Traceability and comparability through crosswalks with the NeuroMET Memory Metric.

Accurate assessment of memory ability for persons on the continuum of Alzheimer's disease (AD) is vital for early diagnosis, monitoring of disease progression and evaluation of new therapies. However, currently available neuropsychological tests suffer from a lack of standardization and metrological quality assurance. Improved metrics of memory can be created by carefully combining selected items from legacy short-term memory tests, whilst at the same time retaining validity, and reducing patient burden. In psychometrics, this is known as "crosswalks" to link items empirically. The aim of this paper is to link items from different types of memory tests. Memory test data were collected from the European EMPIR NeuroMET and the SmartAge studies recruited at Charité Hospital (Healthy controls n = 92; Subjective cognitive decline n = 160; Mild cognitive impairment n = 50; and AD n = 58; age range 55-87). A bank of items (n = 57) was developed based on legacy short-term memory items (i.e., Corsi Block Test, Digit Span Test, Rey's Auditory Verbal Learning Test, Word Learning Lists from the CERAD test battery and Mini Mental State Examination; MMSE). The NeuroMET Memory Metric (NMM) is a composite metric that comprises 57 dichotomous items (right/wrong). We previously reported on a preliminary item bank to assess memory based on immediate recall, and have now demonstrated direct comparability of measurements generated from the different legacy tests. We created crosswalks between the NMM and the legacy tests and between the NMM and the full MMSE using Rasch analysis (RUMM2030) and produced two conversion tables. Measurement uncertainties for estimates of person memory ability with the NMM across the full span were smaller than all individual legacy tests, which demonstrates the added value of the NMM. Comparisons with one (MMSE) of the legacy tests showed however higher measurement uncertainties of the NMM for people with a very low memory ability (raw score ≤ 19). The conversion tables developed through crosswalks in this paper provide clinicians and researchers with a practical tool to: (i) compensate for ordinality in raw scores, (ii) ensure traceability to make reliable and valid comparisons when measuring person ability, and (iii) enable comparability between test results from different legacy tests.

Acute neurological care in north-east Germany with telemedicine support (ANNOTeM): protocol of a multi-center, controlled, open-label, two-arm intervention study.

BACKGROUND: Both diagnosis and treatment of neurological emergencies require neurological expertise and are time-sensitive. The lack of fast neurological expertise in regions with underserved infrastructure poses a major barrier for state-of-the-art care of patients with acute neurological diseases and leads to disparity in provision of health care. The main purpose of ANNOTeM (acute neurological care in North East Germany with telemedicine support) is to establish effective and sustainable support structures for evidence based treatments for stroke and other neurological emergencies and to improve outcome for acute neurological diseases in these rural regions. METHODS: A "hub-and-spoke" network structure was implemented connecting three academic neurological centres ("hubs") and rural hospitals ("spokes") caring for neurological emergencies. The network structure includes (1) the establishment of a 24/7 telemedicine consultation service, (2) the implementation of standardized operating procedures (SOPs) in the network hospitals, (3) a multiprofessional training scheme, and (4) a quality management program. Data from three major health insurance companies as well as data from the quality management program are being collected and evaluated. Primary outcome is the composite of first time of receiving paid outpatient nursing care, first time of receiving care in a nursing home, or death within 90 days after hospital admission. DISCUSSION: Beyond stroke only few studies have assessed the effects of telemedically supported networks on diagnosis and outcome of neurological emergencies. ANNOTeM will provide information whether this approach leads to improved outcome. In addition, a health economic analysis will be performed. STUDY REGISTRATION: German Clinical Trials Register DRKS00013067, date of registration: November 16 th, 2017, URL: http://www.drks.de/DRKS00013068.

Physically active life style is associated with increased grey matter brain volume in a medial parieto-frontal network.

