Renske Hamel

Anxiety as a Predictor for Cognitive Decline and Dementia: A Systematic Review and Meta-Analysis

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

The Influence of Co-Morbidity and Frailty on the Clinical Manifestation of Patients with Alzheimer's Disease

Co-morbidity and frailty are common in Alzheimers 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 (β = -0.21, p < 0.01) and frailty (β = -0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (β = -0.12, p = 0.12) lost statistical significance when both were combined (frailty: β = -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 (β = -0.22, p = 0.01), and between DAD and frailty (β = -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.

The trajectory of cognitive decline in the pre-dementia phase in memory clinic visitors: findings from the 4C-MCI study

BACKGROUND We 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 Alzheimers disease (AD) dementia at follow-up and subjects who did not progress. METHOD In 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. RESULTS The 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. CONCLUSIONS Differences 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.

Progression to dementia in memory clinic patients without dementia A latent profile analysis

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.

Gait Speed and Grip Strength Reflect Cognitive Impairment and Are Modestly Related to Incident Cognitive Decline in Memory Clinic Patients With Subjective Cognitive Decline and Mild Cognitive Impairment: Findings From the 4C Study

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

A profile of The Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment and Dementia Study (The 4C study): two complementary longitudinal, clinical cohorts in the Netherlands.

BackgroundHeterogeneous disease trajectories of mild cognitive impairment (MCI) and dementia are frequently encountered in clinical practice, but there is still insufficient knowledge to understand the reasons and mechanisms causing this heterogeneity. In addition to correlates of the disorder, patient characteristics such as their health status, social environment, comorbidities and frailty may contribute to variability in trajectories over time. The current paper outlines the study design and the study population of and provides an overview of the data collected in the Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment (4C-MCI cohort, n = 315) and Dementia (4C-Dementia cohort, n = 331) Study.MethodsThe two complementary longitudinal cohorts part of the 4C study began enrolment in March 2010. Participants were prospectively recruited from three collaborating Dutch Alzheimer Centers, with three annual follow-up assessments after baseline. Extensive neuropsychological assessments, and detailed profiling of comorbidities, health and frailty at each follow up were the key features of the 4C study. As such, the 4C study was designed to study if and how patients’ comorbidities and frailty are associated with the course of MCI and dementia measured with a comprehensive and multidimensional set of outcomes including cognition, daily functioning, quality of life, behavioral disturbances, caregiver burden, institutionalization and death and whether the effects of medical health and frailty differ between MCI and dementia stages of cognitive disorders.ConclusionSampled in a clinical setting, the 4C study complements population-based studies on neurodegenerative disorders in terms of the type of assessment (e.g. comorbidity, frailty, and functional status were repeatedly assessed). The 4C study complements available clinical cohorts of MCI and dementia patients, because the exclusion criteria were kept to a minimum, to obtain a sample that is representative for the average patient visiting a memory clinic.

Slow gait speed and low grip strength are related to worse attention and mental speed in patients with subjective cognitive decline and mild cognitive impairment

O2-02-06 SLOW GAIT SPEED AND LOW GRIP STRENGTH ARE RELATED TOWORSE ATTENTION AND MENTAL SPEED IN PATIENTSWITH SUBJECTIVE COGNITIVE DECLINE AND MILD COGNITIVE IMPAIRMENT Astrid M. Hooghiemstra, Inez H.G.B. Ramakers, Nicole Sistermans, Yolande A.L. Pijnenburg, Pauline Aalten, Renske E.G. Hamel, Ren e J.F. Melis, Frans R.J. Verhey, Marcel G.M. Olde Rikkert, Philip Scheltens, Wiesje M. van der Flier, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; Radboud University Medical Center, Nijmegen, Netherlands. Contact e-mail: a.hooghiemstra@vumc.nl

The influence of severity of total comorbidity on cognitive decline and conversion to dementia in memory clinic visitors

Background:Clinical trials in vascular dementia (VaD) are plagued by heterogeneity in etiologies, baseline, and progression patterns, and lack of standardized biomarker and clinical tools to measure outcome.MRI biomarkers are usually required [eg strategic or multiple cortical infarcts, subcortical lacunes/extensive white matter hyperintensities (WMH)], but not advanced MR measures (eg connectivity). Diagnostic criteria struggle to balance sensitivity and specificity. Methods: Using NINDS-AIREN criteria to study cholinesterase inhibitor efficacy in VaD, clinical trial designs either excluded Alzheimer’s Disease (AD) clinically or allowed mixed AD-VaD. Conversely, AD trial inclusion criteria allow a few lacunes but limit severity of WMH, and anti-amyloid trials limit microbleeds. Results: Results showed modest cognitive benefits, but several factors defeated regulatory approval. These factors included attribution to co-existing AD, insensitivity to executive dysfunction, and difficulty disentangling functional decline from cognitive vs physical deficits. Consensus has been developed for standardized investigations of VCID (e.g. NINDS-CSN Standards 2006; ASA/ AHA Statement on VCID 2011) and classification of small vessel disease, with variable impact. At autopsy, AD -vascular pathology relationships (additive/interactive) with pre-morbid dementia vary. Surveying whole brain pathologically (eg microinfarcts/ vessel wall disease) is challenging, and benefits fromMRI-guidance. Molecular PET reveals amyloid, tau pathology, and inflammation invivo, enabling novel insights into co-morbidities. Conclusions: The neurovascular unit (endothelium, neurons, glia and microglia) unifies experimental models (eg BBB dysfunction, amyloidosis in ischemia models, and microvasculature in AD transgenics), yielding new targets, that may translate into human protection and repair. Novel candidates may emerge (eg vasculotide, to reduce endothelial permeability). Repurposing trials (e.g. cilostazol, telmisartan, propentofylline, nimodipine) may fare better in designs which optimize imaging biomarker and clinical outcomes.

The trajectory of cognitive decline in preclinical dementia in people attending a memory clinic: The 4C-MCI study

P2-242 THE TRAJECTORY OF COGNITIVE DECLINE IN PRECLINICAL DEMENTIA IN PEOPLE ATTENDING A MEMORY CLINIC: THE 4C-MCI STUDY Renske Hamel, Sebastian Koehler, Nicole Sistermans, Wiesje Van der Flier, Pieter Jelle Visser, Pauline Aalten, Philip Scheltens, Frans R. J. Verhey, Inez Ramakers, Maastricht University Medical Centre/Alzheimer Centre Limburg/School for Mental Health and Neuroscience, Maastricht, Netherlands; VUMC Alzheimer Centre/VUMC Medical Centre, Amsterdam, Netherlands; Maastricht University Medical Centre/Alzheimer Centre Limburg/School for Mental Healthy and Neuroscience/VUMC Alzheimer Centre/VUMC Medical Centre, Maastricht, Netherlands. Contact e-mail: r.hamel@maastrichtuniversity.nl