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Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1–4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George‘s respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.

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.

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENTKey structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.

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.

This individual participant data analysis assesses the cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Key Points Question Is thyroid dysfunction associated with cognitive decline? Findings In this individual participant data analysis of 23 cohorts including 74 565 participants with cognitive function and/or dementia measurements, subclinical thyroid dysfunction was not associated with global cognitive function at baseline (standardized mean difference, −0.02 for subclinical hyperthyroidism and 0.05 for subclinical hypothyroidism) or annual decline (standardized mean difference, −0.02 for subclinical hyperthyroidism and −0.00 for subclinical hypothyroidism). Meaning These findings do not support the need for screening for subclinical thyroid dysfunction for prevention of cognitive decline or dementia., Importance In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism—cross-sectionally (−0.06 standardized mean difference in score; 95% CI, –0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, –0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

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.

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPSEDU) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPSEDU in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPSSZ) and bipolar disorder (GPSBD) were associated with cognitive outcomes. GPSEDU explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPSSZ or GPSBD with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPSEDU on cognitive outcomes. GPSEDU explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.

Background Accurate assessment of health-related quality of life as an endpoint in intervention studies is a major challenge in dementia research. The DEMQOL (29 items) and the proxy version (32 items), which is partly based on the DEMQOL, are internationally used instruments. To date, there is no information on the structural validity, item distribution, or internal consistency for the German language version of these questionnaires. Methods This psychometric study is based on a secondary data analysis of a sample of 201 outpatients with a mild form of Alzheimer’s disease (AD) and their informal caregivers. The informal caregivers who were interviewed were involved in the care of the person with AD several times per week. The analysis for the evaluation of the structural validity was performed using Mokken scale analysis. The internal consistency was calculated using the ρ of the Molenaar Sijtsma statistic and Cronbach’s α. Results For both versions, four subscales were identified: [A] “positive emotions”, [B] “negative emotions”, [C] “physical and cognitive functioning”, and [D] “daily activities and social relationships”. For both instruments, the internal consistency of all subscales was considered “good” (ρ = 0.71–0.88, α = 0.72–0.87). Conclusions The results are a first indication of good construct validity of the instruments used for the German setting. We recommend further investigations of the test-retest reliability and the inter-rater reliability of the proxy instrument. Electronic supplementary material The online version of this article (10.1186/s12877-018-0930-0) contains supplementary material, which is available to authorized users.

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).

Background Previous studies suggest that genetic polymorphisms and aging modulate inter-individual variability in brain stimulation-induced plasticity. However, the relationship between genetic polymorphisms and behavioral modulation through transcranial direct current stimulation (tDCS) in older adults remains poorly understood. Objective Link individual tDCS responsiveness, operationalized as performance difference between tDCS and sham condition, to common genetic polymorphisms in healthy older adults. Methods 106 healthy older participants from five tDCS-studies were re-invited to donate blood for genotyping of apoliproprotein E (APOE: e4 carriers and e4 non-carriers), catechol-O-methyltransferase (COMT: val/val, val/met, met/met), brain-derived neurotrophic factor (BDNF: val/val, val/met, met/met) and KIdney/BRAin encoding gene (KIBRA: C/C, C/T, T/T). Studies had assessed cognitive performance during tDCS and sham in cross-over designs. We now asked whether the tDCS responsiveness was related to the four genotypes using a linear regression models. Results We found that tDCS responsiveness was significantly associated with COMT polymorphism; i.e., COMT val carriers (compared to met/met) showed higher tDCS responsiveness. No other significant associations emerged. Conclusion Using data from five brain stimulation studies conducted in our group, we showed that only individual variation of COMT genotypes modulated behavioral response to tDCS. These findings contribute to the understanding of inherent factors that explain inter-individual variability in functional tDCS effects in older adults, and might help to better stratify participants for future clinical trials.

