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Abstract Background New research criteria for the diagnosis of Alzheimer’s disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiology by relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model. Methods/design In a cohort design 241 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period. A decision analytic model is built combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. Discussion Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems. Trial registration NCT01450891

Abstract Background Early onset dementia has serious consequences for patients and their family members. Although there has been growing attention for this patient group, health care services are still mainly targeted at the elderly. Specific knowledge of the needs of early onset dementia patients and their families is limited but necessary for the development of adequate health care services and specific guidelines. This research project is mainly targeted at delineating the course of early onset dementia, the functional characteristics and needs of early onset dementia patients and their caregivers, the risk factors for institutionalization and the interaction with the caring environment. Methods/Design The NeedYD-study (Needs in Young Onset Dementia) is a longitudinal observational study investigating early onset dementia patients and their caregivers (n = 217). Assessments are performed every six months over two years and consist of interviews and questionnaires with patients and caregivers. The main outcomes are (1) the needs of patients and caregivers, as measured by the Camberwell Assessment of Needs for the Elderly (CANE) and (2) neuropsychiatric symptoms, as measured by the NeuroPsychiatric Inventory (NPI). Qualitative analyses will be performed in order to obtain more in-depth information on the experiences of EOD patients and their family members. The results of this study will be compared with comparable data on late onset dementia from a historical cohort. Discussion The study protocol of the NeedYD-study is presented here. To our knowledge, this study is the first prospective cohort study in this research area. Although some limitations exist, these do not outweigh the strong points of this study design.

Abstract Background Paratonia, a form of hypertonia, is associated with loss of mobility and with the development of contractures especially in the late stages of the dementia. Passive movement therapy (PMT) currently is the main physiotherapeutic intervention. General doubt about the beneficial effects of this widely used therapy necessitates a randomised clinical trial (RCT) to study the efficacy of PMT on the severity of paratonia and on the improvement of daily care. Methods/Design A RCT with a 4-week follow-up period. Patients with dementia (according to the DSM-IV-TR Criteria) and moderate to severe paratonia are included in the study after proxy consent. By means of computerised and concealed block randomisation (block-size of 4) patients are included in one of two groups. The first group receives PMT, the second group receives usual care without PMT. PMT is given according to a protocol by physical therapist three times a week for four weeks in a row. The severity of paratonia (Modified Ashworth scale), the severity of the dementia (Global Deterioration Scale), the clinical improvement (Clinical Global Impressions), the difficulty in daily care (Patient Specific Complaints) and the experienced pain in daily care of the participant (PACSLAC-D) is assessed by assessors blind to treatment allocation at baseline, after 6 and 12 treatments. Success of the intervention is defined as a significant increase of decline on the modified Ashworth scale. The 'proportion of change' in two and four weeks time on this scale will be analysed. Also a multiple logistic regression analysis using declined/not declined criteria as dependent variable with correction for relevant confounders (e.g. stage of dementia, medication, co-morbidity) will be used. Discussion This study is the first RCT of this size to gain further insight on the effect of passive movement therapy on the severity of paratonia. Trial registration Current Controlled Trials ISRCTN43069940

Abstract Background The EQ-5D is a reliable tool for measuring Health-Related Quality of Life (HRQoL). However, concern has been expressed that it may ignore elements of HRQoL, particularly cognition. In response to this concern, the EQ-5D has been extended with a cognitive dimension (EQ-5D+C). The aim of this study was to compare the performance of the EQ-5D and the EQ-5D+C in elderly patients with cognitive impairments by assessing their construct validity and responsiveness. Methods Data from the MEDICIE study (n = 196) were used, in which all questionnaires were rated by proxies. Results Regarding construct validity, we found similar correlations between the EQ-5D and the Mini Mental State Examination (MMSE) and between the EQ-5D+C and the MMSE. Furthermore, both the EQ-5D and the EQ-5D+C were responsive to changes in the MMSE, with the EQ-5D performing slightly better. Conclusion We conclude that the EQ-5D performs well for evaluating HRQoL in a population with cognitive impairments. Based on the results of this explorative study, it does not seem necessary to adjust the current classification system by adding a cognitive dimension. However, in order to compare both instruments regarding utility values, it is necessary to develop a new scoring algorithm for the EQ-5D+C by conducting a general population study. Considering the explorative nature of this study, it is recommended that more aspects of the validity of both the EQ-5D and the EQ-5D+C are explored in patients with cognitive impairments using a more tailored study design.

Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20-70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40-50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.

ImportanceCerebral amyloid-β 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.ObjectiveTo investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.Design, setting, and participantsThis 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 measuresGlobal 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 ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.ResultsAmong 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P

ObjectiveRenal dysfunction has been linked with increased risk for cognitive impairment and dementia, but studies are conflicting. For that reason, the aim of the present systematic review and meta-analysis is to summarize the best available evidence on the prospective association between potential markers of renal dysfunction and development of cognitive impairment or dementia.MethodsMedline, Embase, and Cochrane Database of Systematic Reviews were searched for potential publications until August 1, 2016. Studies were eligible if they fulfilled the following criteria: population-based study, prospective design, ≥100 participants, aged ≥45 years, ≥1 year follow-up, and cognition/dementia outcomes. Where appropriate, random effects meta-analyses were conducted yielding pooled odds ratios (OR) and 95% confidence intervals (CI).ResultsTwenty-two out of 8,494 abstracts fulfilled the eligibility criteria. Sufficient evidence was found for albuminuria, mixed results for estimated glomerular filtration rate (eGFR), insufficient support for cystatin C, and tentative evidence for serum creatinine and creatinine clearance. Meta-analyses of 5 studies representing 27,805 persons showed a 35% increased risk of cognitive impairment or dementia in those with albuminuria (OR 1.35, 95% CI 1.06-1.73, p = 0.015), whereas eGFR

ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Background: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. Methods: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. Results: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05–1.39) and OR = 1.21 (1.02–1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94–1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95–1.17) and OR 1.08 (0.83–1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. Conclusions: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings. [ABSTRACT FROM AUTHOR]

Background: We have updated our previous amyloid positivity prevalence estimates (Jansen, 2015; Ossenkoppele, 2015; Table 1) with data from 19,097 individuals from 85 cohorts. We tested if prevalence estimates differed for positron emission tomography (PET) or cerebrospinal fluid (CSF) amyloid. We calculated data‐driven CSF cut‐points as previous studies suggested a drift in Innotest‐assay performance. Method: We included 9,908 participants with normal cognition (CN); 1,542 with subjective cognitive decline (SCD); 5,405 with mild cognitive impairment (MCI); and 2,260 with clinical Alzheimer's disease (AD) dementia. 10,139 participants had an amyloid‐PET measure and 8,958 participants had an amyloid‐CSF measure. Amyloid‐ß aggregation was originally dichotomized as normal or abnormal according to study‐specific cut‐points, and we defined data‐driven CSF cut‐points using Gaussian mixture modelling. Generalized‐estimating‐equations adjusting for within‐study clustering of individuals were used to estimate amyloid positivity prevalence according to age, cognitive status, and biomarker modality and compared original with updated cut‐points. Result: Amyloid positivity prevalence was higher with older age and advancing disease severity. Using original cut‐points as provided by the cohort, the prevalence of amyloid positivity at the median age of 70 was similar for PET and CSF estimates for CN (24%), SCD (26%), and MCI (51%), and was higher in PET (87%) than CSF (79%) for clinical AD dementia. Using the data‐driven CSF cut‐points, the prevalence of amyloid positivity was higher for CSF‐based estimates than PET‐based estimates in CN (CSF 33%, PET 24%), SCD (CSF 36%, PET 27%), and MCI (CSF 60%, PET 49%), but comparable in CSF and PET in clinically diagnosed AD dementia (CSF 83%, PET 87) (Table 1, Figure 1). Conclusion: We provide updated amyloid positivity estimates from the Amyloid Biomarker Study. CSF‐based estimates using a data‐driven approach resulted in higher estimates (up to 11% higher) in people without clinical AD dementia than PET‐based estimates. Whether CSF‐based estimates are more sensitive than PET‐based estimates for amyloid pathology among people without dementia needs to be explored in cohorts that use both modalities. These updated estimates may be useful to understand potential eligible patient population sizes for anti‐amyloid therapies and to inform recruitment strategies for clinical trials investigating anti‐amyloid therapies. [ABSTRACT FROM AUTHOR]

