Background: Montreal Cognitive Assessment (MoCA) represents a short screening tool for neuropsychological deficits. The study's aim was to test feasibility and acceptance of MoCA in patients with brain tumours perioperatively. Methods: Patients with supratentorial located brain tumours were assessed preoperatively (t1, day 1) and postoperatively (t2, day 3-5) using EORTC-QLQ-C30 + BN20, Distress Thermometer (DT) and the MoCA test (different versions). Feasibility was evaluated by a feedback form and patients were asked about perceived discomfort, overstraining or complexity of MoCA. Results of MoCA were correlated with clinical factors. Results: 63 patients participated, 19 were male. Mean age was 56 years. Mean completion time of MoCA was 11 min (both t1 and t2). At t1, in 27% "moderate or major difficulties" occurred during MoCA assessment vs. 41% at t2. Most of the patients (t1, 93% vs. t2, 86%) negated to be overstrained by MoCA. Better "physical function" according to EORTC-QLQ-C30 (p = 0.041, Pearson = 0.321) and higher KPS (p = 0.012, Pearson = 0.578) correlated to higher MoCA scores. Higher distress at t2 was found to be correlated with a stronger deterioration of MoCA at t2 vs. t1 (p = 0.03, Spearman-Rho =.695). Conclusion: The MoCA test was well accepted by the patients and implementable in clinical routine. Further investigations evaluating the sensitivity and specificity of the test in brain tumour patients are required. (C) 2018 Elsevier Ltd. All rights reserved.

A recent study in cognitively healthy elderly and patients of mild cognitive impairment has demonstrated an association of the posterior cingulate cortex (PCC) metabolism and hippocampal volume (HV), both known biomarkers of AD, possibly reflective of synchronous activity (DOI 10.1007/s00259-015-3222-3). The authors theorized that this association might be driven by white matter (WM) connectivity between the hippocampus and the PCC. Interestingly, WM micro- and macrostructure have been shown recently to be altered in cognitively healthy elderly with significant cerebral amyloid burden (DOI 10.3233/JAD-150049 / DOI 10.1016/j.nicl.2015.06.007). We aim to connect these findings and investigate whether the association between HV and PCC metabolism in cognitively healthy elderly is dependent on WM connectivity. A group of cognitively healthy elderly was selected from the ADNI database, FDG and AV45 PET scans as well als diffusion weighted MRI images were downloaded. Fiber tractography will be performed between the hippocampus and PCC, and indices of microstructural WM integrity extracted. Statistical analyses will be performed to investigate whether the association between HV and PCC metabolism differs between groups of higher and lower WM microstructural integrity in the fibers connecting both regions. The relationship between amyloid burden and local WM fiber integrity will be investigated. The association between HV and PCC may be different between groups. A stronger association in the higher WM integrity group may indicate maintained WM integrity as a prerequisite for synchronous activity of the hippocampus and the PCC.

Cerebral deposition of ß-amyloid and and impairment of white matter (WM) integrity are hallmarks of clinical Alzheimer's disease. They have also been reported in cognitively healthy older adults. Studies investigating the relationship of ß-amyloid deposition and WM integrity to date have shown contradictory associations, even within the same WM tracts. In this study, we proposed a load dependent association of WM integrity and cerebral ß-amyloid. AV45-PET and DTI scans of 44 cognitively healthy older adults aged 60 to 89 years from the Alzheimer's Disease Neuroimaging Initiative databank were included in the analysis. Linear and quadratic regression analyses were conducted on indices of global WM integrity and ß-amyloid deposition. Regression analyses revealed a quadratic (u-shaped) relationship between amyloid deposition and WM integrity. In subjects with lower ß-amyloid burden, higher deposition was associated with increased WM integrity. This association was found to be inverted in subjects with higher ß-amyloid burden, where higher depostion was associated with decreased WM integrity. Furthermore, participants with higher ß-amyloid burden exhibited lower cognitive perfortmances. Increased WM integrity at lower levels of ß-amyloid deposition may reflect compensation of neurodegeneration associated with ß-amyloid. At higher levels of ß-amyloid deposition, compensation may become insufficient leading to decreasing WM integrity.

