamental for cognitive flexibility. Recent evidence showed that newborn neurons differentially modulate input to the infra- and supra-pyramidal blades of the DG during the processing of spatial and contextual information, respectively. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved both memory precision and flexibility. Interestingly, each of these gains was associated with distinct subregional patterns of activity and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision and indexing and suggests their anatomical allocation within specific DG-CA3 compartments, together contributing to cognitive flexibility.

Neurodegenerative diseases such as Parkinson's disease (PD) have a huge impact on patients, caregivers, and the health-care system. To date, the diagnosis of mild cognitive impairments in PD has been established based on domain-general functions such as executive functions, attention, or working memory. However, specific numerical deficits observed in clinical practice have not yet been systematically investigated. PD-immanent deterioration of domain-general functions and domain-specific numerical areas suggests the mechanisms of both primary and secondary dyscalculia. The current study will systematically investigate basic number processing performance in PD patients for the first time, targeting domain-specific cognitive representations of numerosity and the influence of domain-general factors. The overall sample consists of patients with a diagnosis of PD, according to consensus guidelines, and healthy controls. PD patients will be stratified into patients with normal cognition or mild cognitive impairment (level I-PD-MCI based on cognitive screening). Basic number processing will be assessed using transcoding, number line estimation, and (non)symbolic number magnitude comparison tasks. Discriminant analysis will be employed to assess whether basic number processing tasks can differentiate between a healthy control group and both PD groups. All participants will be subjected to a comprehensive numerical and a neuropsychological test battery, as well as sociodemographic and clinical measures. Study results will give the first broad insight into the extent of basic numerical deficits in different PD patient groups and will help us to understand the underlying mechanisms of the numerical deficits faced by PD patients in daily life.

Background There is growing evidence for a positive correlation between measures of muscular strength and cognitive abilities. However, the neurophysiological correlates of this relationship are not well understood so far. The aim of this study was to investigate cortical hemodynamics [i.e., changes in concentrations of oxygenated (oxyHb) and deoxygenated hemoglobin (deoxyHb)] as a possible link between measures of muscular strength and cognitive performance. Methods In a cohort of younger adults (n = 39, 18–30 years), we assessed (i) handgrip strength by a handhold dynamometer, (ii) short-term working memory performance by using error rates and reaction times in the Sternberg task, and (iii) cortical hemodynamics of the prefrontal cortex (PFC) via functional near-infrared spectroscopy (fNIRS). Results We observed low to moderate negative correlations (rp = ~ − 0.38 to − 0.51; p p = ~ 0.34 to 0.45; p p (35) = 0.401; p = 0.014) and lower levels of deoxyHb (rp (34) = − 0.338; p = 0.043) in specific parts of the PFC were linked to higher percentage of correct answers. We also found low to moderate correlations (p p = ~ 0.35; p p = ~ − 0.25 to − 0.49; p 0.05). Conclusion The present study provides evidence for a positive neurobehavioral relationship between cortical hemodynamics and cognitive performance. Our findings further imply that in younger adults higher levels of handgrip strength positively influence cortical hemodynamics although the latter did not necessarily culminate in better cognitive performance. Future research should examine whether the present findings can be generalized to other cohorts (e.g., older adults).

ObjectiveTo evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.MethodsIn this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.ResultsNineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p= 0.003), total tau (p< 0.001), and phosphorylated tau (p= 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r= 0.64,p= 0.003), neuropsychiatric symptoms (r= 0.73,p< 001), motor evoked potential latency (r= 0.48,p= 0.030), and parietal lobe atrophy.ConclusionsOur study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

Despite a growing number of functional MRI studies reporting exercise-induced changes during cognitive processing, a systematic determination of the underlying neurobiological pathways is currently lacking. To this end, our neuroimaging meta-analysis included 20 studies and investigated the influence of physical exercise on cognition-related functional brain activation. The overall meta-analysis encompassing all experiments revealed physical exercise-induced changes in the left parietal lobe during cognitive processing. Subgroup analysis further revealed that in the younger-age group (< 35years old) physical exercise induced more widespread changes in the right hemisphere, whereas in the older-age group (≥ 35years old) exercise-induced changes were restricted to the left parietal lobe. Subgroup analysis for intervention duration showed that shorter exercise interventions induced changes in regions connected with frontoparietal and default mode networks, whereas regions exhibiting effects of longer interventions connected with frontoparietal and dorsal attention networks. Our findings suggest that physical exercise interventions lead to changes in functional activation patterns primarily located in precuneus and associated with frontoparietal, dorsal attention and default mode networks. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer's disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer's dementia (AD; MMSE = 23.9±2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD + test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (ΔMMSE 5.8±8.64; ΔCDR-SOB 4.32±4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures. Keywords: Alzheimer’s disease; bayer activities of daily living scale; cognitive changes; disease progression; functional changes; lead and lag analysis.

