Grey zone amyloid burden affects memory function: the SCIENCe project.

PURPOSE: To determine thresholds for amyloid beta pathology and evaluate associations with longitudinal memory performance with the aim to identify a grey zone of early amyloid beta accumulation and investigate its clinical relevance. METHODS: We included 162 cognitively normal participants with subjective cognitive decline from the SCIENCe cohort (64 ± 8 years, 38% F, MMSE 29 ± 1). Each underwent a dynamic [18F] florbetapir PET scan, a T1-weighted MRI scan and longitudinal memory assessments (RAVLT delayed recall, n = 655 examinations). PET scans were visually assessed as amyloid positive/negative. Additionally, we calculated the mean binding potential (BPND) and standardized uptake value ratio (SUVr50-70) for an a priori defined composite region of interest. We determined six amyloid positivity thresholds using various data-driven methods (resulting thresholds: BPND 0.19/0.23/0.29; SUVr 1.28/1.34/1.43). We used Cohen's kappa to analyse concordance between thresholds and visual assessment. Next, we used quantiles to divide the sample into two to five subgroups of equal numbers (median, tertiles, quartiles, quintiles), and operationalized a grey zone as the range between the thresholds (0.19-0.29 BPND/1.28-1.43 SUVr). We used linear mixed models to determine associations between thresholds and memory slope. RESULTS: As determined by visual assessment, 24% of 162 individuals were amyloid positive. Concordance with visual assessment was comparable but slightly higher for BPND thresholds (range kappa 0.65-0.70 versus 0.60-0.63). All thresholds predicted memory decline (range beta - 0.29 to - 0.21, all p < 0.05). Analyses in subgroups showed memory slopes gradually became steeper with higher amyloid load (all p for trend < 0.05). Participants with a low amyloid burden benefited from a practice effect (i.e. increase in memory), whilst high amyloid burden was associated with memory decline. Memory slopes of individuals in the grey zone were intermediate. CONCLUSION: We provide evidence that not only high but also grey zone amyloid burden subtly impacts memory function. Therefore, in case a binary classification is required, we suggest using a relatively low threshold which includes grey zone amyloid pathology.

Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

Identifying a task-invariant cognitive reserve network using task potency.

Cognitive reserve (CR) is thought to protect against the consequence of age- or disease-related structural brain changes across multiple cognitive domains. The neural basis of CR may therefore comprise a functional network that is actively involved in many different cognitive processes. To investigate the existence of such a "task-invariant" CR network, we measured functional connectivity in a cognitively normal sample between 20 and 80 years old (N â€‹= â€‹265), both at rest and during the performance of 11 separate tasks that aim to capture four latent cognitive abilities (i.e. vocabulary, episodic memory, processing speed, and fluid reasoning). For each individual, we determined the change in functional connectivity from the resting state to each task state, which is referred to as "task potency" (Chauvin et al., 2018, 2019). Task potency was calculated for each pair among 264 nodes (Power et al., 2012) and then summarized across tasks reflecting the same cognitive ability. Subsequently, we established the correlation between task potency and IQ or education (i.e. CR factors). We identified a set of 57 pairs in which task potency showed significant correlations with IQ, but not education, across all four cognitive abilities. These pairs were included in a principal component analysis, from which we extracted the first component to obtain a latent variable reflecting task potency in this task-invariant CR network. This task potency variable was associated with better episodic memory (ߠ​= â€‹0.19, p â€‹< â€‹.01) and fluid reasoning performance (ߠ​= â€‹0.17, p â€‹< â€‹.01) above and beyond the effects of cortical thickness (range [absolute] ߠ​= â€‹0.28-0.32, p â€‹< â€‹.001). Our identification of this task-invariant network contributes to a better understanding of the mechanism underlying CR, which may facilitate the development of CR-enhancing treatments. Our work also offers a useful alternative operational measure of CR for future studies.

Non-memory cognitive symptom development in Alzheimer's disease.