Surrogates of whole-brain white matter (WM) networks reconstructed using diffusion tensor imaging (DTI) are novel markers of structural brain connectivity. Global connectivity of networks has been found impaired in clinical Alzheimer's disease (AD) compared to cognitively healthy aging. We hypothesized that network alterations are detectable already in preclinical AD and investigated major global WM network properties. Other structural markers of neurodegeneration typically affected in prodromal AD but seeming largely unimpaired in preclinical AD were also examined. 12 cognitively healthy elderly with preclinical AD as classified by florbetapir-PET (mean age 73.4 ± 4.9) and 31 age-matched controls without cerebral amyloidosis (mean age 73.1 ± 6.7) from the ADNI were included. WM networks were reconstructed from DTI using tractography and graph theory. Indices of network capacity and the established imaging markers of neurodegeneration hippocampal volume, and cerebral glucose utilization as measured by fludeoxyglucose-PET were compared between the two groups. Additionally, we measured surrogates of global WM integrity (fractional anisotropy, mean diffusivity, volume). We found an increase of shortest path length and a decrease of global efficiency in preclinical AD. These results remained largely unchanged when controlling for WM integrity. In contrast, neither markers of neurodegeneration nor WM integrity were altered in preclinical AD subjects. Our results suggest an impairment of WM networks in preclinical AD that is detectable while other structural imaging markers do not yet indicate incipient neurodegeneration. Moreover, these findings are specific to WM networks and cannot be explained by other surrogates of global WM integrity.

Cerebral amyloid-β accumulation and changes in white matter (WM) microstructure are imaging characteristics in clinical Alzheimer's disease and have also been reported in cognitively healthy older adults. However, the relationship between amyloid deposition and WM microstructure is not well understood. Here, we investigated the impact of quantitative cerebral amyloid load on WM microstructure in a group of cognitively healthy older adults. AV45-positron emission tomography and diffusion tensor imaging (DTI) scans of forty-four participants (age-range: 60 to 89 years) from the Alzheimer's Disease Neuroimaging Initiative were analyzed. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (DR), and axial diffusivity (DA) were calculated to characterize WM microstructure. Regression analyses demonstrated non-linear (quadratic) relationships between amyloid deposition and FA, MD, as well as RD in widespread WM regions. At low amyloid burden, higher deposition was associated with increased FA as well as decreased MD and DR. At higher amyloid burden, higher deposition was associated with decreased FA as well as increased MD and DR. Additional regression analyses demonstrated an interaction effect between amyloid load and global WM FA, MD, DR, and DA on cognition, suggesting that cognition is only affected when amyloid is increasing and WM integrity is decreasing. Thus, increases in FA and decreases in MD and RD with increasing amyloid load at low levels of amyloid burden may indicate compensatory processes that preserve cognitive functioning. Potential mechanisms underlying the observed non-linear association between amyloid deposition and DTI metrics of WM microstructure are discussed.

Higher general intelligence attenuates age-associated cognitive decline and the risk of dementia. Thus, intelligence has been associated with cognitive reserve or resilience in normal aging. Neurophysiologically, intelligence is considered as a complex capacity that is dependent on a global cognitive network rather than isolated brain areas. An association of structural as well as functional brain network characteristics with intelligence has already been reported in young adults. We investigated the relationship between global structural brain network properties, general intelligence and age in a group of 43 cognitively healthy elderly, age 60-85 years. Individuals were assessed cross-sectionally using Wechsler Adult Intelligence Scale-Revised (WAIS-R) and diffusion-tensor imaging. Structural brain networks were reconstructed individually using deterministic tractography, global network properties (global efficiency, mean shortest path length, and clustering coefficient) were determined by graph theory and correlated to intelligence scores within both age groups. Network properties were significantly correlated to age, whereas no significant correlation to WAIS-R was observed. However, in a subgroup of 15 individuals aged 75 and above, the network properties were significantly correlated to WAIS-R. Our findings suggest that general intelligence and global properties of structural brain networks may not be generally associated in cognitively healthy elderly. However, we provide first evidence of an association between global structural brain network properties and general intelligence in advanced elderly. Intelligence might be affected by age-associated network deterioration only if a certain threshold of structural degeneration is exceeded. Thus, age-associated brain structural changes seem to be partially compensated by the network and the range of this compensation might be a surrogate of cognitive reserve or brain resilience.

Background: The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown. Methods: The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up. Results: MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n = 25 on ERT, n = 16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n = 11, 39-68 years) showed an increase in the number of WMLs (p = 0.005). A greater proportion of younger patients (≤50 years) on ERT (n = 18) had stable WML burden compared with younger patients in the placebo group (n = 13): 44% (8 of 18) versus 31% (4 of 13), p = 0.014. The number needed to treat was 8. Conclusions: This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk.

