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Objective:To compare the effects of 2 forms of exercise, i.e., a 6-week trial of treadmill training with virtual reality (TT + VR) that targets motor and cognitive aspects of safe ambulation and a 6-week trial of treadmill training alone (TT), on brain activation in patients with Parkinson disease (PD).Methods:As part of a randomized controlled trial, patients were randomly assigned to 6 weeks of TT (n = 17, mean age 71.5 ± 1.5 years, disease duration 11.6 ± 1.6 years; 70% men) or TT + VR (n = 17, mean age 71.2 ± 1.7 years, disease duration 7.9 ± 1.4 years; 65% men). A previously validated fMRI imagery paradigm assessed changes in neural activation pretraining and post-training. Participants imagined themselves walking in 2 virtual scenes projected in the fMRI: (1) a clear path and (2) a path with virtual obstacles. Whole brain and region of interest analyses were performed.Results:Brain activation patterns were similar between training arms before the interventions. After training, participants in the TT + VR arm had lower activation than the TT arm in Brodmann area 10 and the inferior frontal gyrus (cluster level familywise error–corrected [FWEcorr] p < 0.012), while the TT arm had lower activation than TT + VR in the cerebellum and middle temporal gyrus (cluster level FWEcorr p < 0.001). Changes in fall frequency and brain activation were correlated in the TT + VR arm.Conclusions:Exercise modifies brain activation patterns in patients with PD in a mode-specific manner. Motor-cognitive training decreased the reliance on frontal regions, which apparently resulted in improved function, perhaps reflecting increased brain efficiency.

The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer's disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11.2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD.

Hypothalamus is a key brain region regulating several essential homeostatic functions, including the sleep–wake cycle. Alzheimer’s disease (AD) pathology affects nuclei controlling sleep–wake rhythm sited in this brain area. Since only post-mortem studies documented the relationship between hypothalamic atrophy and sleep–wake cycle impairment, we investigated in AD patients the possible hypothalamic in vivo alteration using 2-deoxy-2-(18F) fluoro-d-glucose ([18F]FDG) positron emission tomography ([18F]FDG PET), and its correlations with sleep impairment and cerebrospinal-fluid (CSF) AD biomarkers (tau proteins and β-amyloid42). We measured sleep by polysomnography, CSF AD biomarkers and orexin levels, and hypothalamic [18F]FDG PET uptake in a population of AD patients compared to age- and sex-matched controls. We documented the significant reduction of hypothalamic [18F]FDG PET uptake in AD patients (n = 18) compared to controls (n = 18) (p

It has been challenging to identify clinical cognitive markers that can differentiate patients with Alzheimer’s disease (AD) from those with behavioral variant frontotemporal dementia (bvFTD). The Short-term Memory Binding (STMB) test assesses the ability to integrate colors and shapes into unified representations and to hold them temporarily during online performance. The objective of this study is to investigate whether free recall deficits during short-term memory binding (STMB) test can differentiate patients with AD from those with bvFTD and controls. Participants were 32 cognitively intact adults, 35 individuals with AD and 18 with bvFTD. All patients were in the mild dementia stage. Receiver-operating characteristics (ROC) analyses were used to examine the diagnostic accuracy of the STMB. The results showed that AD patients performed significantly worse than controls and bvFTD patients in the STMB test, while the latter groups showed equivalent performance. The bound condition of the STMB test showed an AUC of 0.853, with 84.4% of sensitivity and 80% of specificity to discriminate AD from controls and an AUC of 0.794, with 72.2% of sensitivity and 80% of specificity to differentiate AD from bvFTD. Binding deficits seem specific to AD. The free recall version of the STMB test can be used for clinical purposes and may aid in the differential diagnosis of AD. Findings support the view that the STMB may be a suitable cognitive marker for AD.

Objective:Whereas Alzheimer disease (AD) is associated with inner retina thinning visualized by spectral-domain optical coherence tomography (SD-OCT), we sought to determine if the retina has a distinguishing biomarker for frontotemporal degeneration (FTD).Methods:Using a cross-sectional design, we examined retinal structure in 38 consecutively enrolled patients with FTD and 44 controls using a standard SD-OCT protocol. Retinal layers were segmented with the Iowa Reference Algorithm. Subgroups of highly predictive molecular pathology (tauopathy, TAR DNA–binding protein 43, unknown) were determined by clinical criteria, genetic markers, and a CSF biomarker (total tau: β-amyloid) to exclude presumed AD. We excluded eyes with poor image quality or confounding diseases. SD-OCT measures of patients (n = 46 eyes) and controls (n = 69 eyes) were compared using a generalized linear model accounting for intereye correlation, and correlations between retinal layer thicknesses and Mini-Mental State Examination (MMSE) were evaluated.Results:Adjusting for age, sex, and race, patients with FTD had a thinner outer retina than controls (132 vs 142 μm, p = 0.004). Patients with FTD also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 μm, p = 0.003) and ellipsoid zone (EZ) (14.5 vs 15.1 μm, p = 0.009) than controls, but had similar thicknesses for inner retinal layers. The outer retina thickness of patients correlated with MMSE (Spearman r = 0.44, p = 0.03). The highly predictive tauopathy subgroup (n = 31 eyes) also had a thinner ONL (88.7 vs 97.4 μm, p = 0.01) and EZ (14.4 vs 15.1 μm, p = 0.01) than controls.Conclusions:FTD is associated with outer retina thinning, and this thinning correlates with disease severity.

