The value of the GP's clinical judgement in predicting dementia: a multicentre prospective cohort study among patients in general practice.

BACKGROUND: Clinical judgement is intrinsic to diagnostic strategies in general practice; however, empirical evidence for its validity is sparse. AIM: To ascertain whether a GP's global clinical judgement of future cognitive status has an added value for predicting a patient's likelihood of experiencing dementia. DESIGN AND SETTING: Multicentre prospective cohort study among patients in German general practice that took place from January 2003 to October 2016. METHOD: Patients without baseline dementia were assessed with neuropsychological interviews over 12 years; 138 GPs rated the future cognitive decline of their participating patients. Associations of baseline predictors with follow-up incident dementia were analysed with mixed-effects logistic and Cox regression. RESULTS: A total of 3201 patients were analysed over the study period (mean age = 79.6 years, 65.3% females, 6.7% incident dementia in 3 years, 22.1% incident dementia in 12 years). Descriptive analyses and comparison with other cohorts identified the participants as having frequent and long-lasting doctor-patient relationships and being well known to their GPs. The GP baseline rating of future cognitive decline had significant value for 3-year dementia prediction, independent of cognitive test scores and patient's memory complaints (GP ratings of very mild (odds ratio [OR] 1.97, 95% confidence intervals [95% CI] = 1.28 to 3.04); mild (OR 3.00, 95% CI = 1.90 to 4.76); and moderate/severe decline (OR 5.66, 95% CI = 3.29 to 9.73)). GPs' baseline judgements were significantly associated with patients' 12-year dementia-free survival rates (Mantel-Cox log rank test P<0.001). CONCLUSION: In this sample of patients in familiar doctor-patient relationships, the GP's clinical judgement holds additional value for predicting dementia, complementing test performance and patients' self-reports. Existing and emerging primary care-based dementia risk models should consider the GP's judgement as one predictor. Results underline the importance of the GP-patient relationship.

Subregional volume reduction of the cholinergic forebrain in subjective cognitive decline (SCD).

Subjective cognitive decline (SCD) patients are considered as a risk population for preclinical Alzheimer's Disease (AD). Supporting this idea, previous studies in SCD populations report subtle alterations in various cognitive and neuroimaging biomarkers that are typically affected during AD progression. To extend these observations, the present study examined whether SCD patients show atrophy of cholinergic basal forebrain nuclei (chBFN), analogous with recent findings in prodromal and clinical AD patients. We assessed volume reductions of the chBFN in 24 SCD subjects compared to 49 matched controls on 3D-T1-weighted MR images based on a postmortem derived atlas. Furthermore, we assessed whether chBFN atrophy was linked with cognitive, structural and metabolic biomarker alterations we previously reported in this SCD cohort: Using correlation analyses we tested for associations between the volumes of the chBFN with the hippocampal gray matter volume, and posterior medial glucose consumption, and the trajectory of verbal memory performance. The SCD cases showed a significant total volume reduction of the chBFN, with largest effect sizes in the Ch1/2 and Ch4p subdivisions of the chBFN. The latter was associated with a reduced glucose metabolism in the precuneus for the SCD group only. These data show an early involvement of the cholinergic basal forebrain nuclei in SCD predominantly in Ch1/2 and Ch4p which supports the conceptual link between SCD and preclinical AD.

Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment.

BACKGROUND: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD). OBJECTIVE: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort. METHODS: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n = 82) or MCI (n = 134), distinguished by actuarial neuropsychological MCI criteria ("Jak-Bondi criteria"). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models. RESULTS: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups. CONCLUSION: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a "pre-MCI" at risk stage of AD.

Face-Name Associative Recognition Deficits in Subjective Cognitive Decline and Mild Cognitive Impairment.

BACKGROUND: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the preclinical stage of Alzheimer's disease (AD). Associative memory is a cognitive function supported by the hippocampus and affected early in the process of AD. OBJECTIVE: We developed a short computerized face-name associative recognition test (FNART) and tested whether it would detect memory impairment in memory clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). METHODS: We recruited 61 elderly patients with either SCD (n = 32) or MCI (n = 29) and 28 healthy controls (HC) and compared performance on FNART, self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced sample (n = 46), performance on the visual Paired Associates Learning of the CANTAB battery. RESULTS: A significant effect of group on FNART test performance in the total sample was found (p < 0.001). Planned contrasts indicated a significantly lower associative memory performance in the SCD (p = 0.001, d = 0.82) and MCI group (p < 0.001, d = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory in SCD patients (p = 0.024) but not in MCI patients. CONCLUSIONS: Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes.