Purpose Mild cognitive impairment (MCI) is a widespread phenomenon, especially affecting older individuals. We will analyze in how far MCI affects different facets of quality of life (QOL). Methods We used a sample of 903 participants (110 with MCI) from the fifth follow-up of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe), a prospective longitudinal study, to analyze the effects of MCI on different facets of the WHOQOL-OLD. We controlled for age, gender, marital status, education, living situation, daily living skills, and the ability to walk, see, and hear. Results Univariate analyses showed that individuals with MCI exhibited lower QOL with regard to the facets autonomy; past, present, and future activities; social participation; and intimacy, but less fears related to death and dying. No significant difference was shown with regard to the facet sensory abilities. In multivariate analyses controlling for age, gender, marital status, education, living situation, daily living skills, and the ability to walk, see and hear, MCI-status was significantly associated with QOL in the facet autonomy. Conclusion Effects of MCI go beyond cognition and significantly impact the lives of those affected. Further research and practice will benefit from utilizing specific facets of QOL rather than a total score.

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function., Alterations of locus coeruleus signal intensity have been associated with functional changes in health and disease. Here, the authors tested a pre-registered hypothesis on a large number of subjects as part of the Cam-CAN consortium.

An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.

Background Age-related hearing loss (impairment in hearing sensitivity and/or higher-order auditory processing) and cognitive decline are common co-occurring impairments in elderly adults. Their relation in the process of aging remains insufficiently understood. We aim to assess the temporal relations of decline in hearing sensitivity, higher-order auditory processing, and cognition in middle-aged adults. Methods This study included 1,274 Beaver Dam Offspring Study participants who participated in three examinations (baseline, 5-year, and 10-year follow-up). We assessed hearing sensitivity through pure-tone audiometry (PTA, averaged thresholds of 0.5, 1, 2, 4 kHz of the better ear), higher-order auditory processing as word recognition in competing message (WRCM) using the Northwestern University 6 word list in the better ear, and cognition through trail-making test performance (TMT). Linear mixed-effects models and linear regression models were used to determine associations over time and to what extent these measures influence each other over time. Results The longitudinal decline between all functions was associated with the strongest relationships between PTA and WRCM. The effect of baseline PTA on WRCM 10 years later (standardized ß = –.30) was almost twice as big as the effect of baseline WRCM on PTA 10 years later (standardized ß = –.18). The effect of baseline WRCM on TMT 10 years later and vice versa were small (standardized ß = –.05). No directional relationship between PTA and TMT was identified (standardized ß ≤ .02). Conclusions While hearing sensitivity might affect higher-order auditory processing, associations between hearing and cognition appear bidirectional and weak in midlife. We need to be cautious before inferring causal effects of hearing on cognition.

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF A beta(1-42) (amyloid beta-peptide 1 to 42; A+) and CSF p-tau(181) (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF A beta(1-42) and CSF p-tau(181) (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau(181) concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF A beta(1-42) and CSF p-tau(181). These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.