To examine the association between the amount of sports activity performed during leisure time and gray matter volume (GMV) of the brain we investigated differences in GMV in a large cohort study of community-dwelling older adults. 967 individuals indicated their average weekly sports activity via a questionnaire, and underwent high resolution T1-weighted structural imaging of the brain. We used voxel based morphometry (CAT 12) in a region of interest approach for (1) comparing participants with higher versus lower sports activity (median split) and (2) calculating a linear regression on GMV and sports activity. We carefully corrected for other factors known to have an impact on GMV (sex, age, total brain volume, education, cigarettes and alcohol consumption, body mass index) and excluded pathology (history of psychiatric or neurological disease; visual inspection of brain scans). Those participants who spend more time performing sports activity per week (median split with > 1 h/week) showed higher GMV in the dorsomedial frontal lobe, the superior parietal lobe, and the precuneus/cuneus area. When splitting participants by their median (55.5 years) into two groups we found a stronger protective effect of sports against age related GMV decline for the older part of the cohort. Overall, a more active lifestyle was associated with increased GMV in areas associated with self-awareness and working memory. These cohort data support data on the protective role of sports activity for the GMV.

Effects of Omega-3 Fatty Acids on Resting Cerebral Perfusion in Patients with Mild Cognitive Impairment: A Randomized Controlled Trial.

Alteration of cerebral perfusion can be considered as a possible therapeutic target in mild cognitive impairment. This randomized, placebo-controlled, double-blind proof-of-concept study assessed effects of omega-3 fatty acids on cerebral perfusion in patients with mild cognitive impairment. In thirteen patients (omega:n=5; placebo:n=8) cerebral perfusion was measured before and after 26-weeks intervention within posterior cortical regions using magnetic resonance imaging. There was a medium effect of intervention on cerebral blood flow (η2=0.122) and blood volume (η2=0.098). The omega group showed an increase in blood flow (mean difference: 0.02 [corresponds to 26.1%], 95% confidence interval:0.00-0.05) and blood volume (mean difference: 0.08 [corresponds to 18.5%], 95% confidence interval:0.01-0.15), which was not observed in the placebo group. These preliminary findings suggest that omega-3 fatty acids supplementation may improve perfusion in cerebral regions typically affected in mild cognitive impairment.Regulation of perfusion may help to maintain brain structure and function and potentially delay conversion to dementia.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

[Aphasia: evidence-based therapy approaches]. / Aphasie: evidenzbasierte Therapieansätze.

Speech and language therapy is essential in the rehabilitation of aphasic disorders following a stroke. Due to the predicted increase of aphasia and limited resources within the healthcare system, the development of efficient and sustainable treatment methods is of exceptional importance. The effectiveness of both traditional and innovative approaches needs to be evaluated against the standards of evidence-based medicine. Class I evidence has been established for high-intensity speech and language therapy in subacute and chronic stages of aphasia. Innovative training-based approaches have so far only been evaluated in small studies but promising results have been shown for computer-based naming, video-based exercises for verbalization of complex contents and approaches modeled according to "forced-use" principles with standardized contents. Adjuvant training therapies are being developed to increase and prolong the impact of training alone, most notably non-invasive brain stimulation and pharmacological modulation. Transcranial direct current stimulation has been shown to effectively enhance training in several small randomized controlled trials but several questions still remain to be answered, including the location of electrode placement as well as the length and intensity of stimulation. Mixed evidence has been collected for the effectiveness of pharmacotherapy on speech learning and further randomized controlled trials are also needed to allow more firmly based recommendations.

Genetic Variants of the FADS Gene Cluster Are Associated with Erythrocyte Membrane LC PUFA Levels in Patients with Mild Cognitive Impairment.

BACKGROUND: Long-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI). METHODS: The present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes). RESULTS: Minor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck's depression-inventory). DISCUSSION AND CONCLUSION: These findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

[Non-invasive brain stimulation in neurology : Transcranial direct current stimulation to enhance cognitive functioning]. / Nichtinvasive Stimulationsverfahren in der Neurologie : Transkranielle Gleichstromstimulation zur kognitiven Funktionsverbesserung.

Transcranial direct current stimulation (tDCS) has been successfully used in neuroscientific research to modulate cognitive functions. Recent studies suggested that improvement of behavioral performance is associated with tDCS-induced modulation of neuronal activity and connectivity. Thus, tDCS may also represent a promising tool for reconstitution of cognitive functions in the context of memory decline related to Alzheimer's disease or aphasia following stroke; however, evidence from randomized sham-controlled clinical trials is still scarce. Initial results of tDCS-induced behavioral improvement in patients with Alzheimer's dementia and its precursors indicated that an intense memory training combined with tDCS may be effective. Early interventions in the stage of mild cognitive impairment could be crucial but further evidence is needed to substantiate this. In patients with aphasia following stroke tDCS was applied to the left and right hemispheres, with varying results depending on the severity of the symptoms and polarity of the stimulation. Patients with mild aphasia can benefit from tDCS of the language dominant hemisphere while in patients with severe aphasia tDCS of right hemispheric homologous brain language areas may be particularly relevant. Moreover, recent studies suggested that an intervention in the subacute phase of aphasia could be most promising. In summary, tDCS could provide the exciting possibility to reconstitute cognitive functions in patients with neurological disorders. Future studies have to elucidate whether tDCS can be used in the clinical routine to prevent further cognitive decline in neurodegenerative diseases and whether beneficial effects from experimental studies translate into long-term improvement in activities of daily life.