Effect of Visual Impairment on Physical and Cognitive Function in Old Age: Findings of a Population-Based Prospective Cohort Study in Germany.

OBJECTIVES: To examine how visual impairment affects physical and cognitive function in old age. DESIGN: A longitudinal population-based prospective cohort study. SETTING: General practitioner offices at six study centers in Germany. They were observed every 1.5 years over four waves. PARTICIPANTS: Individuals aged 77-101 at follow-up Wave 2 (N = 2,394). MEASUREMENTS: Physical and cognitive function were assessed using an adapted scale that had been previously developed, and visual impairment was rated on a Likert scale (none, mild, severe or profound). RESULTS: Adjusting for sociodemographic factors and comorbidity, linear fixed-effects regression showed that the onset of severe visual impairment was associated with a decline in physical function score in the total sample (ß = -0.15, P = .01) and in women (ß = -.15, P = .03). Moreover, the onset of severe visual impairment was associated with decline in cognitive function score in the total sample (ß = -0.38, P < .001) and in women (ß = -0.38, P < .001) and men (ß = -0.37, P = .001). CONCLUSION: Visual impairment affects physical and cognitive function in old age. Interventional strategies to postpone visual impairment may contribute to maintaining physical and cognitive function.

Incident Subjective Cognitive Decline Does Not Predict Mortality in the Elderly--Results from the Longitudinal German Study on Ageing, Cognition, and Dementia (AgeCoDe).

OBJECTIVE: Subjective cognitive decline (SCD) might represent the first symptomatic representation of Alzheimer's disease (AD), which is associated with increased mortality. Only few studies, however, have analyzed the association of SCD and mortality, and if so, based on prevalent cases. Thus, we investigated incident SCD in memory and mortality. METHODS: Data were derived from the German AgeCoDe study, a prospective longitudinal study on the epidemiology of mild cognitive impairment (MCI) and dementia in primary care patients over 75 years covering an observation period of 7.5 years. We used univariate and multivariate Cox regression analyses to examine the relationship of SCD and mortality. Further, we estimated survival times by the Kaplan Meier method and case-fatality rates with regard to SCD. RESULTS: Among 971 individuals without objective cognitive impairment, 233 (24.0%) incidentally expressed SCD at follow-up I. Incident SCD was not significantly associated with increased mortality in the univariate (HR = 1.0, 95% confidence interval = 0.8-1.3, p = .90) as well as in the multivariate analysis (HR = 0.9, 95% confidence interval = 0.7-1.2, p = .40). The same applied for SCD in relation to concerns. Mean survival time with SCD was 8.0 years (SD = 0.1) after onset. CONCLUSION: Incident SCD in memory in individuals with unimpaired cognitive performance does not predict mortality. The main reason might be that SCD does not ultimately lead into future cognitive decline in any case. However, as prevalence studies suggest, subjectively perceived decline in non-memory cognitive domains might be associated with increased mortality. Future studies may address mortality in such other cognitive domains of SCD in incident cases.

The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment.

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aß42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

Determinants of health-related quality of life in older primary care patients: results of the longitudinal observational AgeCoDe Study.

BACKGROUND: In older patients with chronic diseases, focusing on subjective, patient-relevant outcomes, such as health-related quality of life (HRQoL), is more pertinent than pursuing clinical or laboratory target values. AIM: To investigate factors influencing the course of HRQoL in older (aged ≥78 years) primary care patients and to derive non-pharmacological recommendations for improving their quality of life. DESIGN AND SETTING: A population-based prospective longitudinal observational study featuring data analysis from waves 2 to 5 of the AgeCoDe study, which was conducted in six cities in Germany. METHOD: The HRQoL of 1968 patients over the course of 4.5 years was observed. Patients were, on average, aged 82.6 (±3.4) years and their HRQoL was measured using the EQ-5D visual analogue scale in a face-to-face assessment. Fixed-effects regression models were calculated to examine impact of change in potential influencing factors. This method allows unobserved heterogeneity to be controlled. RESULTS: The course of the participants' HRQoL declined with increasing age, walking and incident hearing impairment. Increasing the number of physical activities improved the HRQoL. These findings were modified by sex, education level, and depression. Especially in females and patients with rather low education levels, increased physical activity improved the subjects' HRQoL, while hearing impairment decreased it. Moving to an institution only improved the HRQoL in patients without depression or those with a low level of education (primary education). CONCLUSION: Motivating patients to increase their weekly physical activity and to focus on preserving their ability to walk are promising approaches to improving HRQoL in older age. Less-educated patients and those without depression can also benefit from moving into an institution (for example, a care or retirement home).