The NIH Toolbox Cognition Battery (NTCB) is a brief computerized method for evaluating neuropsychological functions in children, adolescents, and adults. We examined how performance on the 2 executive function measures of cognitive flexibility and inhibitory control was related to performance on the other NTCB measures across development.Participants were 1,020 typically developing individuals between the ages of 3 and 21 from the Pediatric Imaging, Neurocognition, and Genetics Study who were divided into 5 age groups (3-6, 7-9, 10-13, 14-17, and 18-21). Scores were adjusted for sex, level of parental education, and family income.Although the correlations between the 2 executive function measures were moderate and consistent across age groups, their correlations with the other 5 cognitive measures were highest in the youngest age group and decreased across the older age groups. Exploratory factor analysis revealed that all NTCB measures loaded onto a single factor for the 3- to 6-year-olds. Across the older age groups, the executive function and processing speed measures loaded onto one factor, and the vocabulary knowledge, oral reading, and working memory measures loaded onto a second factor.These results indicate that younger children's performance on the NTCB is more intercorrelated and less differentiated, while performance on the NTCB executive function measures becomes more differentiated from performance on the other measures with development. These results support the hypothesis that executive functions become increasingly differentiated from other cognitive functions with development as the functional specialization of neural systems progresses throughout childhood and young adulthood. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Positron Emission Tomography (PET) bears a unique potential for examining the effects of physical exercise (acute or chronic) within the central nervous system in vivo, including cerebral metabolism, neuroreceptor occupancy, and neurotransmission. However, application of Neuro-PET in human exercise science is as yet surprisingly sparse. To date the field has been dominated by non-invasive neuroelectrical techniques (EEG, MEG) and structural/functional magnetic resonance imaging (sMRI/fMRI). Despite PET having certain inherent disadvantages, in particular radiation exposure and high costs limiting applicability at large scale, certain research questions in human exercise science can exclusively be addressed with PET: The 'metabolic trapping' properties of (18)F-FDG PET as the most commonly used PET-tracer allow examining the neuronal mechanisms underlying various forms of acute exercise in a rather unconstrained manner, i.e. under realistic training scenarios outside the scanner environment. Beyond acute effects, (18)F-FDG PET measurements under resting conditions have a strong prospective for unraveling the influence of regular physical activity on neuronal integrity and potentially neuroprotective mechanisms in vivo, which is of special interest for aging and dementia research. Quantification of cerebral glucose metabolism may allow determining the metabolic effects of exercise interventions in the entire human brain and relating the regional cerebral rate of glucose metabolism (rCMRglc) with behavioral, neuropsychological, and physiological measures. Apart from FDG-PET, particularly interesting applications comprise PET ligand studies that focus on dopaminergic and opioidergic neurotransmission, both key transmitter systems for exercise-related psychophysiological effects, including mood changes, reward processing, antinociception, and in its most extreme form 'exercise dependence'. PET ligand displacement approaches even allow quantifying specific endogenous neurotransmitter release under acute exercise interventions, to which modern PET/MR hybrid technology will be additionally fruitful. Experimental studies exploiting the unprecedented multimodal imaging capacities of PET/MR in human exercise sciences are as yet pending.

Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease.

© 2018 Elsevier Inc. The mechanisms underlying superior cognitive performance in some older adults are poorly understood. We used a multimodal approach to characterize imaging and cognitive features of 26 successful agers (SA; defined by superior episodic memory ability) and 103 typical older adults. Cortical thickness was greater in multiple regions in SA including right anterior cingulate and prefrontal cortex and was related to baseline memory performance. Similarly, hippocampal volume was greater in SA and associated with baseline memory. SA also had lower white matter hypointensity volumes and faster processing speed. While PiB burden did not differ, there was a significant group interaction in the relationship between age and PiB such that older SA individuals were less likely to have high brain β-amyloid. Over time, memory performance in typical older adults declined more rapidly than in SA, although there was limited evidence for different rates of brain atrophy. These findings indicate that superior memory in aging is related to greater cortical and white matter integrity as well as slower decline in memory performance.

Background: Cognitive dysfunction is one of the most prevalent non-motor symptoms in Parkinson’s disease (PD), often experienced as more debilitating for patients and caregivers than motor problems. Therefore, a deeper understanding of the course of cognitive decline and the identification of valid progression markers for Parkinson’s disease dementia (PDD) is essential. Objective: This systematic review summarizes the current state of knowledge on cognitive decline over time by reporting effect sizes of cognitive changes in neuropsychological tests. METHODS: 1368 studies were identified by a PubMed database search and 25 studies by additionally scanning previous literature. After screening all records, including 69 full-text article reviews, 12 longitudinal studies on the progression of cognitive decline in PD met our criteria (e.g., sample size ≥50 patients). Results: Only a few studies monitored cognitive decline over a longer period (>4 years). Most studies focused on the evaluation of change in global cognitive state by use of the Mini-Mental State Examination, whereas the use of neuropsychological tests was highly heterogenic among studies. Only one study evaluated patients’ cognitive performance in all specified domains (executive function, attention & working memory, memory, language, and visual-spatial function) allowing for diagnosis of cognitive impairment according to consensus guidelines. Medium to strong effect sizes could only be observed in studies with follow-up intervals of four years or longer. Conclusions: The results emphasize the need for the assessment of larger PD cohorts over longer periods of follow-up with a comprehensive neuropsychological battery.