BACKGROUND AND PURPOSE: Memory is known to be the most common first symptom in Alzheimer's disease (AD). Assessing non-memory cognitive symptom development in AD is important for understanding disease progression and the potential identification of treatment-responsive subtypes. METHODS: Data from the National Alzheimer's Coordinating Center were examined. Logistic regression models were fitted evaluating the development of judgement, language, visuospatial and attention symptoms at first and second visits to Alzheimer's Disease Centers. Predictors were age and prior symptoms, adjusting for symptom length and sex. The models were then refitted assessing apolipoprotein E ε4 (APOE-ε4) effects. RESULTS: Each decade reduction in presentation age increased the odds of language, visuospatial and attention symptom development at both visits by 8%-18% (P < 0.05, all tests), and judgement symptoms at the second visit by 13% (P < 0.05). Prior symptoms were not equally predictive of symptom development. For example, having first predominant language symptoms carried the lowest risk of developing other first-visit symptoms and having memory symptoms was a stronger predictor of developing judgement than other symptoms. The APOE-ε4 gene showed little impact on symptom development when included as a predictor. CONCLUSIONS: Our findings provide support for the concept that younger-onset AD is associated with the progressive development of more non-memory symptoms beyond the first time point. Associations between symptoms were evident, which may reflect that pathology can remain isolated in a network for some time. APOE-ε4 status had little influence on cognitive symptom development which may indicate that the effect it has occurs very early in the disease course.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Concomitant AD pathology affects clinical manifestation and survival in dementia with Lewy bodies.

OBJECTIVE: To investigate whether concomitant Alzheimer's disease (AD) pathology, reflected by cerebrospinal fluid (CSF) biomarkers, has an impact on dementia with Lewy bodies (DLB) in terms of clinical presentation, cognitive decline, nursing home admittance and survival. PARTICIPANTS: We selected 111 patients with probable DLB and CSF available from the Amsterdam Dementia Cohort. On the basis of the AD biomarker profile (CSF tau/amyloid-ß 1-42 (Aß42) ratio >0.52), we divided patients into a DLB/AD+ and DLB/AD- group. Of the 111 patients, 42 (38%) had an AD CSF biomarker profile. We investigated differences between groups in memory, attention, executive functions, language and visuospatial functions. Difference in global cognitive decline (repeated Mini-Mental State Examination (MMSE)) was investigated using linear mixed models. Cox proportional hazard analyses were used to investigate the effects of the AD biomarker profile on time to nursing home admittance and time to death. RESULTS: Memory performance was worse in DLB/AD+ patients compared with DLB/AD- patients (p<0.01), also after correction for age and sex. Hallucinations were more frequent in DLB/AD+ (OR=3.34, 95% CI 1.22-9.18). There was no significant difference in the rate of cognitive decline. DLB/AD+ patients had a higher mortality risk (HR=3.13, 95% CI 1.57 to 6.24) and nursing home admittance risk (HR=11.70, 95% CI 3.74 to 36.55) compared with DLB/AD- patients. CONCLUSIONS: DLB-patients with a CSF AD profile have a more severe manifestation of the disease and a higher risk of institutionalisation and mortality. In clinical practice, CSF biomarkers may aid in predicting prognosis in DLB. In addition, DLB-patients with positive AD biomarkers could benefit from future treatment targeting AD pathology.

Trajectories of cognitive decline in different types of dementia.

BACKGROUND: To investigate trajectories of cognitive decline in patients with different types of dementia compared to controls in a longitudinal study. METHOD: In 199 patients with Alzheimer's disease (AD), 10 with vascular dementia (VaD), 26 with dementia with Lewy bodies (DLB), 20 with behavioural variant frontotemporal dementia (bvFTD), 15 with language variant frontotemporal dementia (lvFTD) and 112 controls we assessed five cognitive domains: memory, language, attention, executive and visuospatial functioning, and global cognition (Mini-Mental State Examination, MMSE). All subjects had at least two neuropsychological assessments (median 2, range 2-7). Neuropsychological data were standardized into z scores using baseline performance of controls as reference. Linear mixed models (LMMs) were used to estimate baseline cognitive functioning and cognitive decline over time for each group, adjusted for age, gender and education. RESULTS: At baseline, patients with dementia performed worse than controls in all cognitive domains (p < 0.05) except visuospatial functioning, which was only impaired in patients with AD and DLB (p < 0.001). During follow-up, patients with AD declined in all cognitive domains (p < 0.001). DLB showed decline in every cognitive domain except language and global cognition. bvFTD showed rapid decline in memory, language, attention and executive functioning (all p < 0.01) whereas visuospatial functioning remained fairly stable. lvFTD declined mostly in attention and executive functioning (p < 0.01). VaD showed decline in attention and executive functioning. CONCLUSIONS: We show cognitive trajectories of different types of dementia. These estimations of natural disease course have important value for the design of clinical trials as neuropsychological measures are increasingly being used as outcome measures.