Neural correlates of unihemispheric and bihemispheric motor cortex stimulation in healthy young adults.

Bihemispheric non-invasive motor cortex stimulation has shown promise for facilitating motor learning and recovery after stroke. However, previous studies yielded mixed results that can primarily be attributed to inter-individual variability in response. We therefore aimed at investigating neural correlates of bihemispheric transcranial direct current stimulation (tDCS) effects using multimodal magnetic resonance imaging (MRI). Twenty-four young healthy adults underwent diffusion tensor imaging (DTI), resting state and task-related functional MRI in a randomized sham-controlled, double-blind study using a triple cross-over design. We compared two active stimulation conditions-bihemispheric (or "dual") and unihemispheric anodal tDCS-with sham tDCS. The anode was placed over the left primary motor cortex in all conditions, and subgroups of responders were defined according to task-related activity in this area while subjects pressed a response button with their right index fingers during a choice reaction time task. Compared to sham, "dual responders" and "anodal responders" were characterized by mean beta value increases of 86±55% and 126±55%, respectively. In line with electrophysiological studies, tDCS effects on motor cortex activation appeared to be highly variable across the group. At rest, dual tDCS caused widespread bihemispheric alterations of functional connectivity, possibly mediating its most striking effect, which consisted of bilateral motor cortex disinhibition during the task-related functional MRI. In contrast, unihemispheric anodal tDCS was characterized by more local modulations of functional motor networks. As in aging and after stroke, the impact of dual tDCS on the motor system in young adults seems to depend on the microstructural status of transcallosal motor tracts as well. In sum, these results shed light on the neural correlates of dual and anodal tDCS effects in young adults and help in explaining the great inter-individual variability in response.

The Cortical Signature of Central Poststroke Pain: Gray Matter Decreases in Somatosensory, Insular, and Prefrontal Cortices.

It has been proposed that cortical structural plasticity plays a crucial role in the emergence and maintenance of chronic pain. Various distinct pain syndromes have accordingly been linked to specific patterns of decreases in regional gray matter volume (GMV). However, it is not known whether central poststroke pain (CPSP) is also associated with cortical structural plasticity. To determine this, we employed T1-weighted magnetic resonance imaging at 3 T and voxel-based morphometry in 45 patients suffering from chronic subcortical sensory stroke with (n = 23) and without CPSP (n = 22), and healthy matched controls (n = 31). CPSP patients showed decreases in GMV in comparison to healthy controls, involving secondary somatosensory cortex (S2), anterior as well as posterior insular cortex, ventrolateral prefrontal and orbitofrontal cortex, temporal cortex, and nucleus accumbens. Comparing CPSP patients to nonpain patients revealed a similar but more restricted pattern of atrophy comprising S2, ventrolateral prefrontal and temporal cortex. Additionally, GMV in the ventromedial prefrontal cortex negatively correlated to pain intensity ratings. This shows for the first time that CPSP is accompanied by a unique pattern of widespread structural plasticity, which involves the sensory-discriminative areas of insular/somatosensory cortex, but also expands into prefrontal cortex and ventral striatum, where emotional aspects of pain are processed.

[Differences in Attitudes of Patients with Mild Cognitive Impairment Towards Early Diagnosis at a University Clinic and a Specialist Physician's Office]. / Unterscheiden sich die Einstellungen von MCI-Patienten einer Gedächtnissprechstunde von denen einer Versorgerpraxis?