Feature Binding Deficits in Subjective Cognitive Decline and in Mild Cognitive Impairment.

BACKGROUND: Feature binding is a sensitive and specific cognitive marker for Alzheimer's disease (AD). Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are clinical categories associated with an increased risk for AD. OBJECTIVE: To investigate whether the SCD and MCI group are impaired with regard to feature binding. METHODS: The feature binding test was administered to memory clinic patients with either SCD (n = 19, mean MMSE: 29.2) or with MCI (n = 23, mean MMSE: 26.5), and to a group of healthy controls (HC, n = 23, mean MMSE: 29.0). Participants were assessed with the CERAD Plus neuropsychological test battery. Cognitive performance of the three groups was compared by ANCOVA with age, gender and education as covariates and planned contrasts. RESULTS: Groups differed in the binding condition. Planned contrasts showed significant differences in adjusted means between HC and SCD (p = 0.003), as well as between HC and MCI (p <  0.0001). DISCUSSION: The feature binding task detects subtle cognitive impairments in participants with SCD, who are unimpaired in traditional neuropsychological testing. This corroborates the use of feature binding tests in preclinical AD studies and suggests that specific cognitive deficits can be found in SCD. Future studies incorporating AD biomarkers and longitudinal follow-up are needed to further establish the clinical utility of feature binding.

Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI.

OBJECTIVE: To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). METHODS: We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. RESULTS: Abnormal CSF ß-amyloid 1-42 (Aß42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aß42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concerns, respectively. In addition, both SCD measures predicted risk of having a biomarker signature indicative of prodromal AD defined as presence of low CSF Aß42 together with either high CSF tau or CSF phosphorylated tau 181 levels. CONCLUSIONS: In MCI, specific aspects of SCD severity and quality are related to CSF biomarkers indicative of AD. This extends findings in pre-MCI samples and calls for an improved operational assessment of SCD in MCI. This might be useful for sample enrichment strategies for increased likelihood of AD pathology.

Cognitive performance before and after the onset of subjective cognitive decline in old age.

BACKGROUND: Our objectives were (1) to test the association between the report of subjective cognitive decline (SCD) and prospective objective cognitive performance in high age individuals and (2) to study the course of longitudinal cognitive performance before and after the first report of SCD. METHODS: Cognitively normal elderly participants of the German Study on Ageing, Cognition, and Dementia study (N = 2330) with SCD (subjective decline in memory with and without associated concerns) and without SCD at baseline were assessed over 8 years with regard to immediate and delayed verbal recall, verbal fluency, working memory, and global cognition. Baseline performance and cognitive trajectories were compared between groups. In addition, cognitive trajectories before and after the initial report of SCD (incident SCD) were modelled in those without SCD at baseline. RESULTS: Baseline performance in the SCD group was lower and declined more steeply in immediate and delayed verbal recall than in the control group (no SCD at baseline). This effect was more pronounced in the SCD group with concerns. Incident SCD was preceded by decline in immediate and delayed memory and word fluency. CONCLUSIONS: SCD predicts future memory decline. Incident SCD is related to previous cognitive decline. The latter finding supports the concept of SCD indicating first subtle decline in cognitive performance that characterizes preclinical Alzheimer's disease.

Gray matter atrophy pattern in elderly with subjective memory impairment.

BACKGROUND: Individuals with subjective memory impairment (SMI) report worsening of memory without impairment in cognitive tests. Despite normal cognitive performance, they may be at higher risk of cognitive decline compared with individuals without SMI. METHODS: We used a discriminative function (a support vector machine) trained on an independent data set of 226 healthy control subjects and 191 patients with probable Alzheimer's disease (AD) dementia to characterize the baseline gray matter patterns of 24 individuals with SMI and 53 control subjects. We tested for associations of these gray matter patterns with SMI presence, cognitive performance at baseline, and cognitive decline at follow-up. RESULTS: Individuals with SMI showed greater similarity to an AD gray matter pattern compared with control subjects without SMI. In addition, episodic memory decline was associated with an AD gray matter pattern in the SMI group. CONCLUSIONS: Our results indicate a link between the gray matter atrophy pattern of patients with AD and the presence of SMI. Furthermore, multivariate pattern recognition approaches seem to be a sensitive method for identifying subtle brain changes that correspond to future memory decline in SMI.