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Aims/hypothesis Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. Methods Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders. Results Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism. Conclusions/interpretation Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies. Graphical abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n = 82), mild cognitive impairment (MCI) (n = 98) and AD dementia (n = 88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta(1-42), total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta(1-42) was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology. (C) 2021 The Authors. Published by Elsevier Inc.

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4hydroxyphenylethyleneglycol (MHPG), A beta 42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of A beta 42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. (C) 2021 The Authors. Published by Elsevier Inc.

Contains fulltext : 234323.pdf (Publisher’s version ) (Open Access) Feedback of neuropsychological test results to patients and family members include psychoeducation and implications for daily life. This scoping review aimed to provide an overview of the literature on neuropsychological feedback and to offer clinical recommendations. In accordance with formal scoping review methodology, PubMed, PsycInfo, Web of Science, CINAHL, and Embase databases were searched. Studies were included if they reported on neuropsychological feedback, if full papers were available, and if they included human participants. All languages were included, and no limit was placed on the year of publication. Of the 2,173 records screened, 34 publications met the inclusion criteria. Five additional publications were included after cross-referencing. An update of the search led to the inclusion of two additional papers. Of these 41 publications, 26 were research papers. Neuropsychological feedback is provided for a wide spectrum of diagnoses and usually given in-person and has been related to optimal a positive effect on patient outcomes (e.g. increase the quality of life). Most papers reported on satisfaction and found that satisfaction with an NPA increased when useful feedback was provided. However, information retention was found to be low, but communication aids, such as written information, were found to be helpful in improving retention. The current review demonstrated the benefits of neuropsychological feedback and that this should be part of standard clinical procedures when conducting a neuropsychological assessment. Further research on the benefits of neuropsychological feedback and how to improve information provision would enrich the neuropsychological literature. 22 p.

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.

Contains fulltext : 227913.pdf (Publisher’s version ) (Open Access) Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g., a multidisciplinary brainstorm session, think-aloud sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70-87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes. 14 p.

Objectives To examine trajectories of depression and apathy over a 5-year follow-up period in (prodromal) Alzheimer's disease (AD), and to relate these trajectories to AD biomarkers. Methods The trajectories of depression and apathy (measured with the Neuropsychiatric Inventory or its questionnaire) were separately modeled using growth mixture models for two cohorts (National Alzheimer's Coordinating Center, NACC, n = 22 760 and Alzheimer's Disease Neuroimaging Initiative, ADNI, n = 1 733). The trajectories in ADNI were associated with baseline CSF AD biomarkers (A beta(42,)t-tau, and p-tau) using bias-corrected multinomial logistic regression. Results Multiple classes were identified, with the largest classes having no symptoms over time. Lower A beta(42)and higher tau (ie, more AD pathology) was associated with increased probability of depression and apathy over time, compared to classes without symptoms. Lower A beta(42)(but not tau) was associated with a steep increase of apathy, whereas higher tau (but not A beta(42)) was associated with a steep decrease of apathy. Discussion The trajectories of depression and apathy in individuals on the AD spectrum are associated with AD biomarkers.

BACKGROUND: The relation between vascular risk factors (VRFs) and Alzheimer's disease (AD) is important due to possible pathophysiological association.OBJECTIVE: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context.METHODS: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site.RESULTS: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ 42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition.CONCLUSION: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia.

Objective: To identify determinants within 3 different domains (ie, somatic comorbidities, cognitive functioning, and neuropsychiatric symptoms [NPS]) of health-related quality of life (HRQoL) over time in memory clinic patients without dementia. Methods: This longitudinal multicenter cohort study with a 3-year observation period recruited 315 individuals (age: 69.8 ± 8.6, 64.4% males, Mini-Mental State Examination score 26.9 ± 2.6). A multivariable explanatory model was built using linear mixed effects models (forward selection per domain) to select determinants for self-perceived HRQoL over time, as measured by the EuroQoL-5D visual analogue scale (EQ VAS). Results: Mean HRQoL at study entry was 69.4 ± 15.6. The presence of agitation, appetite and eating abnormalities, and eyes/ears/nose (ie, sensory impairment) comorbidities were associated with a change in HRQoL over time. Agitation was most strongly associated with HRQoL over time. Conclusions: The association of somatic comorbidities and NPS in memory clinic patients with course of HRQoL shows that these should receive more awareness, detection, and monitoring by clinicians.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Introduction Alzheimer’s disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting. Methods CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria. Result Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers. Discussion Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given.

There has been increasing interest in finding non-invasive biomarkers for neurodegenerative diseases such as Alzheimer’s disease (AD). This observational study investigated AD-specific biomarkers in tear fluid. Tear fluid was collected from a total of 65 subjects, including 23 patients with subjective cognitive decline (SCD), 22 patients with mild cognitive impairment (MCI), 11 dementia patients and 9 healthy controls (HC). Levels of amyloid-beta peptides (AB38, AB40, AB42), total-tau (t-tau) and phosphorylated-tau (p-tau) were determined using multiplex immunoassays. Levels of AB40 and t-tau were detectable in the vast majority (> 94%) of tear fluid samples. Cerebrospinal fluid (CSF) was available from a subset of patients. In this group, tear t-tau levels were significantly higher in people with dementia compared to SCD patients. Tear t-tau levels were elevated in patients with neurodegeneration (classified according to the A/T/N system) compared to patients without neurodegeneration. Negative correlations were found between CSF AB42 and CSF t-tau, and between CSF AB42 and tear t-tau. In summary, this study shows the potential of tau proteins in tear fluid to be associated with disease severity and neurodegeneration.

The vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF).We assessed microvascular, parenchymal integrity, and a proxy of ISF volume alterations with intravoxel incoherent motion imaging in 21 healthy controls and 53 memory clinic patients - mainly affected by neurodegeneration (mild cognitive impairment, Alzheimer's disease dementia), vascular pathology (vascular cognitive impairment), and presumed to be without significant pathology (subjective cognitive decline).The microstructural components were quantified with spectral analysis using a non-negative least squares method. Linear regression was employed to investigate associations of these components with hippocampal and white matter hyperintensity (WMH) volumes. In the normal appearing white matter, a large f(int )(a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large f(int) value was associated with a lower hippocampal volume in the hippocampi.Large ISF volume (f(int)) was shown to be a prominent factor associated with both WMHs and neurodegenerative abnormalities in memory clinic patients and is argued to play a potential role in impaired glymphatic functioning. (C) 2021 The Author(s). Published by Elsevier Inc.

Background Apathy is a pervasive neuropsychiatric syndrome in people with neurocognitive and psychiatric disorders. The diagnostic criteria for apathy (DCA) have been revised in 2018. Objectives Employing the 2018 DCA, in the present study, we investigated in groups of elderly subjects suffering from different neuropsychiatric disorders (a) the apathy prevalence; (b) the most commonly affected apathy dimensions (behavior/cognition, emotion, and social interaction); (c) the sensitivity and specificity of those dimensions for apathy diagnosis; and (d) the concurrent validity of 2018 DCA compared with the 2009 DCA. Methods This multicenter survey included 166 subjects. Each center checked the presence of apathy in subjects belonging to the following DSM-5 diagnoses: mild neurocognitive disorders (mild NCDs); major NCDs; affective disorders (Aff D); and subjective cognitive decline (SCD). Results The frequency of apathy varied significantly based on the diagnostic groups (0% of subjects with apathy in the SCD group; 25% in the mild NCD group; 77% in the major NCD group; and 57% in the Aff. D group). All subjects with apathy fulfilled the criteria for the behavior/cognition dimension, 73.1% fulfilled the criteria for the emotion dimension, and 97.4% fulfilled the criteria for the social interaction dimension. Behavior/cognition showed the highest sensitivity, the copresence of emotion and social interaction the highest specificity. The concordance between the 2009 and the 2018 DCA indicated an almost perfect agreement. Conclusions These results are consistent with previous reports and confirm that the social interaction dimension added to the 2018 DCA is present in most of subjects with apathy referred to specialized memory centers.

Contains fulltext : 205886.pdf (Publisher’s version ) (Open Access) Objectives: Memory clinics (MCs) have been established to improve diagnosis and treatment of cognitive disorders, including dementia. The aim of this study was to determine the characteristics and working methods of MCs in the Netherlands in 2016. More insight into different working methods can be used to improve the quality of care in Dutch MCs. Additionally, the findings will be compared with earlier results to investigate the development of MCs since 1998. Methods: A survey was sent in 1998, 2004, 2009, and 2017 to all operational Dutch MCs with questions about organization, collaboration, patients, and diagnostic procedures. Results: From 1998 to 2016, the number of MCs increased substantially from 12 to 91. The capacity increased from 1,560 patients to 24,388. In 1998, most patients received a dementia diagnosis (85%), while in 2016, half of the patients were diagnosed with milder cognitive problems. MCs are more often part of regional care chains and are better embedded within regional care organizations. Diagnostic tools, such as blood tests (97%), neuropsychological assessment (NPA) (95%) and neuroimaging (92%), were used in nearly all MCs. The number of patients in whom these tools were used differed greatly between MCs (NPA: 5-100%, neuroimaging: 10-100%, CSF: 0.5-80%). There was an increase in the use of NPA, while the use of neuroimaging, CSF, and EEG/ECG decreased by 8 to 15% since 2009. Conclusions: Since 1998, MCs have developed substantially and outgrown the primarily research-based university settings. They are now accepted as regular care facilities for people with cognitive problems. 8 p.

Item does not contain fulltext Background: It is uncertain whether self- and proxy-reported cognitive decline in older adults reflect an actual objective cognitive dysfunction in the clinical sense, and if these are predictive for developing dementia. Objective: The aim of the present study is to investigate the cross-sectional and longitudinal relation between subjective cognitive decline and objective cognitive performance, depressive symptoms, and to determine the predictive value for development of dementia. Methods: We included 405 patients without dementia at first visit from the Maastricht memory clinic participating in a longitudinal cohort study. Subjective cognitive decline was measured using a self- and proxy-report questionnaire. All patients underwent a standardized neuropsychological assessment. Follow-up assessments were performed yearly for three consecutive years, and once after five years. Results: Subjective cognitive decline was associated with lower cognitive performance and more depressive symptoms. When comparing self- (n = 342, 84% ) and proxy-reported decline (n = 110, 27% ), it was shown that proxy reports were associated with a more widespread pattern of lower cognitive performance. In participants without cognitive impairment proxy-reported decline was not associated with depressive symptoms. In contrast, self-reported decline was associated with a stable course of depressive symptoms at follow-up. Proxy-reported cognitive decline (HR = 1.76, 95% CI = 1.12- 2.78), and mutual complaints (HR = 1.73, CI:1.09- 2.76) predicted incident dementia while self-reported decline did not reach statistical significance (HR = 1.26, 95% CI = 0.65- 2.43). Conclusion: Proxy-reported cognitive decline was consistently associated with lower cognitive performance and conversion to dementia over 5 years. Self-reported cognitive decline in patients without cognitive impairment might indicate underlying depressive symptoms and thus deserve clinical attention as well. 15 p.

Contains fulltext : 214113.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Previous studies have identified several subgroups (ie, latent trajectories) with distinct disease progression among people with dementia. However, the methods and results were not always consistent. This study aims to perform a coordinated analysis of latent trajectories of cognitive and functional progression in dementia across two datasets. METHODS: Included and analyzed using the same statistical approach were 1628 participants with dementia from the US National Alzheimer's Coordinating Center (NACC) and 331 participants with dementia from the Dutch Clinical Course of Cognition and Comorbidity study (4C-Study). Trajectories of cognition and instrumental activities of daily living (IADL) were modeled jointly in a parallel-process growth mixture model. RESULTS: Cognition and IADL tended to decline in unison across the two samples. Slow decline in both domains was observed in 26% of the US sample and 74% of the Dutch sample. Rapid decline in cognition and IADL was observed in 7% of the US sample and 26% of the Dutch sample. The majority (67%) of the US sample showed moderate cognitive decline and rapid IADL decline. CONCLUSIONS: Trajectories of slow and rapid dementia progression were identified in both samples. Despite using the same statistical methods, the number of latent trajectories was not replicated and the relative class sizes differed considerably across datasets. These results call for careful consideration when comparing progression estimates in the literature. In addition, the observed discrepancy between cognitive and functional decline stresses the need to monitor dementia progression across multiple domains.

Contains fulltext : 208145.pdf (Publisher’s version ) (Open Access) BACKGROUND: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. OBJECTIVE: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer's disease (AD) and controls. METHODS: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69+/-6), 68 AD patients (age 70+/-6), and 41 controls (age 70+/-5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). RESULTS: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: beta+/-SE = -7.6+/-2.8, controls: beta+/-SE = -7.9+/-3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (beta+/-SE = 2.9+/-1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS beta+/-SE = -1.8+/-0.3, EQ5D-utility beta+/-SE = -3.7+/-0.4; DAD: VAS = 0.1+/-0.0, EQ5D-utility beta+/-SE = 0.1+/-0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model. CONCLUSION: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL.

The Semantic Verbal Fluency Task (SVF) is an efficient and minimally invasive speech-based screening tool for Mild Cognitive Impairment (MCI). In the SVF, testees have to produce as many words for a given semantic category as possible within 60 seconds. State-of-the-art approaches for automatic evaluation of the SVF employ word embeddings to analyze semantic similarities in these word sequences. While these approaches have proven promising in a variety of test languages, the small amount of data available for any given language limits the performance. In this paper, we for the first time investigate multilingual learning approaches for MCI classification from the SVF in order to combat data scarcity. To allow for cross-language generalisation, these approaches either rely on translation to a shared language, or make use of several distinct word embeddings. In evaluations on a multilingual corpus of older French, Dutch, and German participants (Controls=66, MCI=66), we show that our multilingual approaches clearly improve over single-language baselines.

Contains fulltext : 219602.pdf (Publisher’s version ) (Open Access) Objective: The aim of this study was to gain insight into the experiences of patients and their family members regarding a neuropsychological assessment (NPA) and the diagnostic disclosure given by the medical specialist (psychiatrist, geriatrician, or their residents) at the memory clinic (MC). Method: Patients with and without a cognitive impairment and their family members were recruited from three Dutch MCs. Four focus groups with 14 patients and 13 family members were analyzed using both inductive and deductive content analysis. Results: Three themes were identified: uncertainty, early diagnostic paradox, and knowledge utilization. High levels of uncertainty were experienced throughout the NPA and diagnostic disclosure. The early diagnostic paradox refers to the coexistence of negative emotions, feeling distressed due to undergoing an NPA that made them aware of their cognitive complaints, and the experience of relief due to insight given by the outcome of the NPA and medical diagnosis. Knowledge utilization refers to a low retention of medical information. Conclusion: Clinicians can reduce uncertainty by using clear communication, limiting interruptions during an NPA, and paying attention to contextual factors. Low information retention could possibly be improved by involving a family member and using visual aids or written information during the diagnostic disclosure. Finally, participants also appreciated being provided with neuropsychological feedback on the strengths and weaknesses of their cognitive profiles and with guidance on how to manage this diagnosis in their daily lives. 17 p.

Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10−9, rs117204439: OR = 4.9, P = 6.0 × 10−9) and replication analysis (P −3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10−58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10−260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive preprocessing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924-0.955) and CNN (0.933; 95%CI: 0.918-0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p < 0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855-0.932) and CNN (0.876; 95%CI: 0.836-0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p = 0.01). Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.

Background There is growing interest in finding non-invasive alternatives to cerebrospinal fluid (CSF) that could serve as front-line diagnostics for Alzheimer’s disease (AD). In this study, we investigated AD-specific biomarkers in tear fluid.Methods Tear fluid was collected from 25 patients with subjective cognitive decline SCD), 24 patients with mild cognitive impairment (MCI), 11 dementia patients and nine controls. Amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau levels in tear fluid were determined using multiplex immunoassays.Results Tear t-tau levels in dementia, MCI and SCD patients were higher than in HC (p = 0.002, p = 0.002 and p = 0.013, respectively). A negative correlation between AB42 and t-tau was found in both tear fluid and CSF. Levels of tear p-tau were detectable in patients but not in HC.Conclusions This study shows for the first time presence of amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau in tear fluid.

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

Contains fulltext : 174202.pdf (Publisher’s version ) (Closed access) Background: Prospective studies in the general population show that slow gait speed is associated with cognitive decline and clinical progression to dementia. However, longitudinal studies in memory clinic populations are mostly lacking. We aimed to study the association between gait speed and grip strength and cognitive functioning at baseline and cognitive decline over time in memory clinic patients with subjective cognitive decline and mild cognitive impairment. Methods: We included 309 patients (age 70 +/- 9 years, 108 [35%] women, Mini-Mental State Examination 27 +/- 3 points). Baseline gait speed was assessed over 15 feet, grip strength with a hydraulic hand dynamometer. Cognitive functioning was assessed annually with a comprehensive test battery during 3 years. Results: Age- and gender-adjusted linear mixed models showed that slower gait speed was related to worse baseline attention, memory, information processing speed, and verbal fluency. Longitudinally, gait speed was related to decline in information processing speed and executive functioning. Weaker grip strength was related to worse baseline information processing speed and executive functioning but there were no longitudinal associations. Cox proportional hazards models revealed no significant associations with clinical progression. Conclusions: Our findings suggest that markers of physical performance are related to current cognitive status and modestly related to cognitive decline but are seemingly not useful as an early marker of incident clinical progression.

Background:Dementia is a neurodegenerative syndrome that interferes with multiple aspects of life, including cognition, daily functioning, and behavior. Despite the large heterogeneity in symptom development, these three domains are seldom studied simultaneously. This study investigates how trajectories of these domains are interrelated within individuals over time, and how they in turn are related to dementia severity and quality of life (QoL).Methods:We used data from a longitudinal clinical cohort study, including 331 dementia patients. Cognitive status was measured using the Mini-Mental State Examination, daily functioning was measured with the disability assessment for dementia and neuropsychiatric symptoms (NPS) were scored using the neuropsychiatric inventory. We investigated the relationships in the time course of the various dementia domains using random effects multilevel models and parallel-process growth models.Results:Changes in cognition and daily functioning were highly correlated over time (r = 0.85, p < 0.01), as were changes in NPS and functioning (r = −0.60, p < 0.01), while changes in cognition and NPS were not (r = −0.20, p = 0.06). All three domains were strongly associated with dementia severity over time (p < 0.01). Decreased functioning and increased NPS were both associated with decreased QoL (β = 2.97, p < 0.01 and β = −2.41, p < 0.01, respectively), while cognition was not (β = 0.01, p = 0.93).Conclusion:This study demonstrates the heterogeneity of dementia progression between individuals and between different dementia domains within individuals. To improve our understanding of dementia progression, future research should embrace a broader perspective encompassing multiple outcome measures along with the patient's profile, including neurological factors as well as physical, social, and psychiatric health.

Background Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. Methods In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

Background Affective symptoms are considered a risk factor or prodromal symptom for dementia. Recent reviews indicate that depressive symptoms predict progression from mild cognitive impairment (MCI) to dementia, but results need to be further explored. Objective To investigate the effect of depressive symptoms on the development of dementia in people with MCI, and explore potential sources of between-study variability, including study setting by a systematic review and meta-analysis. Methods Databases were searched for prospective studies defining people with MCI at baseline, investigating dementia at follow-up and giving information about depressive symptoms. Two authors independently extracted data from the studies and rated the methodological quality. Meta-analyses were conducted using random-effect models to yield pooled risk ratios (RR). Meta-regression analyses tested differences between clinical and community-based studies and other sources of heterogeneity. Results Thirty-five studies, representing 14,158 individuals with MCI, were included in the meta-analysis. Depressive symptoms in MCI predicted dementia in 15 community-based studies (RR = 1.69, 95% CI 1.49-1.93, I2 = 0.0%), but not in 20 clinical studies (RR = 1.02, 95% CI 0.92-1.14, I2 = 73.0%). Further investigation of this effect showed that the mean age of community-based studies was significantly higher than of clinical studies but neither this nor other study characteristics explained variability in study outcomes. Conclusions Depressive symptoms are associated with an increased risk of conversion from MCI to dementia in community-based studies. In contrast, evidence in clinical populations was insufficient with high heterogeneity.

Item does not contain fulltext BACKGROUND: Because anxiety is postulated as a risk factor for dementia, we performed a systematic review and meta-analysis to investigate whether anxiety predicts cognitive decline and/or dementia, taking the stage of cognitive decline as well as setting into account. METHODS: A systematic literature search up to January 2015 was performed to identify all longitudinal studies on the association between anxiety and cognition. Data extraction and methodological quality assessment were conducted independently by two authors. Where possible, pooled relative risks were calculated to examine anxiety as a possible risk factor for cognitive decline cognitive impairment and dementia in community studies (objective 1), as well as for conversion to dementia patients referred to memory clinics (objective 2). RESULTS: Twenty studies met inclusion criteria. Data on cognitive decline were too heterogeneous for meta-analysis. Anxiety predicted incident cognitive impairment (4 studies, relative risk [RR]: 1.77, 95% confidence interval [CI]: 1.38-2.26, z = 4.50, p < 0.001) and dementia (6 studies, RR: 1.57, 95% CI: 1.02-2.42, z = 2.05, p = 0.040) in the community, the latter driven by studies with a mean age of 80 years or above. Among clinical mild cognitive impairment samples, anxiety did not predict conversion to dementia (RR: 1.21, 95% CI: 0.90-1.63, z = 1.28, p = 0.200). CONCLUSIONS: Anxiety is associated with an increased risk for cognitive impairment and dementia in the community. Stronger associations were driven by higher age, suggesting that it is a prodromal symptom. Causal biological pathways have also been described, which could explain the risk for incident cognitive impairment in the community. Future studies should include mediating mechanism when studying anxiety as a predictor for cognitive decline and/or dementia.

Background: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. Objective: This study aims to investigate the added prognostic value of AD CSF biomarkers. Methods: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information. Results: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. Conclusion: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.