Background: The prescribing behaviour of doctors is influenced by the pharmaceutical industry. This study investigated the extent to which contacts with pharmaceutical sales representatives (PSR) and the perception of these contacts influence prescribing habits.Method: An online questionnaire regarding contact with PSRs and perceptions of this contact was sent to 1,388 doctors, 11.5% (n = 160) of whom completed the survey. Individual prescribing data over a year (number of prescriptions, expenditure, and daily doses) for all on-patent branded, off-patent branded, and generic drugs were obtained from the Bavarian Association of Statutory Health Insurance Physicians.Results: 84% of the doctors saw PSR at least once a week, and 14% daily. 69% accepted drug samples, 39% accepted stationery and 37% took part in sponsored continuing medical education (CME) frequently. 5 physicians (3%) accepted no benefits at all. 43% of doctors believed that they received adequate and accurate information from PSRs frequently or always and 42% believed that their prescribing habits were influenced by PSR visits occasionally or frequently. Practices that saw PSRs frequently had significantly higher total prescriptions and total daily doses (but not expenditure) than practices that were less frequently visited. Doctors who believed that they received accurate information from PSRs showed higher expenditures on off-patent branded drugs (thus available as generics) and a lower proportion of generics. The eschewal of sponsored CME was associated with a lower proportion of on patent-branded drug prescriptions, lower expenditure on off-patent branded drug prescriptions and a higher proportion of generics. Acceptance of office stationery was associated with higher daily doses.Conclusions: Avoidance of industry-sponsored CME is associated with more rational prescribing habits. Furthermore, gift acceptance and the belief that one is receiving adequate information from a PSR are associated with changed prescribing habits. Further studies with larger sample sizes are needed.

Higher cognitive functions like intelligence depend on efficient functional integration of different regions of the brain. Structural brain networks provide the basis for this integration and have been found to be associated with intelligence in young and elderly healthy people. We wanted to investigate whether brain networks are associated with executive functions and the presence of amyloid in a sample of clinically healthy elderly people. We investigated this hypothesis in a subsample of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort of 46 clinically healthy elderly who received DTI as well as 18 F-AV-45 amyloid imaging, 13 of which were labeled as amyloid positive. Structural brain networks were reconstructed using DTI and determinstic fiber tractography. Network efficiency was assessed using graph theory. Executive functions were considered as a composite score as proposed by Gibbons et al. Linear regression analyses were used to investigate associations between global network efficiency, executive functions and amyloid burden. Controlling for age and education, network efficiency was positively associated with executive functions. Controlling for age, education and executive functions, network efficiency was decreased in subjects labeled as amyloid positive. However, amyloid was not associated with executive functions. We provide further evidence that white matter brain network efficiency is associated with higher cognitive functions in clinically healthy elderly. Furthermore, the efficiency of the networks seems to be negatively affected by the presence of amyloid.

OBJECTIVES:Comparability of measures of quality of life in dementia and in other diagnostic groups, such as mild cognitive impairment, normal aging, or other diseases, is highly desirable. However, the impact of cognitive deficits and impaired insight on applicability and validity of generic instruments is sparsely studied.PARTICIPANTS AND MEASUREMENTS:Sixty patients with dementia [38 women; age: mean (SD) = 78.7 (6.4) years; Mini-Mental State Examination (MMSE): mean (SD) = 20.2 (6.0)] recruited as part of the start-modem study, a multicenter care research study in Germany, completed the generic instrument SF-36 and the specific instrument Quality of Life-Alzheimer's Disease (QOL-AD).RESULTS:QOL-AD self-rating scores [mean (SD) = 32.8 (5.9)] and SF-36 subscales indicated moderate to good quality of life in the total group. Reliability and validity of five subdomains of the SF-36 were poor in subgroups of patients with impaired insight or with MMSE scores less than 17 (Cronbach's α <0.7, no significant correlation to the QOL-AD). In contrast, for patients with both adequate insight and MMSE score greater than 16 (n = 33; 55%) Cronbach's α of the subdomains of the SF-36 ranged between 0.920 and 0.676. Seven of the eight subdomains correlated significantly with the QOL-AD self-rating and composite score in this group of patients (0.355 ≤ r ≤ 0.709).CONCLUSIONS:Despite the impact of insight and cognition on self-rated quality of life, we found reliable and valid data for a broad spectrum of patients with dementia. According to the present data, the SF-36 is suitable for dementia patients with both insight into their deficits and an MMSE score greater than 16.