Background: Alzheimer’s disease (AD) progression varies substantially among patients, hindering calculation of residual total life expectancy (TLE) and its decomposition into disability-free life expectancy (DFLE) and disabled life expectancy (DLE) for individual patients with AD. The objective of the present study was to assess the accuracy of a new synthesis of Sullivan’s life table (SLT) and longitudinal Grade of Membership (L-GoM) models that estimates individualized TLEs, DFLEs, and DLEs for patients with AD. If sufficiently accurate, such information could enhance the quality of important decisions in AD treatment and patient care. Methods: We estimated a new SLT/L-GoM model of the natural history of AD over 10 years in the Predictors 2 Study cohort: N = 229 with 6 fixed and 73 time-varying covariates over 21 examinations covering 11 measurement domains including cognitive, functional, behavioral, psychiatric, and other symptoms/signs. Total remaining life expectancy was censored at 10 years. Disability was defined as need for full-time care (FTC), the outcome most strongly associated with AD progression. All parameters were estimated via weighted maximum likelihood using data-dependent weights designed to ensure that the estimates of the prognostic subtypes were of high quality. Goodness of fit was tested/confirmed for survival and FTC disability for five relatively homogeneous subgroups defined to cover the range of patient outcomes over the 21 examinations. Results: The substantial heterogeneity in initial patient presentation and AD progression was captured using three clinically meaningful prognostic subtypes and one terminal subtype exhibiting highly differentiated symptom severity on 7 of the 11 measurement domains. Comparisons of the observed and estimated survival and FTC disability probabilities demonstrated that the estimates were accurate for all five subgroups, supporting their use in AD life expectancy calculations. Mean 10-year TLE differed widely across subgroups: range 3.6–8.0 years, average 6.1 years. Mean 10-year DFLE differed relatively even more widely across subgroups: range 1.2–6.5 years, average 4.0 years. Mean 10-year DLE was relatively much closer: range 1.5–2.3 years, average 2.1 years. Conclusions: The SLT/L-GoM model yields accurate maximum likelihood estimates of TLE, DFLE, and DLE for patients with AD; it provides a realistic, comprehensive modeling framework for endpoint and resource use/cost calculations.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

Introduction: A fall in hospital deaths in dementia has been interpreted as indicating an improvement in end-of-life care. Whether other indicators of quality of end-of-life care, such as emergency department (ED) attendance, show a similar trend is unclear. Methods: Retrospective cohort study using electronic medical records from a large mental health care provider, linked to national mortality and hospital use data (2008–2013). Results: Of 4867 patients, 78.6% (3824) had at least one ED attendance during their last year of life (mean 2.13, standard deviation 2.34, range 0–54). ED attendance increased over the time period (incidence rate ratio 1.62, 95% confidence interval 1.46–1.80 for 2012–2013 compared with 2008–2009). Discussion: ED attendance in the last year of life for people with dementia is common and is increasing. Policy makers must pay attention to a broader range of indicators of poor end-of-life care alongside the place of death.

Background Drugs with anticholinergic properties may be associated with various adverse clinical effects. The relationship between the anticholinergic (AC) burden and functional, global cognitive performance and behavior disturbances was assessed among elderly patients. Methods A cross-sectional study was conducted between January 2012 and June 2014 in a memory clinic among outpatients living at home and with subjective cognitive decline (SCD) or neurocognitive disorders (NCD). The AC burden was measured using the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS), the Anticholinergic Cognitive Burden (ACB), Chew’s score, Han’s score, and the number of drugs with AC activity. Functional, cognitive performance and behavior disturbances were assessed using the Instrumental Activities of Daily Living (IADL) scale (IADL), the Mini Mental State Examination (MMSE), and the Neuropsychiatric Inventory (NPI). Results Among 473 included patients, 46.3% were at major NCD. Patients took on average 5.3 ± 2.6 drugs. MMSE was lower when Han’s score (p = 0.04) and number of AC drugs were higher (p

Background: Although physical exercise has been suggested to influence cognitive function, previous exercise studies show inconsistent results in people with dementia. Objectives: To investigate effects of exercise on cognitive function in people with dementia. Method: The Umea a Dementia and Exercise (UMDEX) study, a cluster-randomized controlled trial, was set in 16 nursing homes in Umea, Sweden. One hundred-and-forty-one women and 45 men with dementia; mean age of 85 y and mean MiniMental State Examination (MMSE) score of 15, were randomized to a High-Intensity Functional Exercise program or a seated attention control activity. Blinded assessors measured global cognitive function using the MMSE and the Alzheimer's disease Assessment Scale -Cognitive subscale (ADAS-Cog), and executive function using Verbal fluency (VF) at baseline and 4 months (directly after intervention completion), and MMSE and VF at 7 months. Results: Linear mixed models showed no between-group effects in mean difference from baseline (95% confidence intervals, CI) at 4 months in MMSE (-0.27; 95% CI -1.4 to 0.87, p = 0.644), ADAS-Cog (-1.04, 95% CI -4 to 1.92, p = 0.491), or VF (-0.53, 95% CI -1.42 to 0.35, p = 0.241) or at 7 months in MMSE (-1.15, 95% CI -2.32 to 0.03, p = 0.056) or VF (-0.18, 95% CI -1.09 to 0.74, p = 0.707). Conclusion: A 4-month, high-intensity functional exercise program had no superior effects on global cognition or executive function in people with dementia living in nursing homes when compared with an attention control activity. Originally published in manuscript form with title [Effects of exercise on cognitive function in older people with dementia: a randomized controlled study]

Background Whether age at onset influences Alzheimer’s disease (AD) progression and the effectiveness of cholinesterase inhibitor (ChEI) therapy is not clear. We aimed to compare longitudinal cognitive and global outcomes in ChEI-treated patients with early-onset Alzheimer’s disease (EOAD) versus late-onset Alzheimer’s disease (LOAD) in clinical practice. Methods This 3-year, prospective, observational, multicentre study included 1017 participants with mild to moderate AD; 143 had EOAD (age at onset

© 2017 Elsevier Ltd Introduction People with Parkinson's disease (PD) have difficulty performing upper extremity (UE) activities. The aim of this study was to investigate if exergames targeting the UE improve arm and hand activities and impairments and to establish the acceptability and feasibility of these games in people with PD. Methods Two tablet-based exergames were developed which were controlled with finger movements or unimanual whole arm movements. Participants with PD were randomized to an exergame (n = 19) or control (n = 19) group. The exergame group performed UE exergames at home, 3 times per week for 12 weeks. The primary outcome measure was the nine hole peg test. Secondary outcomes included measures of UE activities and impairments, including the tapping test [speed (taps/60s), and error (weighted error score/speed)]. Results There were no between group differences in the nine hole peg test, or in any secondary outcome measures except for the tapping test. Horizontal tapping test results showed that exergame participants improved their speed (mean difference = 10.9 taps/60s, p < 0.001) but increased error (mean difference = 0.03, p = 0.03) compared to the control group. Participants enjoyed the games and improved in their ability to play the games. There were no adverse events. Conclusion The UE exergames were acceptable and safe, but did not translate to improvement in functional activities. It is likely that the requirement of the games resulted in increased movement speed at the detriment of accuracy. The design of exergames should consider task specificity.

