Jan Willem van Dalen

Apathy in Parkinson's disease: A systematic review and meta-analysis

Apathy is a frequently reported neuropsychiatric symptom in Parkinsons disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta‐analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta‐analysis showed a prevalence of apathy in PD of 39.8% (n = 5,388, 905% CI 34.6‐45.0%). Apathy was associated with higher age (3.3 years, 95% CI = 1.7‐4.9), lower mean Mini‐Mental State Evaluation (MMSE) score (−1.4 points, 95% CI = −2.1 to −0.8), an increased risk of co‐morbid depression (relative risk [RR] = 2.3, 95% CI = 1.9‐2.8), higher Unified Parkinsons Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI = 2.6‐10.3), and more severe disability (Hedges‐G = 0.5, 95% CI = 0.3‐0.6). Half of the patients with apathy had concomitant depression (57.2%, 95% CI = 49.4‐64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI = 42.2%‐62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self‐care, and reduce cognitive impairment by improving executive functioning.

Accurate white matter lesion segmentation by k nearest neighbor classification with tissue type priors (kNN-TTPs).

Introduction The segmentation and volumetric quantification of white matter (WM) lesions play an important role in monitoring and studying neurological diseases such as multiple sclerosis (MS) or cerebrovascular disease. This is often interactively done using 2D magnetic resonance images. Recent developments in acquisition techniques allow for 3D imaging with much thinner sections, but the large number of images per subject makes manual lesion outlining infeasible. This warrants the need for a reliable automated approach. Here we aimed to improve k nearest neighbor (kNN) classification of WM lesions by optimizing intensity normalization and using spatial tissue type priors (TTPs). Methods The kNN-TTP method used kNN classification with 3.0 T 3DFLAIR and 3DT1 intensities as well as MNI-normalized spatial coordinates as features. Additionally, TTPs were computed by nonlinear registration of data from healthy controls. Intensity features were normalized using variance scaling, robust range normalization or histogram matching. The algorithm was then trained and evaluated using a leave-one-out experiment among 20 patients with MS against a reference segmentation that was created completely manually. The performance of each normalization method was evaluated both with and without TTPs in the feature set. Volumetric agreement was evaluated using intra-class coefficient (ICC), and voxelwise spatial agreement was evaluated using Dice similarity index (SI). Finally, the robustness of the method across different scanners and patient populations was evaluated using an independent sample of elderly subjects with hypertension. Results The intensity normalization method had a large influence on the segmentation performance, with average SI values ranging from 0.66 to 0.72 when no TTPs were used. Independent of the normalization method, the inclusion of TTPs as features increased performance particularly by reducing the lesion detection error. Best performance was achieved using variance scaled intensity features and including TTPs in the feature set: this yielded ICC = 0.93 and average SI = 0.75 ± 0.08. Validation of the method in an independent sample of elderly subjects with hypertension, yielded even higher ICC = 0.96 and SI = 0.84 ± 0.14. Conclusion Adding TTPs increases the performance of kNN based MS lesion segmentation methods. Best performance was achieved using variance scaling for intensity normalization and including TTPs in the feature set, showing excellent agreement with the reference segmentations across a wide range of lesion severity, irrespective of the scanner used or the pathological substrate of the lesions.

Cortical Microinfarcts Detected In Vivo on 3 Tesla MRI Clinical and Radiological Correlates

Background and Purpose— Cortical microinfarcts (CMIs) are a common postmortem finding associated with vascular risk factors, cognitive decline, and dementia. Recently, CMIs identified in vivo on 7 Tesla MRI also proved retraceable on 3 Tesla MRI. Methods— We evaluated CMIs on 3 Tesla MRI in a population-based cohort of 194 nondemented older people (72–80 years) with systolic hypertension. Using a case–control design, participants with and without CMIs were compared on age, sex, cardiovascular risk factors, and white matter hyperintensity volume. Results— We identified 23 CMIs in 12 participants (6%). CMIs were associated with older age, higher diastolic blood pressure, and a history of recent stroke. There was a trend for a higher white matter hyperintensity volume in participants with CMIs. Conclusions— We found an association of CMIs with clinical parameters, including age and cardiovascular risk factors. Although the prevalence of CMIs is relatively low, our results suggest that the study of CMIs in larger clinical studies is possible using 3 Tesla MRI. This opens the possibility of large-scale prospective investigation of the clinical relevance of CMIs in older people.

Apathy is an independent risk factor for incident cardiovascular disease in the older individual: a population-based cohort study.

Although depression is considered to be associated with cardiovascular disease (CVD), specifically symptoms of apathy have been strongly associated with a history of CVD in recent studies. In this study, we prospectively assess whether symptoms of apathy and depression are independent risk factors for incident CVD and stroke.