ObjectiveTo explore if changes over time of plasma phosphorylated tau (p-tau)181 and neurofilament light chain (NfL) predict future tau and amyloid β (Aβ) PET load and cognitive performance, we studied a subsample of the Alzheimer’s disease (AD) neuroimaging cohort with longitudinal blood peptide assessments.MethodsEight hundred and sixty-five AD Neuroimaging Initiative participants were included. Using established AD cut-points for the cerebrospinal fluid concentrations of Aβ42, total-tau and p-tau181, subjects were classified according to the National Institute on Aging-Alzheimer’s Association research framework, grouping markers into those of Aβ deposition (A), tau pathology (T) and neurodegeneration (N). Analysis of variance was used to compare the plasma biomarker data between the ATN groups. The rate of change over time of p-tau181 and NfL was obtained from linear mixed effects models and compared between the ATN groups. Linear regression analysis was used to investigate the association of baseline plasma biomarker concentrations and rates of change with future PET tau and Aβ load and cognitive performance.ResultsP-tau181 and NfL plasma concentrations increased along the AD spectrum, but only NfL showed greater rates of change in AD patients versus controls. Cognitive performance was associated cross-sectionally with NfL in all subgroups, and with p-tau181 only in AD spectrum individuals. The baseline concentrations of both plasma markers predicted PET Aβ and tau load and cognitive performance. The rate of change of NfL predicted future PET tau and cognitive performance.ConclusionsP-tau and NfL behave differently within the same individuals over time and may therefore offer complementary diagnostic information.Trial registration numberNCT02854033, NCT01231971.

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.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

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.

Chronic stress detrimentally affects cognition but evidence from population-based studies is scarce and largely based on one-dimensional stress assessments. In this study, we aimed to investigate associations of subjective and psychological chronic stress measures with cognition in a population-based sample of adults aged 30–95 years from the Rhineland Study. Participants completed the Perceived Stress Scale (subjective measure) and a cognitive test battery (N = 1766). Hair cortisol concentration (physiological measure) was assessed by liquid chromatography tandem mass spectrometry in 1098 participants. Cross-sectional associations between the two measures of chronic stress and cognition were investigated using multivariable linear regression models. Subjective and physiological measures of chronic stress were not associated with each other (B = 0.005 [95 %CI = -0.005 – 0.015]). Participants with higher perceived stress and specifically lower perceived self-efficacy performed worse in all cognitive domains (effect sizes ranged from β = -0.129 [95 %CI = -0.177 – -0.080] to -0.054 [95 %CI = -0.099 – -0.009]; and from β = 0.052 [95 %CI = 0.005 – 0.098] to 0.120 [95 %CI = 0.072 – 0.167], respectively). Relationships between subjective chronic stress measures and executive functioning were stronger in men compared to women (interaction β = -0.144 [95 %CI = -0.221 – -0.067]). Relationships between perceived stress and working memory, and between perceived self-efficacy and executive functioning, processing speed, verbal episodic and working memory, increased with older age. Hair cortisol concentration was not associated with performance in any cognitive domain. Our results suggest that subjective and physiological measures capture different aspects of chronic stress in the general population.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.

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.

Post-navigation awake quiescence, relative to task engagement, benefits the accuracy of a new "cognitive map". This effect is hypothesized to reflect awake quiescence, like sleep, being conducive to the consolidation and integration of new spatial memories. Sleep has been shown to improve cognitive map accuracy over time. It remained unknown whether awake quiescence can induce similar time-related improvements in new cognitive maps, or whether it simply counteracts their decay. We examined this question via two experiments. In Experiment 1, using an established cognitive mapping paradigm, we reveal that map accuracy for a virtual town was significantly better in people whose memory was probed after 10 min of post-navigation awake quiescence or ongoing cognitive engagement, relative to those whose memory was probed shortly after initial navigation. In Experiment 2, using a newly developed cognitive mapping task that involved a more complex and real-life virtual town, we again found that map accuracy was superior in those whose memory was probed after 10 min of awake quiescence than those who were tested soon after navigation. These findings indicate that actual improvements in human memories are not restricted to sleep. Thus, contrary to conventional wisdom and theories, the passage of (day)time need not always result in forgetting.

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.

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer’s disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p

Interval timing performance in cognitive decline is typically characterized by decreased accuracy, precision, or both. One explanation for this decreased performance is a larger clock time variability. However, memory deficiencies associated with cognitive decline might also affect temporal performance in two alternative ways: First, memory deficiencies could lead to reduced encoding of just perceived durations, and thus a stronger reliance on the memory traces of previous experiences (the “prior”), yielding less precise reproductions of the most current experiences. Second, memory deficiencies could hamper the storage of perceived intervals, thus resulting in less influence of the prior. Here, we present data of 15 patients with amnestic Mild Cognitive Impairment (aMCI) and 44 healthy, aged controls, the latter split in two groups based on memory performance. All participants were tested on a temporal production task to assess clock time variability and a multi-duration reproduction task to assess the influence ofmemory traces reflecting current and previous experiences.Patients with aMCI showed the strongest regression towards the mean in a multi-duration reproduction task,followed by low-performing healthy controls and high-performing healthy controls, respectively. As no differencewas observed between the groups in terms of clock time variability, and clock variability did not statisticallycontribute to the observed regression, this increased central tendency effect was not attributable to clocknoise. We therefore, in line with the first explanation, conclude that memory deficiencies result in a stronger(relative) reliance on the prior.