BACKGROUND Subjective cognitive complaints (SCCs) may be an early marker of prodromal Alzheimer's disease. OBJECTIVES Using a 10-item yes/no SCCs questionnaire (Le Questionnaire de Plainte Cognitive [QPC]), we evaluated the prevalence and distribution of SCCs in cognitively healthy Czech older adults and examined total score and specific QPC items in relation to depressive symptomology and cognitive performance. METHODS A sample of 340 cognitively healthy older community-dwelling volunteers aged 60 or older from the third wave of the longitudinal project National Normative Study of Cognitive Determinants of Healthy Aging, who underwent a comprehensive neuropsychological assessment and completed the QPC and the 15-item Geriatric Depression Scale (GDS-15). Regression analysis was controlled for age when GDS-15 was the outcome and for age and GDS-15 with cognitive domains as the outcome. RESULTS 71% reported 1 + SCCs, with prevalence of individual complaints ranging from 4% to 40%. The number of SCCs was associated with GDS-15 (p

Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

Background:To expand on prior literature by examining how various education parameters (performance-based reading literacy, years of education, and self-rated quality of education) relate to a cognitive screening measure's total and subscale scores of specific cognitive abilities.Methods:Black adults (age range: 55–86) were administered self-rated items years of education and quality of education, and a measure of performance-based reading literacy. The Mini-Mental State Examination (MMSE) was used to screen for overall cognitive functioning as well as performance on specific cognitive abilities.Results:Sixty-nine percent of the sample had reading grade levels that were less than their reported years of education. Lower years of education and worse reading literacy are associated with poorer MMSE performance, particularly on the attention and calculation subscales.Conclusions:Years of education, a commonly used measure for education, may not be reflective of Black adults’ educational experiences/qualities. Thus, it is important to account for the unique educational experiences of adults that could influence their MMSE performance. Incorporating quality and quantity of education will provide a more comprehensive understanding of the individual's performance on cognitive measures, specifically as it relates to sociocultural differences.

IntroductionThe etiologies of dementia are complex and influenced by genetic and environmental factors including medical conditions.MethodsWe used Cox regression model to estimate the individual and joint effects of physical activity (PA), apolipoprotein E (APOE) ε4, and diabetes status on risk of dementia and cognitive impairment without dementia (CIND) among 1438 cognitively intact Mexican American elderly who were followed up to 10years.ResultsThe risk of developing dementia/CIND was increased more than threefold in APOE ε4 carriers or diabetics with low levels of PA compared with ε4 noncarriers or nondiabetics who engaged in high PA (ε4: hazard ratio [HR]=3.44, 95% confidence interval [CI]=1.85-6.39; diabetes: HR=3.11, 95% CI=1.87-5.18); the presence of all three risk factors increased risk by nearly 10-fold (HR=9.49, 95% CI=3.57-25.3).DiscussionPA in elderly Hispanics protects strongly against the onset of dementia/CIND, especially in APOE ε4 carriers and those who have diabetes.

Objective:To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife.Methods:We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (β-amyloid 42 [Aβ42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein–1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aβ42 was expressed relative to Aβ40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aβ42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch.Results:Worse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aβ42/Aβ40 and higher t-tau/Aβ42, p-tau/Aβ42, MCP-1/Aβ42, and YKL-40/Aβ42. There were no significant associations between sleep and NFL or neurogranin.Conclusions:Self-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.

Older adults' negative beliefs about ageing are related to their health and functioning, but little is known about how perceptions of ageing (POA) relate to frailty status. This study aimed to explore the relationship between POA and frailty. Secondary analysis of data used were from the English Longitudinal Study of Ageing Waves 2 and 5. A POA score was based on participants' responses to 12 statements using a five-point Likert scale at baseline, and a Frailty Index (FI) score was calculated for each participant for both waves. Multiple linear regression models were conducted to assess the relationship between POA and frailty cross-sectionally and longitudinally in models controlled for age, gender, depression symptoms, and socioeconomic status. Older adults with more negative POA had greater frailty (β = .12, p

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

Parkinson's disease (PD) patients frequently suffer from dexterous deficits impeding activities of daily living. There is controversy whether impaired fine motor skill may stem from limb kinetic apraxia (LKA) rather than bradykinesia. Based on classical models of limb praxis LKA is thought to result when premotor transmission of time-space information of skilled movements to primary motor representations is interrupted. Therefore, using functional magnetic resonance imaging (fMRI) we tested the hypothesis that dexterous deficits in PD are associated with altered activity and connectivity in left parieto-premotor praxis network. Whole-brain analysis of fMRI activity during a task for LKA (coin rotation) showed increased activation of superior and inferior parietal lobule (SPL, IPL) and ventral premotor cortex (vPM) in PD patients compared to controls. For bradykinesia (assessed by finger tapping) a decreased fMRI activity could be detected in patients. Additionally, psychophysical interaction analysis showed increased functional connectivity between IPL and the posterior hippocampi in patients with PD. By contrast, functional connectivity to the right dorsolateral prefrontal cortex was decreased in patients with PD compared to controls. In conclusion, our data demonstrates that dexterous deficits in PD were associated with enhanced fMRI activation of the left praxis network upstream to primary motor areas, mirroring a neural correlate for the behavioral dissociation of LKA and bradykinesia. Furthermore, the findings suggest that patients recruit temporal areas of motor memory as an attempt to compensate for impaired motor skills. Finally, dysexecutive function may contribute to the deficit., Highlights • Impaired dexterity is related to a defective praxis network in PD. • The findings support the concept of an underlying limb kinetic apraxia. • Recruitment of temporal areas may reflect compensatory recall of motor engrams. • Dysexecutive control in PD may contribute to impaired motor skill.