Background: The role of lifestyle factors in the pathophysiology of Alzheimer's disease is unclear. The aim of this study was to assess the contribution of lifestyle factors to cerebral amyloid pathology in cognitively healthy persons at different levels of genetic risk. Methods: We selected sixteen cohorts from the Amyloid Biomarker Study. Lifestyle data were available for 5542 participants with normal cognition. Amyloid positivity was determined with amyloid‐PET (center‐specific cutoffs) or with aß42 level in CSF (data‐driven cutoffs). Participants were classified as being at low, intermediate or high genetic risk for amyloid positivity according to ApoE e4 copy number (0 vs. 1 vs. 2 e4‐alleles). Participants for whom data was available for >=3 lifestyle factors (n=5046) were classified as having a favorable or unfavorable lifestyle profile on basis of the lifestyle information available for that cohort. A favorable lifestyle was defined as (dichotomized): not smoking (ever), not drinking, normal sleep, physically active, socially active, cognitively active and/or adhering to a Mediterranean diet. Associations of both lifestyle profile and individual lifestyle factors with amyloid positivity, and their dependency on genetic risk, were assessed using generalized estimating equations. Age was included as covariate in all models, Results: Independent of genetic risk level, impaired sleep was associated with lower amyloid positivity (p=0.001) and cognitive inactivity was associated with higher amyloid positivity (p<0.001). Smoking, alcohol use, social activity and diet were not associated with amyloid positivity (table 2). The effects of lifestyle profile and physical activity on amyloid positivity were dependent on genetic risk (p<0.001). Prevalence of amyloid positivity was lower for those with a favorable rather than an unfavorable lifestyle at low (mean difference (md) 3%, p<0.001) and intermediate (md 5%, p<0.001) genetic risk, while this association was reversed for persons at high genetic risk (md 7%, p=0.001, table 3). Amyloid positivity was more common in physically active than inactive participants at high genetic risk only (md 9%, p<0.001). Conclusion: Individual lifestyle factors are limitedly associated with amyloid positivity. However, absence of any unfavorable lifestyle factor is related to lower risk of amyloid positivity in persons at low or intermediate genetic risk. [ABSTRACT FROM AUTHOR]

Background: Diabetes is common in persons with dementia and associated with cognitive decline. However, the relation between diabetes and AD pathophysiology is still unclear. Our aim is to assess the association of diabetes diagnosis and blood glucose regulation with CSF AD biomarkers across the AD clinical spectrum, and the potential moderating effects of vascular factors in this relationship. Method: As part of the PRIME project, we included individuals from five European memory clinic cohorts with normal cognition (NC, n=419) mild cognitive impairment (MCI, n=363) and dementia (n=151). Inclusion criteria were availability of diabetes diagnosis, fasting blood glucose or HbA1c levels and cerebrospinal fluid (CSF) biomarkers amyloid‐beta42, p‐tau and t‐tau. Center‐specific cut‐offs were used to define biomarker positivity. We performed logistic and linear regression models adjusted for age, education years, gender, cohort, to assess the relation between diabetes and AD biomarkers, as well as the potential influence of hypertension, hypercholesterolemia and BMI on this relationship. Result: We included 933 participants in our analysis with an average age of 66.1 years (Table 1). Diabetes was associated with lower odds of being amyloid positive in the total group and in individuals with NC and dementia (Table 2). Diabetes was associated with a lower risk for p‐tau and t‐tau positivity in the total group and in the MCI subgroup. Similar trends were found with HbA1c and blood glucose as predictors. A higher BMI was associated with less t‐tau pathology in persons with diabetes only. Presence of hypertension and hypercholesterolemia did not influence the association between diabetes and AD biomarkers. Additionally, post‐hoc analyses with diagnostic group stratified for amyloid positivity were performed. These analyses indicated that amyloid‐negative demented individuals more often had diabetes than amyloid‐negative NC and MCI individuals (Figure 1). Relative to amyloid‐negative NC, amyloid‐negative demented individuals had higher HbA1c and glucose levels (Figure 2). Amyloid‐positive demented individuals had higher HbA1c levels than amyloid‐positive NC and MCI patients. Conclusion: Diabetes and impaired glucose regulation are associated with non‐AD dementia but not with AD‐related cognitive impairments. Surprisingly, amyloid positive individuals with normal cognition less often had diabetes. [ABSTRACT FROM AUTHOR]