There is now increasing evidence that myelin is not only generated early in development, but also during adulthood possibly contributing to lifelong plasticity of the brain. In particular, human cortical areas responsible for the highest cognitive functions seem to require decades until they have reached their maximal amount of myelination. Currently, we know very little about the mechanisms and the functions of grey matter myelination. In this emerging field key questions await to be addressed: How long does myelination last in humans? How is grey matter myelination regulated? What is the function of myelin in the grey matter? Does grey matter myelination limit and/or promote neuronal plasticity? Finding answers to these questions will be important for our understanding of normal, but also abnormal cortex function in a number of neurological and psychiatric diseases.

The restless legs syndrome (RLS) has repeatedly, but not exclusively, been associated with functional thalamic changes as well as changes in GABAergic neurotransmission. This has been linked to the well-known sensory-motor symptoms, but it has never been investigated whether those factors also account for potential cognitive changes in RLS, even though they are known to play an important role for cognitive control. To investigate the potential relationship between thalamic GABA concentrations and cognitive control in n = 25 RLS patients; a neuropsychological experimental paradigm was used in combination with magnetic resonance spectroscopy (MRS). Compared to n = 31 healthy controls, RLS patients displayed reduced cognitive control capacities, which were most likely based on working memory deficits. On the neurobiochemical level, (relatively) elevated thalamic GABA levels attenuated control deficits only in the RLS group, even though there were no group differences with respect to overall GABA levels. Given that RLS patients are known to display thalamic hyperactivity and associated thalamic hypoconnectivity, (relatively) higher GABA levels may have helped RLS patients to “compensate” for this pathological factor. Our findings specify the functional relevance of thalamic GABAergic neurotransmission for cognition in RLS, even though changes in GABAergic neurotransmission might not be the ultimate cause of control deficits.

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.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. 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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.

Animal research indicates that a combination of physical activity and sensory enrichment has the largest and the only sustaining effect on adult neuroplasticity. Dancing has been suggested as a human homologue to this combined intervention as it poses demands on both physical and cognitive functions. For the present exploratory study, we designed an especially challenging dance program in which our elderly participants constantly had to learn novel and increasingly difficult choreographies. This six-month-long program was compared to conventional fitness training matched for intensity. An extensive pre/post-assessment was performed on the 38 participants (63-80 y), covering general cognition, attention, memory, postural and cardio-respiratory performance, neurotrophic factors and-most crucially-structural MRI using an exploratory analysis. For analysis of MRI data, a new method of voxel-based morphometry (VBM) designed specifically for pairwise longitudinal group comparisons was employed. Both interventions increased physical fitness to the same extent. Pronounced differences were seen in the effects on brain volumes: Dancing compared to conventional fitness activity led to larger volume increases in more brain areas, including the cingulate cortex, insula, corpus callosum and sensorimotor cortex. Only dancing was associated with an increase in plasma BDNF levels. Regarding cognition, both groups improved in attention and spatial memory, but no significant group differences emerged. The latter finding may indicate that cognitive benefits may develop later and after structural brain changes have taken place. The present results recommend our challenging dance program as an effective measure to counteract detrimental effects of aging on the brain.

Amyloid-β peptide (Aβ) forms plaques in Alzheimer’s disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target.

Recent evidence challenges the widely held view that the hippocampus is specialized for episodic memory, by demonstrating that it also underpins the integration of information across experiences. Contemporary computational theories propose that these two contrasting functions can be accomplished by big-loop recurrence, whereby the output of the system is recirculated back into the hippocampus. We use ultra-high-resolution fMRI to provide support for this hypothesis, by showing that retrieved information is presented as a new input on the superficial entorhinal cortex—driven by functional connectivity between the deep and superficial entorhinal layers. Further, the magnitude of this laminar connectivity correlated with inferential performance, demonstrating its importance for behavior. Our findings offer a novel perspective on information processing within the hippocampus and support a unifying framework in which the hippocampus captures higher-order structure across experiences, by creating a dynamic memory space from separate episodic codes for individual experiences. The hippocampus is central for storing distinct episodes, while also supporting integration across related episodes. Using ultra-high-resolution fMRI, Koster et al. provide evidence for a core computational principle (big-loop recurrence) that can account for these apparently conflicting hippocampal roles. (Less)