Entorhinal grid cells and hippocampal place cells are key systems for mammalian navigation. By combining information from different sensory modalities, they provide abstract representations of space. Given that both structures are among the earliest to undergo age-related neurodegenerative changes, we asked whether age-related navigational impairments are related to deficient integration of navigational cues. Younger and older adults performed a homing task that required using visual landmarks, self-motion information, or a combination of both. Further, a conflict between cues assessed the influence of each sensory domain. Our findings revealed performance impairments in the older adults, suggestive of a higher noise in the underlying spatial representations. In addition, even though both groups integrated visual and self-motion information to become more accurate and precise, older adults did not place as much influence on visual information as would have been optimal. As these findings were unrelated to potential changes in balance or spatial working memory, this study provides the first evidence that increasing noise and a suboptimal weighting of navigational cues might contribute to the common problems with spatial representations experienced by many older adults. These findings are discussed in the context of the known age-related changes in the entorhinal-hippocampal network.

Objective The prevalence of Alzheimer’s disease and Parkinson’s disease increases with the raising number of elderly, which will be a challenging situation for the healthcare systems and society in the future. There is evidence that there are modifiable risk-factors e.g. physical activity for these diseases. Here, we study the interaction between sports inactivity with prodromal markers for neurodegeneration. Patients and Methods We investigated 667 neurologically healthy individuals cross-sectional and a subgroup longitudinal over six years. Participants were stratified by their weekly sports activity. Prodromal markers (depression and REM sleep behaviour disorder (RBD)) as well as single and dual-tasking parameters and cognitive parameters were compared between the groups. Results At baseline, sports activity was associated with lower BDI scores, lower occurrence of depressive syndrome and RBD, compared to sports inactivity. Further, active participants were faster in cognitive tasks associated with working memory and attention (Trail Making test part-A; TMT-B, ΔTMT-B-A) and better in gait and cognition parameters (single tasks and dual tasks) but not with overall cognition as measured with the MMSE. The association between physical inactivity and depression as well as TMT was present after six years. Conclusion We found that sports activity has a positive effect on cognitive flexibility, depressive symptoms and sleep which are all signs for a possible ongoing neurodegenerative process. Therefore, our results strengthen the potential role of sports activity as a positive disease modifier.

Objectives: To examine cross-sectional and longitudinal associations between physical exercise and cognitive function across different age groups in a nationwide population-based sample of adults aged 18–79 years in Germany. Design: Cross-sectional/prospective. Methods: Cognitive function was assessed in the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1-MH, 2009–2012, n = 3535), using a comprehensive neuropsychological test battery. Cognitive domain scores for executive function and memory were derived from confirmatory factor analysis. Regular physical exercise in the last three months was assessed by self-report and defined as no exercise, Results: Compared to no exercise, more weekly physical exercise was associated with better executive function in cross-sectional (Conclusions: Higher levels of physical exercise were associated with better executive function and memory in cross-sectional and longitudinal analyses with no evidence for differential effects by age.

Background Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (−/−) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (−/−) single mutant mice were augmented in DBH (−/−)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N -methyl-D-aspartate receptor 2A and increased N -methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N -methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.

Background Genome-wide association studies have established 11 genes for late-onset Alzheimer's disease (AD). We investigated whether these genes jointly affect cognition in a nondemented population and improve prediction of AD. Methods In 5171 nondemented people (age 45–99 years) from the population-based Rotterdam Study, we genotyped APOE -e4 and single nucleotide polymorphisms from the genes CLU , PICALM, BIN1, CR1, ABCA7, MS4A6A, MS4A4E, CD2AP, EPHA1, and CD33. We constructed a genetic risk score by adding the risk alleles per individual weighted by the reported effect sizes. All people underwent cognitive testing. With linear regression we investigated the relationship between the genetic risk score and cognition, with and without APOE . In a subcohort, with more than 10 years of follow-up, we assessed whether the risk score predicted AD. Results The genetic risk score was primarily associated with memory (standardized difference [95% confidence interval] per SD increase in genetic risk score: −.05[−.07; −.02], p = 1.5 * 10 −4 ). This association attenuated when APOE was excluded from the genetic risk score (−.03[−.05; .00], p = .047) and would not survive a multiple-testing correction. Similarly, we found that although the genetic risk score without APOE was associated with the development of AD ( p = .010), it only marginally improved prediction of AD beyond age, sex, APOE (area under the curve: .8159 vs. .8148). Conclusions In nondemented people, there is only a marginal joint effect of AD genes on memory independent from APOE . Moreover, although associated with AD, these genes jointly hardly improve prediction of AD.

Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosisin vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.

Human intracranial EEG (iEEG) recordings are primarily performed in epileptic patients for presurgical mapping. When patients perform cognitive tasks, iEEG signals reveal high-frequency neural activities (HFAs, between around 40 Hz and 150 Hz) with exquisite anatomical, functional and temporal specificity. Such HFAs were originally interpreted in the context of perceptual or motor binding, in line with animal studies on gamma-band ('40 Hz') neural synchronization. Today, our understanding of HFA has evolved into a more general index of cortical processing: task-induced HFA reveals, with excellent spatial and time resolution, the participation of local neural ensembles in the task-at-hand, and perhaps the neural communication mechanisms allowing them to do so. This review promotes the claim that studying HFA with iEEG provides insights into the neural bases of cognition that cannot be derived as easily from other approaches, such as fMRI. We provide a series of examples supporting that claim, drawn from studies on memory, language and default-mode networks, and successful attempts of real-time functional mapping. These examples are followed by several guidelines for HFA research, intended for new groups interested by this approach. Overall, iEEG research on HFA should play an increasing role in cognitive neuroscience in humans, because it can be explicitly linked to basic research in animals. We conclude by discussing the future evolution of this field, which might expand that role even further, for instance through the use of multi-scale electrodes and the fusion of iEEG with MEG and fMRI.

The present functional magnetic resonance imaging (fMRI) study sought to characterize neural processes related to aspects of empathy and social cognition. It has been hypothesized previously that merely observing emotions in others automatically activates associated representations of the emotional state in the observer. We tested this prediction by presenting drawings depicting either one or two persons in an emotionally charged or neutral situation. Importantly and in contrast to previous imaging studies on empathy or social cognition, we did not instruct participants to assess the depicted persons' feelings or thoughts, but told them to simply watch the pictures to be able to perform a memory task unrelated to the main experimental question. This novel design allowed us to assess automatically elicited empathy-related effects (contrasting emotional and neutral situations) and to compare them with automatic social cognitive processes (contrasting stimuli with two persons vs. one person). We observed empathy-related increased hemodynamic responses in areas previously shown to be related to emotion processing (ventromedial and ventrolateral prefrontal cortex, PFC) and to social cognitive processes (superior temporal sulcus, STS, and medial PFC). The medial PFC activation was negatively correlated with participants' predisposition to feel distressed in emotional social situations, suggesting that interindividual differences in these higher-order functions might also impact empathic responses in social interactions.

Flexible spatial navigation, e.g. the ability to take novel shortcuts, is contingent upon accurate mental representations of environments-cognitive maps. These cognitive maps critically depend on hippocampal place cells. In rodents, place cells replay recently travelled routes, especially during periods of behavioural inactivity (sleep/wakeful rest). This neural replay is hypothesised to promote not only the consolidation of specific experiences, but also their wider integration, e.g. into accurate cognitive maps. In humans, rest promotes the consolidation of specific experiences, but the effect of rest on the wider integration of memories remained unknown. In the present study, we examined the hypothesis that cognitive map formation is supported by rest-related integration of new spatial memories. We predicted that if wakeful rest supports cognitive map formation, then rest should enhance knowledge of overarching spatial relations that were never experienced directly during recent navigation. Forty young participants learned a route through a virtual environment before either resting wakefully or engaging in an unrelated perceptual task for 10 min. Participants in the wakeful rest condition performed more accurately in a delayed cognitive map test, requiring the pointing to landmarks from a range of locations. Importantly, the benefit of rest could not be explained by active rehearsal, but can be attributed to the promotion of consolidation-related activity. These findings (i) resonate with the demonstration of hippocampal replay in rodents, and (ii) provide the first evidence that wakeful rest can improve the integration of new spatial memories in humans, a function that has, hitherto, been associated with sleep.

Introduction The inhibition of the Histone Deacetylase 6 (HDAC6) increases tubulin acetylation, thus stimulating intracellular vesicle trafficking and brain-derived neurotrophic factor (BDNF) release, that is, cellular processes markedly reduced in Huntington's disease (HD). Methods We therefore tested that reducing HDAC6 levels by genetic manipulation would attenuate early cognitive and behavioral deficits in R6/1 mice, a mouse model which develops progressive HD-related phenotypes. Results In contrast to our initial hypothesis, the genetic deletion of HDAC6 did not reduce the weight loss or the deficits in cognitive abilities and nest-building behavior shown by R6/1 mice, and even worsened their social impairments, hypolocomotion in the Y-maze, and reduced ultrasonic vocalizations. Conclusions These results weaken the validity of HDAC6 reduction as a possible therapeutic strategy for HD. The data are discussed in terms of additional cellular consequences and anatomical specificity of HDAC6 that could explain these unexpected effects.