Validation of the automated method VIENA: an accurate, precise, and robust measure of ventricular enlargement.

BACKGROUND: In many retrospective studies and large clinical trials, high-resolution, good-contrast 3DT1 images are unavailable, hampering detailed analysis of brain atrophy. Ventricular enlargement then provides a sensitive indirect measure of ongoing central brain atrophy. Validated automated methods are required that can reliably measure ventricular enlargement and are robust across magnetic resonance (MR) image types. AIM: To validate the automated method VIENA for measuring the percentage ventricular volume change (PVVC) between two scans. MATERIALS AND METHODS: Accuracy was assessed using four image types, acquired in 15 elderly patients (five with Alzheimer's disease, five with mild cognitive impairment, and five cognitively normal elderly) and 58 patients with multiple sclerosis (MS), by comparing PVVC values from VIENA to manual outlining. Precision was assessed from data with three imaging time points per MS patient, by measuring the difference between the direct (one-step) and indirect (two-step) measurement of ventricular volume change between the first and last time points. The stringent concordance correlation coefficient (CCC) was used to quantify absolute agreement. RESULTS: CCC of VIENA with manual measurement was 0.84, indicating good absolute agreement. The median absolute difference between two-step and one-step measurement with VIENA was 1.01%, while CCC was 0.98. Neither initial ventricular volume nor ventricular volume change affected performance of the method. DISCUSSION: VIENA has good accuracy and good precision across four image types. VIENA therefore provides a useful fully automated method for measuring ventricular volume change in large datasets. CONCLUSION: VIENA is a robust, accurate, and precise method for measuring ventricular volume change.

Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

How healthy participants value additional diagnostic testing with amyloid-PET in patients diagnosed with mild cognitive impairment - a bidding game experiment.

BACKGROUND: To estimate the perceived value of additional testing with amyloid-PET in Euros in healthy participants acting as analogue patients with mild cognitive impairment (MCI). METHODS: One thousand four hundred thirty-one healthy participants acting as analogue MCI patients (mean age 65 ± 8, 929 (75%) female) were recruited via the Dutch Brain Research Registry. Participants were asked to identify with a presented case (video vignette) of an MCI patient and asked whether they would prefer additional diagnostic testing with amyloid PET in this situation. If yes, respondents were asked how much they would be willing to pay for additional diagnostic testing. Monetary value was elicited via a bidding game in which participants were randomized over three conditions: (A) additional testing results in better patient management, (B) Same as condition A and a delay in institutionalization of 3 months, and (C) same as A and a delay in institutionalization of 6 months. Participants who were not willing to take a test were compared with participants who were willing to take a test using logit models. The highest monetary value per condition was analyzed using random-parameter mixed models. RESULTS: The vast majority of participants acting as analogue MCI patients (87% (n = 1238)) preferred additional testing with amyloid PET. Participants who were not interested were more often female (OR = 1.61 95% CI [1.09-2.40]) and expressed fewer worries to get AD (OR = 0.64 [0.47-0.87]). The median "a priori" (i.e., before randomization) monetary value of additional diagnostic testing was €1500 (IQR 500-1500). If an additional amyloid PET resulted in better patient management (not further specified; condition A), participants were willing to pay a median price of €2000 (IQR = 1000-3500). Participants were willing to pay significantly more than condition A (better patient management) if amyloid-PET testing additionally resulted in a delay in institutionalization of 3 months (€530 [255-805] on top of €2000, condition B) or 6 months (€596 [187-1005] on top of €2000, condition C). CONCLUSIONS: Members of the general population acting as MCI patients are willing to pay a substantial amount of money for amyloid-PET and this increases when diagnostic testing leads to better patient management and the prospect to live longer at home.

Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease.

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.

Neuropsychiatric symptoms in patients with possible vascular cognitive impairment, does sex matter?