Summary Physical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer’s disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission., Graphical Abstract, Highlights • Exercising male mice pass a cognitive benefit to their offspring • This phenomenon is mediated by altered expression of sperm RNA • Levels of miR212/132 in sperm play a key role in this intergenerational effect, Environmental enrichment (EE), a combination of physical and mental exercise, has been shown to increase cognitive abilities in mice and in humans. Benito et al. find that offspring of male mice subjected to EE also show this increase. This effect is dependent on sperm RNA and involves microRNA212/132.

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.

The pattern separation task has recently emerged as a behavioral model of hippocampus function and has been used in several pharmaceutical trials. The canine is a useful model to evaluate a multitude of hippocampal-dependent cognitive tasks that parallel those in humans. Thus, this study was designed to evaluate the suitability of pattern separation task(s) for detecting age-related changes in canines. We also assessed the dogs’ ability to show pattern separation and discrimination reversal, which provides a novel extension of the pattern separation learning literature. Our data show that aged dogs are impaired on a complex pattern separation task (six-well task) relative to easier tasks (four-well or six-well pattern discrimination task), and that the age-related deficits are due to loss of perceptual and inhibitory control in addition to the loss of spatial discrimination and pattern separation ability. Our data also suggest that aged animals show pattern separation deficits when the objects are brought progressively closer together while changing the location of both correct and incorrect objects. However, if the location of any one object is fixed the animals tend to use alternate strategies. Overall, these data provide important insight into age-related pattern separation deficits in a higher animal model and offers additional means for evaluating the impact of lifestyle and pharmaceutical interventions on episodic memory in preclinical trials.

Head motion reduces data quality of neuroimaging data. In three functional magnetic resonance imaging (MRI) experiments we demonstrate that people make less head movements under task than resting-state conditions. In Experiment 1, we observed less head motion during a memory encoding task than during the resting-state condition. In Experiment 2, using publicly shared data from the UCLA Consortium for Neuropsychiatric Phenomics LA5c Study, we again found less head motion during several active task conditions than during a resting-state condition, although some task conditions also showed comparable motion. In the healthy controls, we found more head motion in men than in women and more motion with increasing age. When comparing clinical groups, we found that patients with a clinical diagnosis of bipolar disorder, or schizophrenia, move more compared to healthy controls or patients with ADHD. Both these experiments had a fixed acquisition order across participants, and we could not rule out that a first or last scan during a session might be particularly prone to more head motion. Therefore, we conducted Experiment 3, in which we collected several task and resting-state fMRI runs with an acquisition order counter-balanced. The results of Experiment 3 show again less head motion during several task conditions than during rest. Together these experiments demonstrate that small head motions occur during MRI even with careful instruction to remain still and fixation with foam pillows, but that head motion is lower when participants are engaged in a cognitive task. These finding may inform the choice of functional runs when studying difficult-to-scan populations, such as children or certain patient populations. Our findings also indicate that differences in head motion complicate direct comparisons of measures of functional neuronal networks between task and resting-state fMRI because of potential differences in data quality. In practice, a task to reduce head motion might be especially useful when acquiring structural MRI data such as T1/T2-weighted and diffusion MRI in research and clinical settings.

Cognitive reserve (CR) shows protective effects on cognitive function in older adults. Here, we focused on the effects of CR at the functional network level. We assessed in patients with amnestic mild cognitive impairment (aMCI) whether higher CR moderates the association between low internetwork cross-talk on memory performance. In 2 independent aMCI samples (n = 76 and 93) and healthy controls (HC, n = 36), CR was assessed via years of education and intelligence (IQ). We focused on the anti-correlation between the dorsal attention network (DAN) and an anterior and posterior default mode network (DMN), assessed via sliding time window analysis of resting-state functional magnetic resonance imaging (fMRI). The DMN-DAN anti-correlation was numerically but not significantly lower in aMCI compared to HC. However, in aMCI, lower anterior DMN-DAN anti-correlation was associated with lower memory performance. This association was moderated by CR proxies, where the association between the internetwork anti-correlation and memory performance was alleviated at higher levels of education or IQ. In conclusion, lower DAN-DMN cross-talk is associated with lower memory in aMCI, where such effects are buffered by higher CR.