Background:The autism spectrum (AS) is a multifaceted neurodevelopmental variant associated with lifelong challenges. Despite the relevant importance of identifying AS in adults for epidemiological, public health, and quality of life issues, the measurement properties of the tools currently used to screen and diagnose adults without intellectual disabilities (ID) have not been assessed.Objectives:This systematic review addresses the accuracy, reliability, and validity of the reported AS screening and diagnostic tools used in adults without ID.Methods:Electronic databases and bibliographies were searched, and identified papers evaluated against inclusion criteria. The PRISMA statement was used for reporting the review. We evaluated the quality of the papers using the COSMIN Checklist for psychometric data, and QUADAS-2 for diagnostic data. For the COSMIN assessment, evidence was considered to be strong when several methodologically good articles, or one excellent article, reported consistent evidence for or against a measurement property. For the QUADAS ratings, evidence was considered to be “satisfactory” if at least one study was rated with a low risk of bias and low concern about applicability.Results:We included 38 articles comprising 32 studies, five reviews, and one book chapter and assessed nine tools (three diagnostic and six screening, including eight of their short versions). Among screening tools, only AQ-50, AQ-S, and RAADS-R and RAADS-14 were found to provide satisfactory or intermediate values for their psychometric properties, supported by strong or moderate evidence. Nevertheless, risks of bias and concerns on the applicability of these tools limit the evidence on their diagnostic properties. We found that none of the gold standard diagnostic tools used for children had satisfactory measurement properties.Conclusion:There is limited evidence for the measurement properties of the screening and diagnostic tools used for AS adults with a mean normal range of measured intelligence. This may lessen the validity of conclusions and public health decisions on an important fraction of the adult autistic population. This not only justifies further validation studies of screening and diagnostic tools for autistic adults, but also supports the parallel use of self-reported information and clinical expertise with these instruments during the diagnostic process.

Background:Comprehensive neurocognitive assessment may not be performed in clinical practice, as it takes too much time and requires special training. Development of easily applicable, time-saving, and cost effective screening methods has allowed identifying the individuals that require further evaluation. The aim of present study was to assess the diagnostic value of the Attended With (AW) and Head-Turning Sign (HTS) for screening cognitive impairment (CI).Methods:Comprehensive geriatric assessment was performed in 529 elderly outpatients, and the presence or absence of AW and HTS was investigated in them all.Results:Of the 529 patients, of whom the mean age was 75.67 ± 8.29 years, 126 patients were considered as CI (102 dementia, 24 mild CI). The patients with positive AW had significantly lower scores on Mini-Mental State Examination, Cognitive State Test, and Montreal Cognitive Assessment, and activities of daily living compared to AW (−) patients (p < 0.001). Similar significant findings were obtained in the patients with positive and negative HTS (p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of AW in detecting CI were 92%, 37%, 31.4%, and 93.7%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of HTS were 80%, 64%, 41.8%, and 91.5%, respectively. The area under the receiver-operating characteristics curve was 0.90 for AW and 0.82 for HTS.Conclusion:AW and HTS are fast, simple, effective, and sensitive methods for detecting CI. Therefore, they can be used for older adults attending the primary care settings with memory loss. Those with positive AW or HTS can be referred to the relevant centers for detailed cognitive assessment.

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty‐six HE and 27 aMCI patients underwent resting‐state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high‐resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922–4932, 2017. © 2017 Wiley Periodicals, Inc.

Background The interrelationships between omega-3 fatty acids status, brain perfusion, and cognition are not well understood. Objective To evaluate if SPECT brain imaging of cerebral perfusion and cognition varies as a function of omega-3 fatty acid levels. Methods A random sample of 166 study participants was drawn from a psychiatric referral clinical for which erythrocyte quantification of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) (the Omega-3 Index) was available. Quantitative brain SPECT was done on 128 regions based on a standard anatomical Atlas. Persons with erythrocyte EPA+DHA concentrations were dichotomized based on membership in top 50th percentile versus bottom 50th percentile categories. Two-sample t-tests were done to identify statistically significant differences in perfusion between the percentile groups. Partial correlations were modeled between EPA+DHA concentration and SPECT regions. Neurocognitive status was assessed using computerized testing (WebNeuro) and was separately correlated to cerebral perfusion on brain SPECT imaging and omega-3 EPA+DHA levels. Results Partial correlation analyses showed statistically significant relationships between higher omega-3 levels and cerebral perfusion were in the right parahippocampal gyrus (r = 0.20, p = 0.03), right precuneus (r = 0.20, p = 0.03), and vermis subregion 6 (p = 0.21, p = 0.03). Omega-3 Index levels separately correlated to the feeling subsection of the WebNeuro (r = 0.25, p = 0.01). Conclusion Quantitative omega-3 EPA+DHA erythrocyte concentrations are independently correlated with brain perfusion on SPECT imaging and neurocognitive tests. These results have implications for the role of omega-3 fatty acids toward contributing to cognitive reserve.

In this study, we investigated the effects of age and of mild cognitive impairment (MCI) on decision making under risk by adopting a task representing real-life health-related situations and involving complex numerical information. Moreover, we assessed the relationship of real-life decision making to other cognitive functions such as number processing, executive functions, language, memory, and attention. For this reason, we compared the performance of 19 healthy, relatively younger adults with that of 18 healthy older adults and the performance of the 18 healthy older adults with that of 17 patients with MCI. Results indicated difficulties in real-life decision making for the healthy older adults compared with the healthy, relatively younger adults. Difficulties of patients with MCI relative to the healthy older adults arose in particular in difficult items requiring processing of frequencies and fractions. Significant effects of age and of MCI in processing frequencies were also evident in a ratio number comparison task. Decision-making performance of healthy participants and of the patient group correlated significantly with number processing. There was a further significant correlation with executive functions for the healthy participants and with reading comprehension for the patients. Our results suggest that healthy older individuals and patients with MCI make less advantageous decisions when the information is complex and high demands are put on executive functions and numerical abilities. Moreover, we show that executive functions and numerical abilities are not only essential in laboratory gambling tasks but also in more realistic and ecological decision situations within the health context.

PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

Introduction With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk. Methods Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates. Results The score system used total points ranging from −1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system. Discussion This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals.

Background Cognitive impairment is common in patients treated with hemodialysis. The trajectory of cognitive function and risk factors for cognitive decline remain uncertain in this population. Study Design Longitudinal cohort. Setting & Participants 314 prevalent hemodialysis patients. Predictors Age, sex, race, education level, hemodialysis vintage, cause of end-stage renal disease, and baseline history of cardiovascular disease. Outcomes Cognitive function as determined by a comprehensive neurocognitive battery, administered at baseline and yearly when possible. Individual cognitive test results were reduced into 2 domain scores using principal components analysis, representing memory and executive function, which were used as our coprimary outcomes and by definition have a mean of zero and SD of 1. Results Mean age was 63 years; 54% were men, 22% were black, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 0.9-4.2) years, 196 had at least 1 follow-up test, 156 died, and 43 received a kidney transplant. Linear mixed models and joint models, which accounted for competing risks from death, dropout, or kidney transplantation, showed nearly identical results. The joint model demonstrated a decline in executive function (−0.09 [95% CI, −0.13 to −0.05] SD per year), whereas memory improved slightly (0.05 [95% CI, 0.02 to 0.08] SD per year). A significant yearly decline was also seen in the Mini-Mental State Examination score (median change, −0.41; 95% CI, −0.57 to −0.25). Older age was the only significant risk factor for steeper executive function decline (−0.04 [95% CI, −0.06 to −0.02] SD steeper annual decline for each 10 years of age). Limitations Prevalent hemodialysis patients only, limited follow-up testing due to high mortality rate, and exclusion of participants with severe cognitive deficits or dementia. Conclusions Prevalent hemodialysis patients demonstrate significant cognitive decline, particularly within tests of executive function. Older age was the only statistically significant risk factor for steeper cognitive decline, which may have important clinical consequences for patient management and education. Future studies should evaluate strategies to maintain or improve cognitive function.

Purpose It is widely known that there is low striatal 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). However, a consistent quantitative evaluation method for DAT-SPECT has not yet been established. There are two semi-quantitative software packages for DAT-SPECT available in Japan, namely, DaTView and DaTQUANT. The aim of this study was to identify which of these is superior for distinguishing DLB from AD. Moreover, we aimed to identify which region of the striatum is more suitable for distinguishing DLB from AD. Methods Patients with Alzheimer's disease (AD) (n = 95) and patients with DLB (n = 133) who underwent DAT-SPECT were enrolled. DaTView and DaTQUANT were used as semi-quantitative analysis tools for DAT-SPECT. Results There were significant correlations in DAT uptake between DaTView and entire regions by DaTQUANT. There was no significant difference in diagnostic accuracy between DaTView and DaTQUANT except in the posterior putamen by DaTQUANT. Conclusions For distinguishing DLB from AD, both of DaTView and DaTQUANT software are useful. Moreover, assessing the DAT uptake in entire striatum by DaTView might be sufficient for distinguishing DLB from AD.

Background and Objectives Adult attention-deficit/hyperactivity disorder (ADHD) is frequent in patients with substance use disorders (SUD), but information on its prevalence in high-dose benzodiazepine (BZD) dependence is lacking. We estimated the prevalence of adult ADHD in a group of treatment-seeking high-dose BZD dependent patients according to a valid screening tool, and explored the demographic and clinical characteristics of patients that screened positive for ADHD (ADHD+) in comparison to those that screened negative (ADHD−). Methods We prospectively recruited 167 consecutive patients with high-dose BZD dependence and screened them for adult ADHD with the World Health Organization Adult ADHD Self-Report Scale version 1.1 (ASRS-v1.1) Symptom Checklist Part A. We compared demographic and clinical characteristics in ADHD+ and ADHD− groups. Results Fifty-three patients (31.7% of the sample) were positive to adult ADHD screening. ADHD+ patients showed a significantly larger prevalence of poly-drug abuse than ADHD− ones. BZD formulation and active principle significantly differed between the two groups. The other clinical variables, including psychiatric comorbidity, as well as the demographic ones, did not differ in ADHD+ versus ADHD− comparison. Discussion and Conclusions Adult ADHD may be common in treatment-seeking high-dose BZD dependent patients according to ASRS-v1.1 Symptom Checklist Part A. Scientific Significance Screening for ADHD in this type of SUD with this questionnaire is quick and may offer useful information for prognosis and treatment. (Am J Addict 2017;26:610–614)

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer's disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r = 0.26, p = 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p = 0.033) and MCI-AD (p = 0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain.

Spatial proximity of signals from different sensory modalities is known to be a crucial factor in facilitating efficient multisensory processing in young adults. However, recent studies have demonstrated that older adults exhibit strong visuotactile interactions even when the visual stimuli were presented in a spatially disparate position from a tactile stimulus. This suggests that visuotactile peripersonal space differs between older and younger adults. In the present study, we investigated to what extent peripersonal space expands in the sagittal direction and whether this expansion was linked to the decline in sensorimotor functions in older adults. Vibrotactile stimuli were delivered either to the left or right index finger, while visual stimuli were presented at a distance of 5 cm (near), 37.5 cm (middle), or 70 cm (far) from each finger. The participants had to respond rapidly to a randomized sequence of unimodal (visual or tactile) and simultaneous visuotactile targets (i.e., a redundant target paradigm). Sensorimotor functions were independently assessed by the Timed Up and Go (TUG) and postural stability tests. Results showed that reaction times to the visuotactile bimodal stimuli were significantly faster than those to the unimodal stimuli, irrespective of age group [younger adults: 22.0 ± 0.6 years, older adults: 75.0 ± 3.3 years (mean ± SD)] and target distance. Of importance, a race model analysis revealed that the co-activation model (i.e., visuotactile multisensory integrative process) is supported in the far condition especially for older adults with relatively poor performance on the TUG or postural stability tests. These results suggest that aging can change visuotactile peripersonal space and that it may be closely linked to declines in sensorimotor functions related to gait and balance in older adults.