Background: Neuropsychiatric symptoms (NPS) are common in patients with vascular cognitive impairment (VCI). We aimed to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and identify which NPS are determinants of clinical progression in women and men separately. Methods: We included 718 memory clinic patients (age 68 ± 8; 45% women) with cognitive complaints and vascular brain lesions on MRI (i.e. possible VCI). NPS were measured using the 12-item Neuropsychiatric Inventory. Clinical progression after two years (women 18%, men 14%) was defined as increase in CDR ≥1 or institutionalization (available n = 589 without advanced dementia at baseline). The association between NPS and clinical progression was assessed with Cox proportional hazard models stratified by sex, adjusted for age and clinical diagnosis and in a second model additionally for manifestations of vascular brain lesions. Results: Men more often presented with agitation (29% versus 17%, p<.05) and irritability (58% versus 45%, p<.05), the other 10 NPS (delusions, hallucinations, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, nighttime disturbances and appetite & eating abnormalities) did not differ between sexes. In women the presence of apathy (HR 2.1[1.1;4.3]) was associated with higher risk of clinical progression. In men the presence of depression (HR 2.7[1.4;5.1]) and aberrant motor behavior (HR 2.1[1.1;3.8]) were associated with increased risk of clinical progression. Conclusion: Manifestations of NPS in patients with possible VCI differ by sex. Different NPS are associated with future clinical progression in men and women. Management strategies of NPS could benefit from sex-specific approaches.

Plasma proteome profiling identifies changes associated to AD but not to FTD.

BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

Characterization of symptoms and determinants of disease burden in dementia with Lewy bodies: DEvELOP design and baseline results.

BACKGROUND: The DEmEntia with LEwy bOdies Project (DEvELOP) aims to phenotype patients with dementia with Lewy bodies (DLB) and study the symptoms and biomarkers over time. Here, we describe the design and baseline results of DEvELOP. We investigated the associations between core and suggestive DLB symptoms and different aspects of disease burden, i.e., instrumental activities of daily living (IADL) functioning, quality of life (QoL), and caregiver burden. METHODS: We included 100 DLB patients (69 ± 6 years, 10%F, MMSE 25 ± 3) in the prospective DEvELOP cohort. Patients underwent extensive assessment including MRI, EEG/MEG, 123FP-CIT SPECT, and CSF and blood collection, with annual follow-up. Core (hallucinations, parkinsonism, fluctuations, RBD) and suggestive (autonomous dysfunction, neuropsychiatric symptoms) symptoms were assessed using standardized questionnaires. We used multivariate regression analyses, adjusted for age, sex, and MMSE, to evaluate how symptoms related to the Functional Activities Questionnaire, QoL-AD questionnaire, and Zarit Caregiver Burden Interview. RESULTS: In our cohort, RBD was the most frequently reported core feature (75%), while visual hallucinations were least frequently reported (39%) and caused minimal distress. Suggestive clinical features were commonly present, of which orthostatic hypotension was most frequently reported (64%). Ninety-five percent of patients showed EEG/MEG abnormalities, 88% of 123FP-CIT SPECT scans were abnormal, and 53% had a CSF Alzheimer's disease profile. Presence of fluctuations, lower MMSE, parkinsonism, and apathy were associated with higher IADL dependency. Depression, constipation, and lower IADL were associated with lower QoL-AD. Apathy and higher IADL dependency predisposed for higher caregiver burden. CONCLUSION: Baseline data of our prospective DLB cohort show clinically relevant associations between symptomatology and disease burden. Cognitive and motor symptoms are related to IADL functioning, while negative neuropsychiatric symptoms and functional dependency are important determinants of QoL and caregiver burden. Follow-up is currently ongoing to address specific gaps in DLB research.

Neurological signs in relation to white matter hyperintensity volumes in memory clinic patients.

PURPOSE: To determine the frequency of neurological signs in a memory clinic population and to explore their associations with white matter hyperintensity (WMH). METHODS: We included patients with Alzheimer disease (AD; n = 210), vascular dementia (VaD; n = 34), mild cognitive impairment (MCI; n = 86) and subjective complaints (n = 153). The presence of extrapyramidal and unilateral signs was assessed from medical charts. On MRI, WMH volumes were extracted automatically. RESULTS: Extrapyramidal signs were found in 10% and unilateral signs in 12% of the patients. Age- and sex-adjusted extrapyramidal signs occurred more often in VaD compared to patients with subjective complaints. Unilateral signs were more prevalent in all groups compared to patients with subjective complaints. Two-way analysis of variance (ANOVA) with WMH as the dependent variable showed a main effect of diagnosis (p < 0.001), but not of extrapyramidal signs (p = 0.62). In contrast, 2-way ANOVA showed main effects of diagnosis (p < 0.001) and unilateral signs (p = 0.001). Furthermore, there was an interaction between these factors (p = 0.04); if unilateral signs were present, patients with subjective complaints and VaD showed more WMH, whereas there was no relation in AD and MCI. CONCLUSION: Extrapyramidal and unilateral signs are common in memory clinic patients, but are only modestly related to WMH.