Contains fulltext : 165723pub.pdf (Publisher’s version ) (Closed access) Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rhogenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

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.

Adapted from the work of Kahana and colleagues (e.g., Kahana, 1996), we present two measures of order of recall in neuropsychological free recall tests. These are the position on the study list of the first recalled item, and the degree of variability in the order in which items are reported at test (i.e., the temporal distance across the first four recalled items). We tested two hypotheses in separate experiments: (1) whether these measures predicted generalized cognitive ability, and (2) whether they predicted gray matter hippocampal volume. To test hypothesis 1, we conducted ordinal regression analyses on data from a group of 452 participants, aged 60 or above. Memory performance was measured with Rey's AVLT and generalized cognitive ability was measured with the MMSE test. To test hypothesis 2, we conducted a linear regression analysis on data from a sample of 79 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images. Results of Experiment 1 showed that the position of the first item recalled and the degree of output order variability correlated with MMSE scores only in the delayed test, but not in the immediate test. In Experiment 2, the degree of variability in the recall sequence of the delayed trial correlated (negatively) with hippocampal size. These findings confirm the importance of delayed primacy as a marker of cognitive ability, and are consistent with the idea that the hippocampus is involved in coding the temporal context of learned episodes.

Summary A progressive loss of navigational abilities in old age has been observed in numerous studies, but we have only limited understanding of the neural mechanisms underlying this decline [1]. A central component of the brain’s navigation circuit are grid cells in entorhinal cortex [2], largely thought to support intrinsic self-motion-related computations, such as path integration (i.e., keeping track of one’s position by integrating self-motion cues) [3, 4, 5, 6]. Given that entorhinal cortex is particularly vulnerable to neurodegenerative processes during aging and Alzheimer’s disease [7, 8, 9, 10, 11, 12, 13, 14], deficits in grid cell function could be a key mechanism to explain age-related navigational decline. To test this hypothesis, we conducted two experiments in healthy young and older adults. First, in an fMRI experiment, we found significantly reduced grid-cell-like representations in entorhinal cortex of older adults. Second, in a behavioral path integration experiment, older adults showed deficits in computations of self-position during path integration based on body-based or visual self-motion cues. Most strikingly, we found that these path integration deficits in older adults could be explained by their individual magnitudes of grid-cell-like representations, as reduced grid-cell-like representations were associated with larger path integration errors. Together, these results show that grid-cell-like representations in entorhinal cortex are compromised in healthy aging. Furthermore, the association between grid-cell-like representations and path integration performance in old age supports the notion that grid cells underlie path integration processes. We therefore conclude that impaired grid cell function may play a key role in age-related decline of specific higher-order cognitive functions, such as spatial navigation., Highlights • Grid-cell-like representations in human entorhinal cortex are compromised in old age • This effect is predominantly driven by a lack of representational stability over time • Path integration ability in old age is associated with grid-cell-like representations, Stangl et al. found that human grid-cell-like representations are compromised in old age and that reduced magnitudes of grid-cell-like representations are predictive of age-related path integration deficits. Impaired grid cell function, therefore, may provide a mechanistic explanation for a decline of navigational functions in old age.

Skill learning results in changes to brain function, but at the same time individuals strongly differ in their abilities to learn specific skills. Using a 6-week piano-training protocol and pre- and post-fMRI of melody perception and imagery in adults, we dissociate learning-related patterns of neural activity from pre-training activity that predicts learning rates. Fronto-parietal and cerebellar areas related to storage of newly learned auditory-motor associations increased their response following training; in contrast, pre-training activity in areas related to stimulus encoding and motor control, including right auditory cortex, hippocampus, and caudate nuclei, was predictive of subsequent learning rate. We discuss the implications of these results for models of perceptual and of motor learning. These findings highlight the importance of considering individual predisposition in plasticity research and applications.

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.

Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits. BF atrophy in MCI correlated with both impaired memory function and attentional control deficits, whereas hippocampus volume was more specifically associated with memory deficits. BF atrophy was also associated with widespread cortical hypometabolism, and path analytic models indicated that hypometabolism in domain-specific cortical networks mediated the association between BF volume and cognitive dysfunction. The presence of cortical amyloid pathology, as assessed using AV45-PET, did not significantly interact with the observed associations. These data underline the potential of multimodal imaging markers to study structure-function-cognition relationships in the living human brain and provide important in vivo evidence for an involvement of the human BF in cortical activity and cognitive function.