Objective:We sought to understand the trajectory of mild cognitive impairment (MCI) better by examining longitudinally different MCI subtypes and progression to dementia and reversion to normal cognition in a community sample.Methods:We evaluated the stability of MCI subtypes and risk of dementia over 4 biennial assessments as part of an ongoing prospective cohort study, the Sydney Memory and Ageing Study.Results:While prevalence of MCI and different MCI subtypes remains relatively stable across all assessments, reversion from MCI and transitions between different MCI subtypes were common. Up to 46.5% of participants classified with MCI at baseline reverted at some point during follow-up. The majority (83.8%) of participants with incident dementia were diagnosed with MCI 2 years prior to their dementia diagnosis. Both reverters and participants with stable MCI were at an increased risk of progression to dementia compared to those without MCI at baseline (HR 6.4, p = 0.02, and HR 24.7, p < 0.001, respectively); however, the risk of dementia in participants with MCI who did not revert was higher than in reverters (HR 2.5, p = 0.01). This effect was specific to amnestic subtypes (MCI reverters vs nonreverters: amnestic MCI HR 3.3, p = 0.006; nonamnestic MCI: HR 1.3, p = 0.67).Conclusion:Our findings indicate that the relevance of reversion for progression risk depends on the MCI subtype. Subtype specificity and longitudinal characterization are required for the reliable identification of individuals at high risk of developing dementia.

Background: Impaired functional connectivity in the default mode network (DMN) is supposedly involved in Alzheimer’s disease (AD) progression. The posterior cingulate cortex (PCC) might be an imaging marker for monitoring AD progression. Objective: To investigate the alterations in the directed functional connectivity between the PCC and whole brain in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls. Methods: A total of 116 enrolled participants were divided into three groups: AD (n=32), MCI (n=26), and controls (n=58). Using resting-state functional magnetic resonance imaging (rs-fMRI), the directed functional connectivity was studied using Granger causality analysis (GCA). Results: Almost all of the directed functional connections with significant differences were unidirectional. Compared with the NC group, the AD group showed enhanced directed connectivity from the whole brain to the PCC mainly for regions outside the DMN, and reduced connectivity from the PCC to the whole brain mainly for regions inside the DMN. Compared with the NC group, the MCI group showed enhanced directed connectivity from the PCC to the whole brain for the bilateral precuneus and postcentralgyrus, and reduced connectivity from the whole brain to the PCC for regions outside the DMN. Compared with the MCI group, the abnormal directed connectivity in the AD group was predominantly in the left hemisphere, possibly suggesting asymmetric characteristics. Conclusion: In patients with AD, the PCC in the DMN shows disorders in receiving and transmitting information, and these abnormalities are directional.

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

Objective:To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults.Methods:Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ+ vs Aβ−), and the interaction between SMCs and Aβ status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates.Results:Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ+ individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Aβ status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Aβ, even after adjustment for age, hippocampal volume, or depressive symptoms.Conclusions:These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline.

Introduction Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. Methods We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program‘s Uniform Data Set. Mixed-effects statistical models tested whether cognitive decline was associated with Braak stage NFT burden. Results Higher stages of NFT burden in PART, with no evidence or minimal evidence of amyloid pathology, were associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention. Discussion We conclude that PART has cognitive consequences that should be considered in the context of emerging tau-targeted therapies in age-associated neurodegenerative diseases.

Objective:To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging.Methods:Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ+/− status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education.Results:A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ+ participants were 3.55 times (95% confidence interval = 1.77–7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ− peers. Furthermore, Aβ+ participants who scored ≤46/48 had smaller hippocampal volumes (t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ2 = 14.30, p < 0.001), compared with their Aβ+ peers with intact total recall.Conclusions:Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ+ clinically normal individuals at greatest risk of short-term clinical progression.

Apolipoprotein E (APOE) ε4 allele is the genetic risk factor with the most established evidence for sporadic Alzheimer's disease. Previous neuroimaging studies have demonstrated insufficiently consistent functional and structural changes among healthy APOE ε4 carriers when compared to non-carriers. Here, in a cognitively intact elderly group (a total of 110: 45 APOE ε4 carriers, 65 non-carriers), we aimed to investigate the potential role of APOE ε4 in the modulation of grey matter activity, white matter integrity, and brain morphology before the development of clinically significant symptoms and signs, by methods of: amplitude of low frequency fluctuations and regional homogeneity analysis based on resting state fMRI, and fiber tractography approach based on diffusion tensor imaging. Our results revealed that compared to non-carriers, APOE ε4 carriers showed: (1) an inconsistent pattern of activity change in the default mode network, including increased gray matter activity in anterior cingulate cortex and medial prefrontal cortex and decreased activity in precuneus; (2) lower mean diffusivity (MD) in fibers of corona radiata and corpus callosum, and lower axial diffusivity in genu of corpus callosum; and (3) significant positive correlation between the MD value of the right superior corona radiate and gross white matter volume; significant negative correlation between the MD value of the right superior corona radiate and Mini-Mental State Examination (MMSE) score. Our results suggested that APOE ε4 gene can modulate gray matter activity and white matter integrity in cognitive and memory related regions, even before any clinical or neuropsychic symtoms or signs of imminent disease.

Objectives: To compare the 4-year survival, institutionalization, cognitive and functional decline of Alzheimer’s patients with specific follow-up in memory centers versus usual care. Design: Four year longitudinal follow-up. Settings: The French Network of memory centers in Alzheimer’s disease (REAL-FR study) and The French population-based study (3C study). Participants: 728 patients aged ≥ 65, living at home, meeting criteria for probable Alzheimer’s disease and having Mini Mental State Examination (MMSE) scores between 10 and 26 at baseline were included. Measurements: Cox proportional hazards models were performed to test the effectiveness of a specific follow-up in memory centers (REAL-FR study) versus usual care (3C study) on the 4-year survival and institutionalization. Linear mixed models were used to assess cognitive and functional decline in both groups. Results: After adjustment for confounding factors, the 4-year survival did not differ significantly between patients followed-up in memory centers and those who had recourse to usual care (usual care: Hazard Ratio adjusted (HRa) = 0.87, 95% confidence interval (CI) 0.53-1.43, p=0.59). Patients with a specific follow-up in memory centers had a higher risk of being institutionalized (usual care: HRa = 0.24, 95% CI 0.12-0.48, p Conclusion: Our findings failed to demonstrate any potential benefits of a specific follow-up in memory centers on clinically meaningful outcomes in the natural history of Alzheimer’s disease. Recourse to care in memory centers may have been the consequence of a faster dementia progression and a greater burden of Alzheimer’s disease, all leading to detrimental consequences on various prognostic outcomes.