The spatial coefficient of variation in arterial spin labeling cerebral blood flow images

Macro-vascular artifacts are a common arterial spin labeling (ASL) finding in populations with prolonged arterial transit time (ATT) and result in vascular regions with spuriously increased cerebral blood flow (CBF) and tissue regions with spuriously decreased CBF. This study investigates whether there is an association between the spatial signal distribution of a single post-label delay ASL CBF image and ATT. In 186 elderly with hypertension (46% male, 77.4 ± 2.5 years), we evaluated associations between the spatial coefficient of variation (CoV) of a CBF image and ATT. The spatial CoV and ATT metrics were subsequently evaluated with respect to their associations with age and sex – two demographics known to influence perfusion. Bland–Altman plots showed that spatial CoV predicted ATT with a maximum relative error of 7.6%. Spatial CoV was associated with age (β = 0.163, p = 0.028) and sex (β = −0.204, p = 0.004). The spatial distribution of the ASL signal on a standard CBF image can be used to infer between-participant ATT differences. In the absence of ATT mapping, the spatial CoV may be useful for the clinical interpretation of ASL in patients with cerebrovascular pathology that leads to prolonged transit of the ASL signal to tissue.

Apathy is associated with incident dementia in community-dwelling older people

Objective To assess whether apathy and depressive symptoms are independently associated with incident dementia during 6-year follow-up in a prospective observational population-based cohort study. Methods Participants were community-dwelling older people in the Prevention of Dementia by Intensive Vascular Care trial, aged 70–78 years, without dementia at baseline. Apathy and depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Dementia during follow-up was established by clinical diagnosis confirmed by an independent outcome adjudication committee. Hazard ratios (HRs) were calculated using Cox regression analyses. Given its potentially strong relation with incipient dementia, the GDS item referring to memory complaints was assessed separately. Results Dementia occurred in 232/3,427 (6.8%) participants. Apathy symptoms were associated with dementia (HR 1.28, 95% confidence interval [CI] 1.12–1.45; p < 0.001), also after adjustment for age, sex, Mini-Mental State Examination score, disability, and history of stroke or cardiovascular disease (HR 1.21, 95% CI 1.06–1.40; p = 0.007), and in participants without depressive symptoms (HR 1.26, 95% CI 1.06–1.49; p = 0.01). Depressive symptoms were associated with dementia (HR 1.12, 95% CI 1.05–1.19), also without apathy symptoms (HR 1.16, 95% CI 1.03–1.31; p = 0.015), but not after full adjustment or after removing the GDS item on memory complaints. Conclusions Apathy and depressive symptoms are independently associated with incident dementia in community-dwelling older people. Subjective memory complaints may play an important role in the association between depressive symptoms and dementia. Our findings suggest apathy symptoms may be prodromal to dementia and might be used in general practice to identify individuals without cognitive impairment at increased risk of dementia.

Neuropsychiatric symptoms of cholinergic deficiency occur with degradation of the projections from the nucleus basalis of Meynert

This study aims to evaluate the relation between a cluster of neuropsychiatric symptoms related to cholinergic deficiency and degradation of the cortical cholinergic projections which project from the nucleus basalis of Meynert to the cerebral cortex. An atlas of the pathway from the nucleus basalis to the cortex (NbM cortical pathway) was constructed using diffusion tensor imaging and tractography in 87 memory clinic patients. Structural degradation was considered to be represented by lower fractional anisotropy (FA) and higher mean diffusivity (MD). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A predefined cluster including agitation, anxiety, apathy, delusions, hallucinations, and irritability was labeled as the cholinergic deficiency syndrome (CDS). In regression analyses, lower FA and higher MD in the NbM cortical pathway were associated with CDS symptoms but not with other neuropsychiatric symptoms. These associations were independent of cerebral atrophy and overall FA or MD. There was no association between interruption of the NbM cortical pathway by white matter hyperintensities and CDS symptoms. Cox regression suggested a trend for higher mortality with lower FA in the NbM cortical pathway may exist. These findings provide anatomical support for the hypothesis that degradation of the cholinergic projections from the nucleus basalis of Meynert may lead to a distinct clinical syndrome. Future studies could use our results to test the utility of assessing NbM projection integrity to identify patients who may benefit from cholinergic treatment or with a worse prognosis.

Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care)

Background and Purpose— This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension. Methods— The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure ≥140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation. Results— One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, −0.08 mL; 95% confidence interval, −0.30 to 0.15; P=0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes (P for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4–12.1; P=0.36). Conclusions— Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low. Clinical Trial Information— URL: http://www.isrctn.com/ISRCTN29711771. Unique identifier: ISRCTN29711771.

Apathy and depressive symptoms in older people and incident myocardial infarction, stroke, and mortality: a systematic review and meta-analysis of individual participant data

Background Previous findings suggest that apathy symptoms independently of depressive symptoms measured using the Geriatric Depression Scale (GDS) are associated with cardiovascular disease (CVD) in older individuals. Aims To study whether apathy and depressive symptoms in older people are associated with future CVD, stroke, and mortality using individual patient-data meta-analysis. Methods Medline, Embase, and PsycInfo databases up to September 3, 2013, were systematically searched without language restrictions. We sought prospective studies with older (mean age ≥65 years) community-dwelling populations in which the GDS was employed and subsequent stroke and/or CVD were recorded to provide individual participant data. Apathy symptoms were defined as the three apathy-related subitems of the GDS, with depressive symptoms the remaining items. We used myocardial infarction (MI), stroke, and all-cause mortality as main outcomes. Analyses were adjusted for age, sex, and MI/stroke history. An adaptation of the Newcastle–Ottawa scale was used to evaluate bias. Hazard ratios were calculated using one-stage random-effect Cox regression models. Results Of the 52 eligible studies, 21 (40.4%) were included, comprising 47,625 older people (mean age [standard deviation] 74 [7.4] years), over a median follow-up of 8.8 years. Participants with apathy symptoms had a 21% higher risk of MI (95% confidence interval [CI] 1.08–1.36), a 37% higher risk of stroke (95% CI 1.18–1.59), and a 47% higher risk of all-cause mortality (95% CI 1.38–1.56). Participants with depressive symptoms had a comparably higher risk of stroke (HR 1.36, 95% CI 1.18–1.56) and all-cause mortality (HR 1.44, 95% CI 1.35–1.53), but not of MI (HR 1.08, 95% CI 0.91–1.29). Associations for isolated apathy and isolated depressive symptoms were comparable. Sensitivity analyses according to risk of bias yielded similar results. Conclusion Our findings stress the clinical importance of recognizing apathy independently of depressive symptoms, and could help physicians identify persons at increased risk of vascular disease.

Association of Apathy With Risk of Incident Dementia: A Systematic Review and Meta-analysis

Importance Fear of dementia is pervasive in older people with cognitive concerns. Much research is devoted to finding prognostic markers for dementia risk. Studies suggest apathy in older people may be prodromal to dementia and could be a relevant, easily measurable predictor of increased dementia risk. However, evidence is fragmented and methods vary greatly between studies. Objective To systematically review and quantitatively synthesize the evidence for an association between apathy in dementia-free older individuals and incident dementia. Data Sources Two reviewers conducted a systematic search of Medline, Embase, and PsychINFO databases. Study Selection Inclusion criteria were (1) prospective cohort studies, (2) in general populations or memory clinic patients without dementia, (3) with clear definitions of apathy and dementia, and (4) reporting on the association between apathy and incident dementia. Data Extraction and Synthesis PRISMA and MOOSE guidelines were followed. Data were extracted by 1 reviewer and checked by a second. Main Outcomes and Measures Main outcomes were pooled crude risk ratios, maximally adjusted reported hazard ratios (HR), and odds ratios (OR) using DerSimonian-Laird random effects models. Results The mean age of the study populations ranged from 69.2 to 81.9 years (median, 71.6 years) and the percentage of women ranged from 35% to 70% (median, 53%). After screening 2031 titles and abstracts, 16 studies comprising 7365 participants were included. Apathy status was available for 7299 participants. Studies included populations with subjective cognitive concerns (n = 2), mild cognitive impairment (n = 11), cognitive impairment no dementia (n = 1), or mixed cognitive and no cognitive impairment (n = 2). Apathy was present in 1470 of 7299 participants (20.1%). Follow-up ranged from 1.2 to 5.4 years. In studies using validated apathy definitions (n = 12), the combined risk ratio of dementia for patients with apathy was 1.81 (95% CI, 1.32-2.50; I2 = 76%; n = 12), the hazard ratio was 2.39 (95% CI, 1.27-4.51; I2 = 90%; n = 7), and the odds ratio was 17.14 (95% CI, 1.91-154.0; I2 = 60%; n = 2). Subgroup analyses, meta-regression, and individual study results suggested the association between apathy and dementia weakened with increasing follow-up time, age, and cognitive impairment. Meta-regression adjusting for apathy definition and follow-up time explained 95% of heterogeneity in mild cognitive impairment. Conclusions and Relevance Apathy was associated with an approximately 2-fold increased risk of dementia in memory clinic patients. Moderate publication bias may have inflated some of these estimates. Apathy deserves more attention as a relevant, cheap, noninvasive, and easily measureable marker of increased risk of incident dementia with high clinical relevance, particularly because these vulnerable patients may forgo health care.