AIM: To examine the attitude of patients with mild cognitive impairment to diagnostics under different healthcare settings. METHODOLOGY: A comparative survey was carried out of 38 patients at a university outpatient clinic and 91 patients at a specialist practice with regard to their attitudes towards early diagnosis of dementia and willingness to undergo CSF analysis. RESULTS: Willingness to undergo CSF analysis was higher among the patients at the university outpatient unit than those at the specialist practice (p = 0.040), and willingness to undergo early diagnosis was comparable high in both groups. CONCLUSION: Different attitudes of patients with mild cognitive impairment should be reflected in different healthcare settings.

[Stroke - lifestyle and environment]. / Schlaganfall - Lifestyle und Umwelt.

Lifestyle modifications and environmental factors are important for stroke prevention and rehabilitation after stroke. The individual stroke risk may be modified by factors like physical activity, body weight and nutrition, special dietary supplements such as vitamins, smoking, consumption of tea, coffee and alcohol, psychological factors and by keeping a pet. The focus of this article lies on measures for stroke prevention. For certain topics, it also comments on factors that are important during rehabilitation after stroke.

Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance.

The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.

Impact of low mini-mental status on health outcome up to 5 years after stroke: the Erlangen Stroke Project.

Cognitive deficits are frequent stroke sequelae. Data from population-based stroke cohorts on the impact of cognitive deficits on long-term outcome are scarce. The purpose of this study was to investigate the impact of low mini-mental status on health outcome up to 5 years after first-ever stroke. Data were collected from the Erlangen Stroke Project, a population-based stroke registry covering a source population of 103,000 inhabitants. The Mini-Mental State Examination (MMSE) was used to assess global cognitive function. Health outcome included limitations in instrumental activities of daily living (IADL, Frenchay Activities Index), low independence in activities of daily living (ADL, Barthel Index), depressive symptoms (Zung Self Rating Depression Scale), and institutionalization. Using multivariate logistic regression analysis, association of an education-adjusted MMSE score ≤ 24 with these health outcomes was investigated within distinct models at 12, 36, and 60 months after stroke as well as predictors at 3 months for low IADL. A total of 705 patients with first-ever stroke were included. Institutionalization, low levels of ADL and IADL (p < 0.001) are associated with a MMSE score ≤ 24 over 5 years after stroke. Predictors at 3 months for low IADL are low mini-mental status up to 3 years after stroke (OR 2.69, 95% CI 1.2-5.8) as well as older age (p < 0.001), and stroke severity (p < 0.001) up to 5 years. A low mini-mental status has an independent impact on long-term health outcome after stroke. Our results emphasize the importance of cognitive status screening to identify stroke survivors at risk and manage and treat these patients more efficiently.

[Lifestyle and cognition: what do we know from the aging and neurodegenerative brain?]. / Lebensstil und Kognition: Was wissen wir über das alternde und neurodegenerativ veränderte Gehirn?

Epidemiological studies demonstrated positive effects of continuous physical activity and balanced diet on cardiovascular fitness. In chronic neurodegenerative disorders, e.g. Parkinson's disease and Alzheimer's disease, physical activity has become a successful supportive symptomatic therapy. However, it has become evident that physical activity not only improves motor symptoms but also has high impact on cognition in both (elderly) healthy brain and neurodegenerative alterations in the CNS. Nutrition also has been reported to exert positive effects on brain function.Animal studies indicate an increased endogenous plasticity as the underlying mechanism in terms of activation of neuronal precursor cells in different brain areas, leading to improved brain function.First experimental studies in humans also show that physical activity and balanced nutrition increase the release of neurotrophic factors in the brain, increase the volume of grey matter in learning- and memory-associated brain regions and improve cognitive function. This phenomenon opens up noninvasive causal therapeutic options in neurodegenerative disorders and during aging-associated cognitive decline by inducing changes in lifestyle. This option could provide a socioeconomically and ethically reasonable treatment for neurodegenerative disorders.The presented article summarizes the current knowledge from animal experiments and studies in humans. It provides an overview of potential cellular and molecular candidate mechanisms and discusses novel translational clinical studies and first clinical applications.