Structural connectome measurement combined with diffusion magnetic resonance imaging (MRI) and tractography allows generation of a whole-brain connectome. However, current cortical structural connectivity (SC) measurements have not been well combined with the vertex-wise multi-subjects statistical analysis. The aim of this study was to examine the feasibility of using group comparison vertex-wise analysis for cortical SC measurement. A fiber connectivity density (FiCD) method based on a combination of a diffusion fiber tracking technique and cortical surface-based analysis was used to measure the whole-brain cortical SC map (FiCD map). A public MRI dataset (GigaDB) was employed to evaluate the reproducibility of the FiCD method. For group comparison, 14 post-stroke patients (mean age, 68.36 ± 7.33 y) and 19 healthy participants (mean age, 66.84 ± 8.58 y) had FiCD measurement. The intergroup comparison of the FiCD map was performed using vertex-wise multi-subject statistical analysis. Reliability testing showed the mean intra- and inter-subject FiCD variability was 3.51 ± 2.12% and 19.44 ± 4.79%, respectively. The group comparison of the whole-brain FiCD identified cortical regions with altered FiCD values, and there was a spatial consistency between the cortical clusters with low FiCD values and the subcortical lesions of patients. This study demonstrated the feasibility of vertex-wise group comparison for evaluating cortical fiber connectivity density. The FiCD method has good intra- and inter-individual reproducibility, and accurately reflects the affected cortical regions in post-stroke patients. This method may be helpful for neuroscience research.

The objective of this study is to evaluate the relationship between social cognition (SC) and cognitive impairment in persons with multiple sclerosis (PwMS). A prospective study was conducted in 60 PwMS, 30 with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS) and 15 with primary progressive MS (PPMS), and in healthy subjects (HS). All subjects were assessed by the Bordeaux Social Cognition Evaluation Protocol (PECS-B) (facial emotion recognition, theory of mind, emotional awareness and cognitive and affective alexithymia), by a large neuropsychological battery and by questionnaires (depression and anxiety). 43.3% of PwMS were impaired for at least one SC test. The proportion of PwMS with at least two impaired SC tests was similar in all three phenotypes (20%). Mean scores differed significantly between PwMS and HS only for the Reading the Mind in the Eyes Test, a test of Theory of Mind (ToM). ANOVA analyses showed an effect of phenotype on emotional awareness scores with lower scores in PPMS as compared to RRMS. ToM performance was significantly correlated (r 2 = 0.56) with executive functions, working memory and episodic memory scores. SC impairment was found in all phenotypes and was more prominent in cognitively impaired MS patients. Executive functions, and working and episodic memory performance accounts for approximately 50% of ToM performance. Emotional awareness is more impaired in progressive MS.

The number of patients with insomnia is rapidly increasing as society ages. The influence of insomnia on cognitive, affective, and activities of daily living (ADL) functions has not been fully studied.Participants were 142 residents of a local super-aged community who underwent health check-ups provided by the local government. Participants completed cognitive, affective and ADL function tests including the MMSE. We divided participants into two subgroups based on Athens Insomnia Scale (AIS) scores (AIS ≤3 and AIS ≥4) and compared cognitive, affective, and ADL functions by sex and age.Subjective insomnia (AIS ≥4) was found in 36.2% of participants and was more frequent in females than males. No differences were found in cognitive function between the AIS subgroups. For both sexes, Geriatric Depression Scale scores were significantly higher in the AIS ≥4 subgroup than the AIS ≤3 subgroup. Apathy Scale scores were significantly higher in males in the AIS ≥4 subgroup. Of the AIS subscales, 'sleepiness during the day' was significantly higher in females than males (**p 0.01), especially in those aged ≥75 years (**p 0.01). This group of older females also showed a significantly lower Trail Making Test scores (*p 0.05).Insomnia was present in 36.2% of the population in a Japanese super-aged community. Those with insomnia showed more depressive symptoms (both sexes) and males showed more apathy. The most distinct characteristic of females aged ≥75 years was a high frequency of daytime sleepiness, possibly related to a decline in attention and executive function.

Orthostatic hypotension (OH) is highly prevalent in the elderly, and this population can be exposed to serious complications, including falls and cognitive disorders, as well as overall mortality. However, the pathophysiology of OH is still poorly understood, and innovative methods of cerebral blood flow (CBF) assessment have been required to accurately investigate cerebrovascular reactivity in OH.We want to compare brain tissue pulsatility (BTP) changes during an orthostatic challenge in elderly patients over 80 with and without OH.Forty-two subjects aged 80 and over were recruited from the geriatric unit of the Hospital of Tours, France, and were divided into two groups according to the result of an orthostatic challenge. The noninclusion criteria were any general unstable medical condition incompatible with orthostatic challenge, having no temporal acoustic window, severe cognitive impairment (Mini Mental Status Examination15), history of stroke, and legal guardianship. We used the novel and highly sensitive ultrasound technique of tissue pulsatility imaging to measure BTP changes in elderly patients with (n = 22) and without OH (n = 17) during an orthostatic challenge.We found that the mean brain tissue pulsatility related to global intracranial pulsatility, but not maximum brain tissue pulsatility related to large arteries pulsatility, decreased significantly in OH patients, with a delay compared with the immediate drop in peripheral blood pressure.Global pulsatile CBF changes and small vessels pulsatility, rather than changes in only large arteries, may be key mechanisms in OH to account for the links between OH and cerebrovascular disorders.