New research criteria for the diagnosis of Alzheimer's disease applied in a memory clinic population.

BACKGROUND: In the newly proposed research criteria for Alzheimer's disease (AD), patients are defined as having memory dysfunction in addition to either hippocampal atrophy or an abnormal cerebrospinal fluid (CSF) profile. This study applies the criteria in a memory clinic population, using clinical criteria as the reference criterion. METHODS: 138 AD patients, 145 nondemented subjects, 78 patients with other dementias and 91 patients with mild cognitive impairment (MCI) were included. Dichotomized medial temporal lobe atrophy (MTA) score on MRI and dichotomized CSF profiles (based on beta-amyloid1-42, tau and phosphorylated tau at threonine 181 levels) were used in combination with an episodic memory test to assess sensitivity, specificity and likelihood ratios (LR) of the newly proposed criteria and their components separately. RESULTS: We found specificities of 95 and 49% for comparison with nondemented subjects and other demented patients, respectively, with a sensitivity of 86% for AD. Specificity was highest (100 and 77%, respectively, LR+ = 48) when both MTA score and CSF profile were abnormal in addition to the episodic memory test, at the cost of a low sensitivity (48%). CONCLUSION: The newly proposed research criteria for AD yield a good specificity for comparison with nondemented subjects. When the type of dementia is clinically doubted, however, at least two supportive features should be considered (i.e. abnormal MTA score and CSF profile) in addition to memory impairment as core diagnostic criterion.

Sex-specific associations with cerebrospinal fluid biomarkers in dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, post-mortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid ß1-42 (Aß42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB. METHODS: We included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aß42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age- and education-adjusted GLM. RESULTS: Women had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aß42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p < 0.001), more frequent hallucinations (58% vs 38%, p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests. CONCLUSIONS: Women had lower Aß42 and α-syn levels than men, alongside a shorter duration of complaints. Moreover, at the time of diagnosis, women had lower cognitive test scores and more frequent hallucinations. Based on our findings, one could hypothesize that women have a more aggressive disease course in DLB compared to men. Future research should investigate whether women and men with DLB might benefit from sex-specific treatment strategies.

Olfactory and gustatory functioning and food preferences of patients with Alzheimer's disease and mild cognitive impairment compared to controls: the NUDAD project.

Our aim is to compare olfactory and gustatory function and food preferences of patients with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) with controls. We included 22 patients with MCI, 30 patients with AD and 40 controls and assessed olfactory threshold, odor discrimination and odor identification (Sniffin' Sticks), gustatory functioning (Taste Strips), and food preferences (Macronutrient and Taste Preference Ranking Task). Linear regression analyses were used to study associations of five cognitive domains or AD biomarkers with olfactory functioning. Groups did not differ in olfactory threshold, gustatory function and food preferences. Patients with MCI and AD scored lower on odor discrimination and identification than controls. Poorer memory, but no other cognitive domain, was associated with poorer odor discrimination and odor identification, but not with odor threshold. No associations with AD biomarkers were found. In conclusion, patients with MCI and AD have poorer odor discrimination and identification ability than controls, but similar detection thresholds. This is likely a consequence of poorer memory rather than directly caused by AD pathology.

Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users . OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health. DESIGN: 30-day user test; multi-method. SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne). PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female). MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews. RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health. CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study.

PURPOSE: Alpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. METHODS: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. RESULTS: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stß = 0.72) and category fluency (stß = 0.69) tests. Lower parietal R1 was related to lower delayed (stß = 0.50) and immediate (stß = 0.48) recall, VOSP number location (stß = 0.70) and fragmented letters (stß = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stß = 0.61), all p < 0.05. CONCLUSION: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.