The relation between motor control and action cognition - including action-related thoughts and action-related perception - has been subject to controversial discussions in the last three decades. During these decades, cognitive neuroscience has been increasingly confronted with a huge variety of different accounts trying to understand and explain the relation between these systems, their interdependencies and the mediating mechanisms by establishing notions such as 'internal models', 'simulation' or 'shared representation'. These accounts, however, include a large array of partly overlapping, partly contradictory theories using similar terms for different mechanisms and different terms for similar mechanisms. In the absence of a systematic work-up and comparison, this array of accounts and theories leads to confusion in the field, duplication of experimental work, and unconnected parallelism of theory formation within and between different disciplines. Here we provide a systematic comparison of current models and prospective theories that deal with the relation between cognition, perception and motor control mechanisms. In a second step, we propose 'grounded action cognition' as a comprehensive metatheoretical framework which defines different hypothetical possibilities of the relations between these domains, offers systematic insights into current models and theories and last but not least may help to increase comparability of empirical research in the domain of action and action cognition.

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimers disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 4084 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimers disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

The neuropeptide neurokinin 3 (NK3) and its receptor modulate cholinergic activity of the basal forebrain (BF) and are implicated in learning and memory. In Alzheimer's disease, the rs2765 single-nucleotide polymorphism (SNP) of the NK3 receptor-coding gene TACR3 was correlated with the right hippocampus volume. Here, we studied the association of the rs2765 SNP with magnetic resonance imaging-based volumes of the BF and hippocampus in a population-based sample of 1967 participants between 21 and 90 years of age. The rs2765 SNP was significantly associated with the most anterior BF volume corresponding to the medial septum/diagonal band, and with a significantly steeper age-related volume decline. The rs2765 SNP was not associated with other BF subvolumes or hippocampus volumes. Apolipoprotein E ε4 showed no correlation with any brain volume or global cognition. Our findings in a large population-based sample suggest an association of an NK3 receptor SNP with age-related decline of rostral cholinergic BF volume.

Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD. peerReviewed

PLoS one 7(1), e30009 (2012). doi:10.1371/journal.pone.0030009, Published by PLoS [u.a.], Lawrence, Kan.

Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition.

Background Transcranial direct current stimulation (tDCS) is a technique that can systematically modify behaviour by inducing changes in the underlying brain function. In order to better understand the neuromodulatory effect of tDCS, the present study examined the impact of tDCS on performance in a working memory (WM) task and its underlying neural activity. In two experimental sessions, participants performed a letter two-back WM task after sham and either anodal or cathodal tDCS over the left dorsolateral prefrontal cortex (DLPFC). Results Results showed that tDCS modulated WM performance by altering the underlying oscillatory brain activity in a polarity-specific way. We observed an increase in WM performance and amplified oscillatory power in the theta and alpha bands after anodal tDCS whereas cathodal tDCS interfered with WM performance and decreased oscillatory power in the theta and alpha bands under posterior electrode sides. Conclusions The present study demonstrates that tDCS can alter WM performance by modulating the underlying neural oscillations. This result can be considered an important step towards a better understanding of the mechanisms involved in tDCS-induced modulations of WM performance, which is of particular importance, given the proposal to use electrical brain stimulation for the therapeutic treatment of memory deficits in clinical settings.

We investigated whether preservation of encoding-related brain activity patterns in older age reflects successful aging in long-term memory. Using a statistical matching technique, we identified groups of healthy older adults with different degrees of Functional Activity Deviation during Encoding (FADE) from young adults in a memory network comprising hippocampal, temporal, occipital, and retrosplenial regions. High FADE scores were associated with impairment in recollection, abnormal activity in the default mode network, and lower gray matter density in bilateral ventral prefrontal cortex and left rhinal cortex; a constellation previously associated with increased risk for dementia. Low FADE scores functionally phenotyped successful aging because recollection was well preserved and there was no evidence for compensatory prefrontal activation. Thus, for some individuals successful aging in long-term memory reflects the preservation of a functionally specific memory network, and can occur in the absence of compensatory brain activity.

BackgroundDespite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked.Principal findingsAt the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample.ConclusionOur gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.