Previous research has shown that individuals with Parkinson's disease (PD) show preserved learning of tool-related motor skills, while retention was impaired after a three-week delay, possibly as a result of striatal dysfunction. The goal of the current study was to identify if shorter delays and more extensive practice might reduce retention deficits related to complex tool use in PD. PD participants and healthy age and education-matched controls were trained to use novel tools across four sessions, spaced one-day, one-week, and three-weeks apart. Recall of tool attributes (e.g., function) and skilled motor performance using tools was investigated by examining patterns of learning and forgetting over time. Results showed that tool attribute recall was unimpaired in PD participants relative to controls. For motor skill performance, PD participants were unimpaired in motor skill learning within sessions, but they did not retain these skills across one-week and three-week delays between sessions. This dissociation suggests that the striatum plays a critical role in retention of motor skills needed in skilled tool use performance. Finally, in spite of forgetting, individuals with PD still demonstrated improvement across sessions with additional training, suggesting that people with PD may benefit from extensive practice when learning motor skills.

Background Potential role of vascular dysfunction has been suggested in the pathogenesis of Alzheimer's disease (AD). Previous cross-sectional studies have demonstrated relations between abnormal transcranial Doppler (TCD) parameters and cognitive impairment. We aimed to investigate the associations between longitudinal changes of TCD parameters and cognitive decline in patients with AD. Methods We have enrolled patients with mild to moderate AD who aged 60 to 79 years. Mean flow velocity and pulsatility index (PI) of anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries were evaluated. Cognitive functions were assessed using mini-mental state examination (MMSE), clinical dementia rating sum of boxes (SOB), and Alzheimer's Disease Assessment Scale (ADAS-cog), which was further categorized as praxis, language, and memory subscores. TCD and cognitive assessments were followed up 1 year later, and the longitudinal changes (Δ) between the baseline and follow-up measurements were evaluated. Results A total of 51 patients completed the follow-up evaluations (baseline age 71.5 years, MMSE 21.2). In the baseline evaluations, high PI values of ACA and MCA were associated with poor MMSE score, ADAS-cog total, memory, and praxis subscores. After 1 year, the increases of ACA and MCA PI were correlated with the aggravation of ADAS language subscore, and ΔACA PI was also correlated with ΔSOB. The decrease in mean flow velocity of ACA was associated with aggravation of ADAS-cog praxis score. Conclusions There was significant correlation between longitudinal changes of TCD parameters and cognitive dysfunction in patients with mild to moderate AD. Serial assessment of TCD may provide useful information regarding to the disease progression.

We provide and evaluate an open-source software solution for automatically hippocampal segmentation from T1-weighted (T1w) magnetic resonance imaging (MRI). The method is applied for measuring the hippocampal volume, which allows discriminate between patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) and elderly controls (NC). The method is based on a fast patch-based label fusion method, whose selected patches and their weights are calculated from a combination of similarity measures between patches using intensity-based distances and labeling-based distances. These combined similarity measures produces better selection of the patches, and their weights are more robust. The algorithm is trained with the Harmonized Hippocampal Protocol (HarP). The proposal is compared with FreeSurfer and other label fusion methods. To evaluate the performance and the robustness of the proposed label fusion method, we employ two databases of T1w MRI of human brains. For AD vs NC, we obtain a high degree of accuracy, approximately 90 %. For MCI vs NC, we obtain accuracies around 75 %. The average time for the hippocampal segmentation from a T1w MRI is less than 17 minutes.

Objective:To examine the incidence, progression, and reversion of mild cognitive impairment in patients with Parkinson disease (PD-MCI) over 5 years.Methods:A population-based cohort of patients with incident PD underwent repeated neuropsychological testing of attention, executive function, memory, and visuospatial abilities at baseline (n = 178), 1 year (n = 175), 3 years (n = 163), and 5 years (n = 150). Patients were classified as PD-MCI and diagnosed with dementia according to published criteria.Results:Thirty-six patients (20.2%) fulfilled criteria for PD-MCI at baseline. Among those with normal cognition at baseline (n = 142), the cumulative incidence of PD-MCI was 9.9% after 1 year, 23.2% after 3 years, and 28.9% after 5 years of follow-up. Overall, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the 5-year study period. The conversion rate to dementia was 59.1% in patients with persistent PD-MCI at 1 year vs 7.2% in those with normal cognition during the first year (adjusted odds ratio 16.6, 95% confidence interval 5.1–54.7, p < 0.001). A total of 27.8% of patients with baseline PD-MCI and 24.2% of those with incident PD-MCI had reverted to normal cognition at study end, but the reversion rate decreased to 9.4% in those with persistent PD-MCI at 2 consecutive visits. Compared with cognitively normal patients, PD-MCI reverters within the first 3 years of follow-up were at increased risk of subsequently developing dementia (adjusted odds ratio 10.7, 95% confidence interval 1.5–78.5, p = 0.019).Conclusions:Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD.

Neuroinflammation has been raised as a candidate of unifying pathogenesis and a target of a disease-modifying strategy for Alzheimer's disease (AD). Aminoacyl-tRNA synthetase complex (ARS)-interacting multifunctional protein 1 (AIMP1) is a cytokine that is known to amplify the actions of tumor necrosis factor-α and to be involved in microglial activation and neuronal death. In this respect, AIMP1 could be a plausible target for the treatment of AD. Therefore, we aimed to examine whether anti-AIMP1 antibody could exert therapeutic effects against cognitive impairment using 3xTg-AD mice. Through the passive avoidance test, we found that an intraperitoneal injection of anti-AIMP1 antibody over 4 weeks was effective in protecting memory function in 3xTg-AD mice (16 weeks old). In addition, to address the translational implications of AIMP1, we measured blood AIMP1 levels in patients with AD (n=22), mild cognitive impairment (n=25), and normal cognition (n=23). Blood AIMP1 levels were associated negatively with global cognitive function and were significantly higher in individuals with a higher degree of medial temporal lobe atrophy, which is one of the representative clinical markers of AD. Our results suggested a possible association of AIMP1 with AD pathogenesis, as well as the potential of the anti-AIMP1 antibody as a novel therapeutic option for AD.