Changes in cognitive function over 3 years after first-ever stroke and predictors of cognitive impairment and long-term cognitive stability: the Erlangen Stroke Project.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is frequent after stroke, but data from population-based stroke cohorts on the natural course of CI are limited. The purpose of this study was to determine changes in cognitive status over 3 years after stroke. METHODS: Data were collected from the Erlangen Stroke Project, an ongoing population-based stroke registry. The Mini-Mental State Examination (MMSE) for assessing global cognitive function was used; CI was defined as an MMSE score <24. RESULTS: From February 1998 to January 2006, 630 patients with first-ever stroke were included. Prevalence rates of CI at 3 months, 1 and 3 years were 15, 13, and 12%. In multivariable analysis, stroke severity, i.e. Barthel index (p < 0.001), age (OR = 1.03; 95% CI = 1.00-1.05) and diabetes mellitus (OR = 2.03; 95% CI = 1.13-3.67) were associated with CI at 3 months. Recovery rate from CI at 3 months after stroke was found to be 31% over the following 3 years. Intact cognitive function rate was 71% over 3 years and inversely associated with age (OR = 0.96; 95% CI = 0.96-0.94) and stroke severity (p < 0.001). CONCLUSION: CI is frequent among stroke survivors and associated with age, stroke severity, and diabetes mellitus, but recovery occurs in approximately one third of the patients over the course of 3 years. Factors affecting intact cognitive function over time are increasing age and stroke severity.

Impact of common KIBRA allele on human cognitive functions.

The rs17070145 polymorphism (C → T substitution, intron 9) of the KIBRA gene has recently been associated with episodic memory and cognitive flexibility. These findings were inconsistent across reports though, and largely lacked gene-gene or gene-environment interactions. The aim of the present study was to determine the impact of the rs17070145 polymorphism on clinically relevant cognitive domains and its interaction with the modifiers 'lifestyle' and 'cardiovascular risk factors'. Five-hundred forty-five elderly volunteers (mean age 64 years, ±7 years, 56% women) accomplished a comprehensive cognitive testing. Principal component analysis was used to reveal the internal structure of the data, rendering four composite scores: verbal memory, word fluency, executive function/psychomotor speed, and working memory. Lifestyle was assessed with a detailed questionnaire, age-associated risk factors by clinical interview and examination. There was no main effect of the rs17070145 genotype on any cognitive composite scores. However, we found worse performance in executive functions for T-allele carriers in the presence of arterial hypertension (ß=-0.365, p=0.0077 and 0.031 after Bonferroni correction). This association was further modified by gender, showing the strongest association in hypertensive females (ß=-0.500, p=0.0072 and 0.029 after Bonferroni correction). The effect of KIBRA on cognitive function seems to be complex and modified by gender and arterial hypertension.

Physical activity and memory functions: an interventional study.

Previous studies have suggested beneficial effects of physical activity on cognition. Here, we asked in an interventional approach if physical activity performed at different intensity levels would differentially affect episodic memory function. Additionally, we tried to identify mechanisms mediating these changes. Sixty-two healthy elderly individuals were assessed for level of physical activity, aerobic fitness, episodic memory score, neurotrophin and catecholamine levels, and received a magnetic resonance image of the brain at baseline and after a six months intervention of medium or low-intensity physical activity or control. Increase in total physical activity was positively associated with increase in memory score over the entire cohort, without significant differences between intensity groups. It was also positively associated with increases in local gray matter volume in prefrontal and cingulate cortex, and BDNF levels (trend). In conclusion, we showed that physical activity conveys the beneficial effects on memory function independently of its intensity, possibly mediated by local gray matter volume and neurotrophic factors. Our findings may carry significant implications for prevention of cognitive decline in the elderly.

Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link?

Epidemiological studies reveal better cognitive function in physically active individuals. Possible mediators for this effect are neurotrophins, which are up-regulated through physical exercise and induce neuronal growth and synaptogenesis in the animal model. Here we cross-sectionally assessed 75 healthy older individuals for levels of physical activity, aerobic fitness, and memory encoding, as well as neurotrophin levels and cerebral gray matter volume. We found that physical activity, but not cardiovascular fitness, was associated with better memory encoding after controlling for age, sex, education, depression, alcohol consumption, and smoking. Higher levels of physical activity were associated with higher levels of the neurotrophin granulocyte colony stimulating factor (G-CSF) and increased cerebral gray matter volume in prefrontal and cingulate cortex as assessed by magnetic resonance voxel-based morphometry. While mediating factors will need to be further elucidated, these findings indicate that even low-level physical activity exerts beneficial effects on memory functions in older individuals.

Caloric restriction improves memory in elderly humans.

Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.