The Stroop interference task is a widely used paradigm to examine cognitive inhibition, which is a key component of goal-directed behavior. With increasing age, reaction times in the Stroop interference task are usually slowed. However, to date it is still under debate if age-related increases in reaction times are merely an artifact of general slowing. The current study was conducted to investigate the role of general slowing, as measured by Trail-Making-Test-A, in age-related alterations of Stroop interference. We applied Diffusion Tensor Imaging (DTI) to determine the topography of neuronal networks underlying Stroop interference under control of general slowing. On the behavioral level, linear regression analysis demonstrated that age accounted for significant variance on Stroop interference, whereas TMT-A performance did not. Controlling for TMT-A, DTI based white matter analyses demonstrated a strong association of Stroop interference with integrity measures of genu of corpus callosum, bilateral anterior corona radiata, and bilateral anterior limb of capsula interna. These pathways are associated with frontal brain regions by either connecting the bilateral dorsolateral prefrontal cortex or the anterior cingulate cortex with frontal and subcortical regions or by containing fibers which are part of cortico-thalamic circuits that cross prefrontal regions. Importantly, results expand our knowledge of the neural basis of Stroop interference and emphasize the importance of white matter integrity of frontal pathways in the modulation of Stroop interference. Combining behavioral and DTI findings our results further suggest that cognitive inhibition, as measured by Stroop task, is a qualitatively distinct cognitive process that declines with age.

Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 ± 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n = 18) and high (n = 17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p = 0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions.

Normal aging is characterized by brain glucose metabolism decline predominantly in the prefrontal cortex. The goal of the present study was to assess whether this change was associated with age-related alteration of white matter (WM) structural integrity and/or functional connectivity. FDG-PET data from 40 young and 57 elderly healthy participants from two research centers (n=49/48 in Center 1/2) were analyzed. WM volume from T1-weighted MRI (Center 1), fractional anisotropy from diffusion-tensor imaging (Center 2), and resting-state fMRI data (Center 1) were also obtained. Group comparisons were performed within each imaging modality. Then, positive correlations were assessed, within the elderly, between metabolism in the most affected region and the other neuroimaging modalities. Metabolism decline in the elderly predominated in the left inferior frontal junction (LIFJ). LIFJ hypometabolism was significantly associated with macrostructural and microstructural WM disturbances in long association fronto-temporo-occipital fibers, while no relationship was found with functional connectivity. The findings offer new perspectives to understand normal aging processes and open avenues for future studies to explore causality between age-related metabolism and connectivity changes.

AIMSIn the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance.METHODSTwenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated.RESULTSPerformance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas.CONCLUSIONThese findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA.

To evaluate the feasibility of multicenter tractography of the cingulate bundle (CB) in Alzheimer's disease (AD).

The cingulate bundle (CB) is known to be microstructurally altered in MCI and AD. DTI indices have shown promising results in measuring these changes in vivo in single-center studies. However, because of their known susceptibility to center effects, the accuracy and comparatibility of DTI indices with regard to AD pathology has been scarcely studied in multi-center settings so far. A rater-independent algorithm of automated deterministic tractography was applied to scans of patients with probable AD und healthy controls (HC) and the CB was segmented. Scans were obtained on three different scanners by the same manufacturer. Subsequently, diagnosis and center effects on the DTI indices fractional anisotropy (FA), mean diffusivity (MD), streamlines density and track volume were estimated. Additionally, the effect of the tracking parameters on accuracy and comparability was estimated. Coefficients of variance (CV) of the indices across centers were similar to single-center CVs and for HC and AD, respectively. Center effects were significant for all indices. After adjustment for center and age, a significant increase of MD and decrease of FA was observed in the AD group. Tracking parameters of FA≤0.15 and curvature ≤50° yielded most comparable and accurate results with regard to AD. In spite of the presence of strong center effects, a significantly altered microstructural integrity of the CB in AD was consistently detected. DTI indices obtained by rater-independent segmentation of the CB via tractography may qualify as biologically sustained surrogate markers for diagnostics and monitoring in multi-center trials of AD.

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elderly is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this exploratory multi-center study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention.