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Background Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia. Methods We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1–42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (−) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. Results MTA and t-tau were elevated in the Aβ − WMH+, Aβ + WMH−, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. Conclusions In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0328-9) contains supplementary material, which is available to authorized users.

This is the protocol for a review and there is no abstract. The objectives are as follows: Our primary objective is to determine the diagnostic accuracy of the APOE-e4 allele in detecting AD dementia and other types of dementia in people with MCI in a primary care setting. Our secondary objective is to investigate the following potential sources of heterogeneity of test accuracy, where reported: characteristics of participants, namely, baseline MMSE score, age, and gender; APOE-e4 background prevalence; MCI definition; length of follow-up; and reference standards.

Contains fulltext : 190311.pdf (Publisher’s version ) (Closed access) Importance: Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score

Introduction: Dorsal pathway dysfunctions are thought to underlie visuospatial processing problems in Alzheimer disease (AD). Prior studies reported compensatory mechanisms in the dorsal or ventral pathway in response to these functional changes. Since functional and structural connectivity are interrelated, these functional changes could be interpreted as a disconnection between both pathways. To better understand functional alterations in the dorsal pathway, we combined functional imaging with diffusion tensor imaging (DTI) in patients with mild cognitive impairment (MCI), a likely prodromal stage of AD. Methods: Eighteen older male individuals with amnestic MCI (aMCI) and 18 male cognitively healthy individuals, matched for age (range 59-75 years) and education, performed an object recognition task in the Magnetic Resonance Imaging (MRI) scanner. Neural activation was measured during recognition of non-canonically versus canonically oriented objects. Regions showing activation differences between groups were also investigated by DTI. Results: Recognition of non-canonical objects elicited increased frontal, temporal and parietal activation. Combining the functional MRI (fMRI) with the DTI results showed less deactivation in areas with decreased diffusion (mediolateral parietal and orbitofrontal) and increased activation in areas with increased diffusion (parietal and temporal) in aMCI patients. Finally, in aMCI patients decreased diffusion was found in the hippocampal cingulum, connecting both pathways. Conclusions: Our results showed increased activation in early AD patients in ventral and dorsal pathways. A decrease in deactivation and diffusion suggests functional reorganization, while increased activation and diffusion suggests compensatory processes. This is the first study showing structural evidence for functional reorganization, which may be related to connectivity loss in the cingulum. (C) 2012 Elsevier Ltd. All rights reserved.

Background: Impaired olfactory function is an early characteristic of Alzheimer's disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF).Objective: To investigate the association between odor identification and amyloid-beta 1-42 (A beta(42)) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF A beta(42) and t-tau and apolipoprotein E (APOE) genotype.Methods: We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF A beta(42) and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline.Results: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE epsilon 4 carriers and in individuals with abnormal A beta(42).Conclusion: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.

Background Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia. Methods We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1–42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (−) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. Results MTA and t-tau were elevated in the Aβ − WMH+, Aβ + WMH−, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. Conclusions In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up., published version, peerReviewed

Background: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression.Objective: To examine the association between amyloid-beta 1-42 (A beta(42)) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline.Methods: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF A beta(42) and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline.Results: At baseline, decreased CSF A beta(42) correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF A beta(42) was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis.Conclusion: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

Objectives: The predictive value of frailty and comorbidity, in addition to more readily available information, is not widely studied. We determined the incremental predictive value of frailty and comorbidity for mortality and institutionalization across both short and long prediction periods in persons with dementia.Design: Longitudinal clinical cohort study with a follow-up of institutionalization and mortality occurrence across 7 years after baseline.Setting and Participants: 331 newly diagnosed dementia patients, originating from 3 Alzheimer centers (Amsterdam, Maastricht, and Nijmegen) in the Netherlands, contributed to the Clinical Course of Cognition and Comorbidity (4C) Study.Measures: We measured comorbidity burden using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and constructed a Frailty Index (FI) based on 35 items. Time-to-death and time-to-institutionalization from dementia diagnosis onward were verified through linkage to the Dutch population registry.Results: After 7 years, 131 patients were institutionalized and 160 patients had died. Compared with a previously developed prediction model for survival in dementia, our Cox regression model showed a significant improvement in model concordance (U) after the addition of baseline CIRS-G or FI when examining mortality across 3 years (FI: U = 0.178, P = .005, CIRS-G: U = 0.180, P = .012), but not for mortality across 6 years (FI: U = 0.068, P = .176, CIRS-G: U = 0.084, P = .119). In a competing risk regression model for time-to-institutionalization, baseline CIRS-G and FI did not improve the prediction across any of the periods.Conclusions: Characteristics such as frailty and comorbidity change over time and therefore their predictive value is likely maximized in the short term. These results call for a shift in our approach to prognostic modeling for chronic diseases, focusing on yearly predictions rather than a single prediction across multiple years. Our findings underline the importance of considering possible fluctuations in predictors over time by performing regular longitudinal assessments in future studies as well as in clinical practice. (C) 2018 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Mild cognitive impairments and affective symptoms, such as depression, and anxiety are very common and often co-occurring in elderly people. In clinical practice, the differentiation between a primary affective disorder and mild cognitive impairments (e.g., as an early symptom of cognitive deterioration) is very difficult, as both syndromes are largely overlapping in clinical presentation. Etiological heterogeneity, however, leads to differences in clinical course and prognosis.

Contains fulltext : 167669.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Understanding which persons most likely use particular combinations of service types is important as this could lead to a better understanding of care pathways. The aim of this study is to identify combinations of service use within a sample of community-dwelling people with mild cognitive impairment (MCI) and dementia and identify factors related to these service use combinations. METHODS: A latent class analysis performed at baseline on a merged dataset (n = 530) was used to classify care recipients based on following service use types: general practitioner visits, physiotherapist visits, hospital outpatient specialist visits, emergency room visits, hospital inpatient visits with stay over, day care visits, use of domestic homecare, use of personal homecare, and informal care on (instrumental) activities of daily living. Multinomial logistic regression was performed to identify factors associated with service use combinations using clinical characteristics of the care recipient and demographic characteristics of the care recipient and caregiver. RESULTS: Three service use classes were identified; a formal homecare class (10% of participants), an informal care class (46% of participants), and a low user class (44% of participants). Factors increasing the likelihood of being in the formal homecare class compared with the low service use class included a diagnosis of MCI or dementia, activities of daily living impairment, older age of the care recipient, and care recipient not living together with the caregiver. CONCLUSIONS: Besides a diagnosis of MCI or dementia, other factors (activities of daily living impairment, age, and living situation) were associated with service use. We recommend using these factors alongside the diagnostic label for care indication.

Item does not contain fulltext OBJECTIVES: With the lack of a cure for Alzheimer disease (AD), the identification of comorbidity is important to reduce the possibility of excess disability. Although comorbidity in patients with late-onset AD (LO-AD) is common, for people with young-onset AD (YO-AD), it is unclear how often comorbidity occurs. Furthermore, it is uncertain whether comorbidity in patients with YO-AD differs from that in patients with LO-AD. The aim of this study was to explore the prevalence, types of morbidity, and morbidity profiles in patients with YO-AD compared with those of patients with LO-AD. DESIGN: Explorative cohort study from 2 separate Dutch cohorts (Needs in Young-onset Dementia [NeedYD] and the Clinical Course of Cognition and Comorbidity-Dementia Study [4C-Dementia study]). SETTING: Participants were recruited in 2007 and 2008 from (1) the memory clinics of 3 Dutch Alzheimer centers, (2) the memory clinics of general hospitals, (3) mental health services in the southern part of the Netherlands, and (4) young-onset dementia specialized day care facilities. A comparison group of community-dwelling, elderly patients with AD was selected from the 4C-Dementia study. Patients in this study were recruited in 2010 and 2011 from the aforementioned Alzheimer centers. MEASUREMENTS: The prevalence rates of comorbidity were compared between 177 patients with YO-AD and 155 patients with LO-AD. Comorbidity was classified using the International Classification of Diseases, 10th Revision (ICD-10). The total amount of comorbidity was established by counting the number of existing diseases (ICD categories or chapters) and comorbidity was also dichotomized as present or absent. Furthermore, a hierarchical cluster analysis was performed to study clusters of comorbidity. RESULTS: Compared with LO-AD, patients with YO-AD showed less (P < .001) overall comorbidity (58.2% vs 86.5%) and had lower prevalence rates of diabetes, obesity, and circulatory diseases; however, the prevalence rates of diseases of the nervous system in YO-AD (6.2%) were higher compared with those of patients with LO-AD (4.5%). The cluster analysis revealed a distinctive group of patients with YO-AD with either no comorbidity or with a disease of the nervous system. Endocrine, nutritional, and metabolic diseases and diseases of the circulatory system were present in 34% of the patients with YO-AD. CONCLUSION: Comorbidity is less common in YO-AD than in LO-AD. However, general practitioners should be aware that approximately one-third of the patients with YO-AD suffer from or have endocrine, nutritional, and metabolic diseases and/or diseases of the circulatory system. Treatment should therefore not only focus on dementia but also on comorbidity. This attention may slow the functional decline in AD. These exploratory analyses suggested a higher prevalence of nervous system diseases in YO-AD compared with LO-AD. However, the finding did not reach statistical significance and in combination with the exploratory nature of the analyses justifies further investigation. If verified, this finding may help to decrease the time to diagnosis of AD and, subsequently, support in young patients with a neurological disease. Further investigation is needed to gain more insight into the association between comorbidity and AD in younger people.

Introduction: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations. Methods: We prospectively enrolled 3868 patients (50% women, age 66 +/- 11 years, mini mental state examination 25 +/- 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. Results: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. Discussions: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Objectives: Parietal lobe dysfunction is an important characteristic of early Alzheimer disease (AD). Functional studies have shown conflicting parietal activation patterns indicative of either compensatory or dysfunctional mechanisms. This study aimed at examining activation differences in early AD using a visuospatial task. We focused on functional characteristics of the parietal lobe and examined compensation or disconnection mechanisms by combining a fMRI task with effective connectivity measures from Granger causality mapping (GCM). Methods: Eighteen male patients with amnestic mild cognitive impairment (aMCI) and 18 male cognitively healthy older individuals were given a mental rotation task with different rotation angles. Results: There were no behavioral group differences on the fMRI task. Separate measurements at each angle revealed widespread activation group differences. More temporal and parietal activation in the higher angle condition was observed in patients with aMCI. The parametric modulation, which identifies regions associated with increasing angle, confirmed these results. The GCM showed increased connectivity within the parietal lobe and between parietal and temporal regions in patients with aMCI. Decreased connectivity was found between the inferior parietal lobule and posterior cingulate gyrus. Connectivity patterns correlated with memory performance scores in patients with aMCI. Conclusions: Our results demonstrate increased effective temporoparietal connectivity in patients with aMCI, while maintaining intact behavioral performance. This might be a compensational mechanism to counteract a parietal-posterior cingulate gyrus disconnection. These findings highlight the importance of connectivity changes in the pathophysiology of AD. In addition, effective connectivity may be a promising method for evaluating interventions aimed at the promotion of compensatory mechanisms. Copyright © 2012 by AAN Enterprises, Inc.

Objectives: Memory clinics (MCs) are multidisciplinary teams involved with early diagnosis and treatment of people with dementia. The main aim of this study was to gain more insight into the development of MCs in the Netherlands since 1998. Methods: In 1998, 2004 and 2009, an MC survey with questions about patient groups, organisation and working procedures of the MC were sent to all MCs in the Netherlands. Results: The number of MCs increased from 12 in 1998, to 43 in 2004 and to 63 in 2009. In 2009, MCs were better embedded with other regional care and were delivering services for dementia with less emphasis on university-based research. While dementia was still the most common syndromal diagnosis, the proportion of subjects diagnosed with milder memory problems increased to 39%. Diagnostic tools, blood assessments and brain imaging were used in nearly all the facilities. There was an increase both in the use of extensive neuropsychological assessments and in the use of cerebrospinal fluid diagnostics. Conclusion: MCs in the Netherlands have outgrown the primarily university-based setting, have focussed less on scientific research, and have taken a place in the regular care of people with cognitive problems and people in early phases of dementia.

Subjects with Alzheimer's disease (AD) show impaired learning strategies. Whether impaired learning strategies are already present in subjects with prodromal AD remains unknown. The aim of the present study was to investigate the predictive accuracy of learning strategies for AD in subjects with Mild Cognitive Impairment (MCI). Subjects with MCI (n = 202) were selected from the Maastricht Memory Clinic. Subjects were reassessed over a period of 10 years. Fifty-five of the 202 subjects converted to AD. Learning strategies investigated were subjective organization and serial clustering. Lower scores of subjective organization were associated with a higher risk for AD (OR = 2.1, p =. 002). Serial clustering did not predict AD. Prodromal AD is characterized by a decreased use of effortful learning strategies. This finding may have implications for the early detection of AD in MCI subjects and for the development of cognitive training programs.

BackgroundAffective symptoms are common in subjects with mild cognitive impairment (MCI), but there is disagreement whether these symptoms are predictive for Alzheimer's disease (AD). We investigated the predictive accuracy of affective symptoms for AD during a follow-up study in subjects with MCI, and whether the predictive accuracy was modified by age, the presence of amnestic MCI or the length of follow-up.MethodNewly referred subjects (n=263) with MCI older than 55 years were selected from a memory clinic and followed up after 2, 5 and 10 years. Predictors investigated were: symptoms of depression, anxiety, apathy and sleeping problems.ResultsAffective symptoms were present in 50–70% of the subjects. The average follow-up period was 5.4 years and 79 subjects (29%) developed AD. Sleeping problems were associated with a decreased risk for AD [odds ratio (OR) 0.35,pp=0.059) and anxiety (OR 0.58,p=0.051) showed a trend in the same direction. The OR of apathy for AD was 0.67 (p=0.14). Depression was associated with a decreased risk for AD only in subjects without amnestic MCI, but not in subjects with amnestic MCI. Moreover, anxiety was related to the risk for AD differently between subjects diagnosed with AD at the 5-year follow-up (OR 0.23) and subjects diagnosed with AD at the 10-year follow-up (OR 1.7).ConclusionsAffective symptoms are associated with a decreased risk for AD. The risk may be dependent on MCI subtype or length of follow-up, but it does not depend on age.

Objective Memory complaints in the absence of objective test impairments are common. Only a subset of these subjects seeks medical attention for these complaints. The aim of the present study was to investigate which factors determine why people with subjective memory complaints (SMC) seek medical attention. Methods Thirty-three cases with SMC from a memory clinic were compared to 85 control subjects with SMC from a population-based study who did not seek help for their complaints. We investigated whether cases differed from controls with respect to the following: depressive and anxiety symptoms (SCL-90), extraversion and neuroticism (EPQ), meta-memory (MIA), quality of life (SF-36), changes in memory and daily functioning according to a relative (DECO), life-changing events, and a family history of dementia. Results Cases with SMC who seek medical attention, scored lower on memory self-efficacy and quality of life. They were more often worried due to a positive family history of dementia by comparison to the control subjects. Relatives of cases reported more deterioration in daily functioning than relatives of controls. Both the cases and control subjects had similar levels of depressive and anxiety symptoms, as well as levels of extraversion and neuroticism. Conclusion Lower memory self-efficacy and quality of life, deterioration in daily functioning, and worries due to a positive family history for dementia are factors that determine why subjects with SMC seek medical attention. This information may be useful for the development of interventions for these subjects. Copyright © 2008 John Wiley & Sons, Ltd.

Development of memory clinics in the NetherlandsAim Memory Clinics (MC’s) are multidisciplinary teams involved with early diagnosis and treatment of people with dementia. In order to attain more insight into the development of this kind of services in the Netherlands, we compared the data of two inventories, one of 1998 and the other of 2004. Results The number of MC’s increased from 12 to 40. The number of referrals per service has also increased. Dementia was the most important syndromal diagnosis. The focus is less exclusively on academic centres. An growing number of MC’s has structural collaborations with local service providers for mental health. Differences among MC’s exist with regard to the number of referrals per week, the intensity and duration of the diagnostic procedures and the proportion of people without dementia. There is much interest among MC’s to participate in a national network for harmonisation and quality control. Conclusion MC’s are an increasing part of standard care for people with early dementia and other cognitive disorders.

BackgroundWe investigated the course of decline in multiple cognitive domains in non-demented subjects from a memory clinic setting, and compared pattern, onset and magnitude of decline between subjects who progressed to Alzheimer's disease (AD) dementia at follow-up and subjects who did not progress.MethodIn this retrospective cohort study 819 consecutive non-demented patients who visited the memory clinics in Maastricht or Amsterdam between 1987 and 2010 were followed until they became demented or for a maximum of 10 years (range 0.5–10 years). Differences in trajectories of episodic memory, executive functioning, verbal fluency, and information processing speed/attention between converters to AD dementia and subjects remaining non-demented were compared by means of random effects modelling.ResultsThe cognitive performance of converters and non-converters could already be differentiated seven (episodic memory) to three (verbal fluency and executive functioning) years prior to dementia diagnosis. Converters declined in these three domains, while non-converters remained stable on episodic memory and executive functioning and showed modest decline in verbal fluency. There was no evidence of decline in information processing speed/attention in either group.ConclusionsDifferences in cognitive performance between converters to AD dementia and subjects remaining non-demented could be established 7 years prior to diagnosis for episodic memory, with verbal fluency and executive functioning following several years later. Therefore, in addition to early episodic memory decline, decline in executive functions may also flag incident AD dementia. By contrast, change in information processing speed/attention seems less informative.

Background: The relation between psychological distress, personality traits, and cognitive decline in cognitively impaired patients remains unclear. Objective: To investigate the effect of psychological distress and personality traits on cognitive functioning in subjects with mild cognitive impairment (MCI); and to investigate the predictive accuracy of these factors for the development of dementia. Methods: MCI patients (n = 343, age: 60.9 +/- 9.9 years, 38% female, and MMSE score: 28.1 +/- 1.9) were included from the Maastricht memory clinic. All patients underwent a standardized neuropsychological assessment (including tests for measuring mental speed (Trail Making Test (TMT) part A and Stroop Color Word Test (SCWT) part I), executive functioning (TMT part B and SCWT part III), memory (15-Word Learning Tests), and verbal fluency (1-minute animals)), CT or MRI, and blood assessment. The Dutch Personality Questionnaire (DPQ) and the 90-items Symptom Check List (SCL-90) were used to measure personality traits and psychological distress. Conversion to dementia was assessed two, five, and ten years after baseline. The mean follow-up period was 6.7 +/- 3.4 years. Results: The Psychoneuroticism score of the SCL-90 was associated with slower performances on SCWT part I and TMT part A. The subdomain Neuroticism of the DPQ was also associated with slower scores on the TMT part A. At follow-up, 85 (25.9%) subjects had developed dementia. The SCL-90 total score, and the subscales, Anxiety, Somatization, Insufficiency in thought and action, and Sleeping problems were associated with a decreased risk for developing (AD-type) dementia. Conclusion: Psychological distress negatively affected information processing speed, but was not associated with an increased risk of developing dementia in patients with MCI.

Item does not contain fulltext Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.

Background: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile.Methods: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%).Discussion: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.

We found that delayed onset in AD subjects was related to decreased tau, lower BMI, and better cognitive performance (Table 3, Figure 1). We then grouped subjects into "extraordinary delayers" 25 AD and 38 non-AD subjects who had at least a five-year delay between predicted and actual onset compared to all other 380 subjects. "Delayers" had significantly lower BMI, lower cognitive performance, lower Ab 42, and more AD-like atrophy (Table 1). Since the high proportion of AD subjects was a potential confound, we repeated this analysis with just the non-AD subjects. Only lower BMI remained significantly different in the "delayer" group. Conclusions: It was possible to forecast the age of clinical symptoms with a correlation of over 0.3 using variation in the APOE gene. Contrary to previous evidence implicating hypertension in increased risk, we found no clear relationship with blood pressure and accelerated onset. We found no protective effect from more years of education. We also found a consistent relationship that lower BMI is associated with delayed onset (Figure 1). In other cohorts, a higher risk of developing dementia was associated with mid-life obesity (Profenno 2010), but this relationship may reverse in old age, due to weight loss associated with dementia (Buchman 2005; Tolppanen 2014). However, our results suggest that lower BMI is protective, even in subjects without AD.

subject memory impairment (SMI) in identifying those at risk of developing AD has been previously investigated. SMI appears most related to mood, rather than cognition. A recent study published an association between amyloid load at the time of self-reported memory problems (Rowe et al., 2010); however, another study failed to validate these findings (Buckley et al, 2013). To our knowledge, no study has looked at the relationship between SMI and amyloid load a decade later. In this study we aimed to determine whetherSMI is related to b-amyloid load measured a decade later. Methods: We examined the association between SMI (using 4 specific questions on self-perceived memory) determined in 2002, in 95 cognitively normal participants who also had cerebral b-amyloid load measured (by 18 F-Fluorobetaben Positron Emission Tomography) in 2012. Given previous associations of mood with SMI, we also examined the relationship between SMI and affect (Hassle score, CESD). Results:No significant associations were found between the SMI groups identified using 4 questions on memory and 18 F -SUVR measured ten years later. Associations were found between SMI and depression and anxiety. Analysis of which aspects of these mood scales were driving this association found the depressive scale items of clear-headed, p 1⁄4 0.012 and confused p 1⁄4 0.020 and the anxiety item of confused, p 1⁄4 0.021 were the drivers of subjective memory complaint. Conclusions: Subjective memory impairment was found to have no relationship with amyloid load determined a decade later, suggesting their limited clinical use. However, others have found such a relationship on cross-sectional studies using different methods of identifying SMI. It may be more specific questioning is needed to select for those with true pathological memory change. Further research is needed to investigate subjective impairment across different aspects of memory and cognition, and their relationship to Alzheimer’s pathology and progression to disease. It may be that multivariate modelling which weights memory reports with concurrent symptomatology and risk factors will have the greatest value in providing an early marker of those at risk of cognitive decline.

Contains fulltext : 137178.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD). OBJECTIVE: We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. METHODS: We measured CSF amyloid-beta (Abeta) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern. RESULTS: CSF intralaboratory variability was higher for Abeta1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Abeta1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Abeta1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Abeta1-42, 1% based on t-tau, and 22% based on p-tau. CONCLUSIONS: Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Abeta1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.

Item does not contain fulltext Co-morbidity and frailty are common in Alzheimer's disease (AD) and may contribute to the heterogeneity in clinical manifestations of the disease. We cross-sectionally investigated whether co-morbidity and frailty were independently associated with the clinical manifestation of AD in the 4C-Dementia study; a multicenter, longitudinal study in newly diagnosed AD patients. Clinical manifestation was operationalized using a composite of cognitive performance (neuropsychological assessment), activities of daily living (Disability Assessment for Dementia; DAD) and neuropsychiatric symptoms (Neuropsychiatric Inventory). As predictors of prime interest, co-morbidity was determined using the Cumulative Illness Rating Scale (CIRS-G) and frailty by the Fried criteria. In total, 213 AD patients participated (mean age 75 +/- 10 years; 58% females). In linear regression models adjusted for age, gender, education, and disease duration, CIRS-G (beta = -0.21, p < 0.01) and frailty (beta = -0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (beta = -0.12, p = 0.12) lost statistical significance when both were combined (frailty: beta = -0.31, p < 0.001). Models with the individual components of clinical AD manifestation as dependent variables show significant associations between cognitive performance and CIRS-G (beta = -0.22, p = 0.01), and between DAD and frailty (beta = -0.37, p < 0.001). Our findings indicate that physical health and clinical AD manifestation are associated. This association may be responsible for part of the heterogeneity in the presentation of AD. This emphasizes the importance of adequate assessment of co-morbid medical conditions and frailty in patients with AD. 9 p.

BACKGROUND: Evidence on cerebrospinal fluid (CSF) analysis to demonstrate Alzheimer's disease has not yet been implemented in diagnostic guidelines. METHODS: We investigated the use of CSF analysis in a survey amongst all known memory clinics in the Netherlands, of which 85 of 113 (75.2%) responded. RESULTS: Sixty per cent of respondents used CSF analysis in 5% (median) of patients. The analysis almost always confirmed the working diagnosis in 68.4% and sometimes changed it in 28.2%. Complications occurred very infrequently (0%, median) and were mild. Reasons not to perform CSF analysis included the lack of clear recommendations in diagnostic guidelines. CONCLUSIONS: These results ask for a guideline update to clarify the use of CSF analysis as an add-on diagnostic method.

Objective: To identify the existence of discrete cognitive subtypes among memory clinic patients without dementia and test their prognostic values. Methods: In a retrospective cohort study of 635 patients without dementia visiting the Alzheimer centers in Maastricht or Amsterdam, latent profile analysis identified cognitive subtypes based on immediate and delayed memory recall, delayed recognition, information-processing speed, attention, verbal fluency, and executive functions. Time to dementia was tested in weighted Cox proportional hazard models adjusted for confounders. Results: Five latent classes represented participants with high-normal cognition (15%), low-normal cognition (37%), primary memory impairment in recall (MI) (36%), memory impairment in recall and recognition (MI+) (5%), and primary nonmemory impairment (NMI) (6%). Compared with low-normal cognition, participants with NMI had the highest risk of dementia (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.46–10.18) followed by MI (HR = 3.05, 95% CI = 2.09–4.46) and MI+ (HR = 3.26, 95% CI = 1.72–6.17), while participants with high-normal cognition had the lowest risk (HR = 0.24, 95% CI = 0.07–0.80). Subtypes further showed differential relationships with dementia types, with MI and MI+ most often converting to Alzheimer-type dementia and NMI to other forms of dementia. Conclusions: Cognitive subtypes can be empirically identified in otherwise heterogeneous samples of memory clinic patients and largely confirm current strategies to distinguish between amnestic and nonamnestic impairment. Studying more homogeneous cognitive subtypes may improve understanding of disease mechanisms and outcomes.

P2-194 IMPROVING DIAGNOSIS OF DEMENTIA IN A NATIONWIDE SETTING: FIRST RESULTS OF THE DUTCH STRING OF PEARLS INITIATIVE ON NEURODEGENERATIVE DISEASES Pauline Aalten, Wiesje Van der Flier, Geert Jan Biessels, Nico Leenders, Marcel Olde-Rikkert, Ania Oleksik, Edo Richard, John van Swieten, Inez Ramakers, H. Koek, Frans R.J. Verhey, Philip Scheltens, MUMC, Maastricht, Netherlands; VU University Medical Center, Amsterdam, Netherlands; UMC Utrecht, Utrecht, Netherlands; University Medical Center Groningen, Groningen, Netherlands; University Medical Center Nijmegen, Nijmegen, Netherlands; Leiden University Medical Center, Leiden, Netherlands; Academic Medical Center, Amsterdam, Amsterdam, Netherlands; Erasmus Medical Center, Roterdam, Netherlands; Maastricht University Medical Center, Maastricht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands; Alzheimer Center Limburg, Maastricht, Netherlands; Alzheimer Center Amsterdam, Amsterdam, Netherlands.

Cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). We hypothesized that cerebral autoregulation is impaired in patients with AD compared to subjects with mild cognitive impairment (MCI) and controls. Dynamic cerebral autoregulation (dCA) was investigated in 17 AD patients, 19 MCI subjects, and 20 controls (C). Groups were matched for age, gender, and level of education. Electrocardiogram and non-invasive finger arterial blood pressure were measured and transcranial doppler ultrasonography was used to measure cerebral blood flow velocity in right and left middle cerebral artery (MCA). Cerebrovascular resistance index (CVRi) was also computed. dCA in supine position was quantified based on spontaneous blood pressure variations by computation of the linear transfer function between arterial blood pressure and MCA cerebral blood flow velocity. dCA gain and phase were evaluated for different frequency bands. Results were also evaluated using a 3-parameter windkessel model (WKM). CVRi was significantly higher in AD (2.9 ± 0.2) compared to both MCI (2.3 ± 0.1, p = 0.02) and C (2.1 ± 0.1 mmHgs/cm, p = 0.002). Five MCI patients who converted to AD during the course of the study also had higher CVRi compared to non-converters (2.8 ± 0.6 versus 2.1 ± 0.5 mmHgs/cm, p < 0.05). No significant differences in dCA gain and phase were found. In terms of the WKM approach, in the order C→MCI→AD groups showed about equal arterial resistance and peripheral compliance, but increased peripheral vasculature resistance (26 ± 2 versus 36 ± 3 mmHgs/ml in C resp. AD, p = 0.004). In conclusion, AD patients compared to MCI patients and controls have increased CVRi, whereas dCA parameters do not seem to differentiate AD patients. For MCI patients, CVRi might have predictive value in developing AD.

in both anterior temporal lobes while FDG PET scan showed posterior hypofixation atypical for AD. The CSF of tau-protein (600 pg/ml), phosphorylated tau (87 pg/ml) were increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (480 pg/ml) according to our cut-off (Dumurgier et al.) suggesting AD CSF profile. Conclusions: Among different clinical AD phenotype, FTD clinical presentation must not be misdiagnosed. CSF biomarkers are helpful to diagnose these patients, establish an accurate diagnosis and introduce a specific treatment.

Background The identification of subjects with mild cognitive impairment (MCI) at high risk for Alzheimer's disease (AD) is important for prognosis and early intervention. The APOE-epsilon 4 allele is the strongest known genetic risk factor for AD. The authors performed a meta-analysis to establish the predictive accuracy of the APOE-epsilon 4 allele for progression from MCI to AD-type dementia. Methods The authors included 35 prospective cohort studies of subjects with MCI, including 6095 subjects, of whom 1236 progressed to AD-type dementia after 2.9 years of follow-up. Pooled estimates of the OR, sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR-) were obtained using random-effects models. Results The OR for subjects with MCI who are carriers of APOE-epsilon 4 allele to progress to AD-type dementia was 2.29 (95% CI 1.88 to 2.80), the sensitivity was 0.53 (95% CI 0.46 to 0.61), the specificity was 0.67 (95% CI 0.62 to 0.71), the PPV was 0.57 (95% CI 0.48 to 0.66), the NPV was 0.75 (95% CI 0.70 to 0.80), the LR+ was 1.60 (95% CI 1.48 to 1.72), and the LR- was 0.75 (95% CI 0.67 to 0.82). Meta-regression showed that sensitivity, specificity and NPV were dependent on age, APOE-epsilon 4 allele background prevalence or follow-up length. Conclusions The APOE-epsilon 4 allele is associated with a moderately increased risk for progression from MCI to AD-type dementia. The low sensitivity and PPV makes genotyping of limited value for predicting AD-type dementia in clinical practice. For trials aiming to prevent progression from MCI to AD-type dementia, APOE genotyping may be useful in selecting subjects with a higher risk for progression to AD-type dementia.