Apathy and Depression Impact on Cognitive Decline: Neuropsychological Specificities across Neurodegenerative Diseases

Frequency and Correlates of Involuntary Emotional Expression Disorder in Parkinson's Disease

INTRODUCTIONWe investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases.METHODSGlial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p‐tau)181 and amyloid beta (Aβ)42/40 were measured using ultra‐sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD).RESULTSGFAP, NfL, and/or p‐tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p‐tau181 were highly predictive across diseases, p‐tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40.DISCUSSIONGFAP, NfL, and p‐tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

To perform a critical review of scales designed to measure frontal behavior change. Changes in cognition due to frontal disease or damage have been well described, but noncognitive changes in behavior are often more deleterious functionally for frontal patients. The review concentrates on five behavior rating scales: the Behavior Rating Inventory of Executive Functions (BRIEF), the Dysexecutive Questionnaire (DEX), the Frontal Behavior Inventory (FBI), the Frontal Systems Behavior Scale (FrSBe), the Iowa Rating Scales of Personality Change (IRSPC), and the Neuropsychiatric Inventory (NPI). Other scales purporting to measure specific aspects of frontal functioning, but having less research support, are described briefly. The BRIEF and FrSBe have good reliability and large-scale norms. No norms are available for the other scales. The FrSBe and IRSPC have been shown to be valid in discriminating frontal from nonfrontal lesioned patients, but this has not been shown in the other scales. The FBI and NPI require trained raters, whereas the FrSBe, IRSPC, and BRIEF are administered to patients and/or family informants directly. The NPI and FBI are sensitive to certain changes in behavior attributed to frontal systems disruption but have been used primarily in dementia.

The association between fatigue and apathy in patients with either Parkinson's disease or multiple sclerosis.

BackgroundThough previous research supports diffusion tensor imaging (DTI) as a biomarker for white matter integrity in diseases such as Alzheimer's disease/mild cognitive impairment (ADMCI), Parkinson's disease (PD), and cerebrovascular disease (CVD), few studies have compared white matter microstructure between different neurodegenerative aetiologies. This study aimed to characterize and compare the microstructure of white matter tracts in ADMCI, PD, and CVD patients using DTI data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).MethodThe ONDRI study included 119 ADMCI, 149 CVD, and 137 PD patients with usable DTI and T1 MRI data. FreeSurfer's TRACULA [https://dmri.mgh.harvard.edu/tract‐atlas/] was used to reconstruct 39 white matter pathways and calculate average DTI metrics (fractional anisotropy, FA; mean diffusivity, MD; axial diffusivity, AxD; and radial diffusivity, RD) in each pathway. Patients with severe cerebral infarcts, hypointensities, or ventricular dilation that compromised tract reconstruction were excluded from further analyses. The final dataset included 96 ADMCI [n(%)female=50(52%); median(range)age=71(53‐87)], 107 CVD [n(%)female=35(33%); median(range)age=69(55‐85)], and 117 PD [n(%)female=28(24%); median(range)age=68(55‐84)] participants. Multivariate general linear models evaluated the effect of diagnosis on FA, MD, AxD, and RD in all 39 tracts.Result3D segmentations of the 39 white matter tracts in a representative subject are shown in Figure 1. In the multivariate analyses, diagnosis had a strong, significant effect on all four DTI metrics (FA: p = 0.002, ηp2=0.180; MD: p = 0.001, ηp2=0.183; AxD: p = 0.003, ηp2=0.178; RD: p = 0.002, ηp2=0.181). Figures 2 and 3 display the post hoc pairwise comparisons of FA and MD, respectively, in only the tracts for which diagnosis had a significant (p <0.05) effect in the univariate analyses. On average, PD participants had higher FA (2.3%, ηp2=0.030) and lower MD (1.7%; ηp2=0.032), AxD (1.3%; ηp2=0.036), and RD (2.3%; ηp2=0.027) within these tracts compared to ADMCI and CVD participants. There were very few significant differences between ADMCI and CVD participants.ConclusionPD participants had slightly more preserved white matter tract microstructural integrity than ADMCI or CVD participants who had lower FA and higher RD and MD values. Higher‐quality, advanced diffusion imaging may be necessary to detect the more subtle changes in white matter microstructure present in Parkinson's disease patients.

Vulnerable Neural Systems and the Borderland of Brain Aging and Neurodegeneration

BackgroundApathy, a decline in goal-directed motivated behavior, is a common non-motor symptom (NMS) in Parkinson’s disease (PD). Previous studies have suggested that PD patients with apathy exhibit increased iron levels in the cerebrospinal fluid (CSF) and the iron levels are positively correlated with the severity of apathy, indicating that apathy in PD may be related with brain iron accumulation. Specifically, quantitative susceptibility mapping (QSM), an emerging brain magnetic resonance imaging (MRI) technique, can be used to sensitively detect the iron deposition in the brain in vivo, to reflect the neurodegeneration processes. This study thus used QSM to detect the brain iron deposition in PD with pure apathy (PD-PA) and examined apathy symptoms-related regional brain iron deposition, and aimed to explore the underlying mechanism of neurodegeneration of PD-PA.MethodsA total of 29 patients with PD-PA, 33 PD without pure apathy (PD-NPA), and 32 healthy controls (HCs) were collected. All participants underwent three-dimensional T1-weighted imaging (3DT1) and QSM scans. The susceptibility values of PD-PA, PD-NPA, and HC groups were compared at whole brain voxel-wise level and the region of interest (ROI)-wise level, respectively. Moreover, correlation analysis between apathy symptoms and brain iron deposition was further performed in the PD-PA group.ResultsRelative to the HCs, patients with PD demonstrated increased susceptibility values (consistent with higher brain tissue iron deposits) in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of the midbrain [Pfalse discovery rate (FDR)<0.05]. Further PD subgroup analysis suggested that compared with HCs, patients with PD-NPA showed increased iron deposition in the right medial superior frontal gyrus (SFGmed), whereas those with PD-PA exhibited more extensive increased iron deposition in SFGmed, extending to bilateral SFGmed [voxel-level P<0.001, cluster-level Pfamily-wise error (FWE)<0.05]. The Apathy Scale (AS) score was positively correlated with the mean susceptibility values of the left SFGmed in the PD-PA group (r=0.651, P=0.001). In the PD-PA group, voxel-wise whole-brain correlation analysis found a positive correlation between the AS score and the susceptibility values in the left SFGmed, left anterior cingulate cortex (ACC), right thalamus, as well as the right superior temporal gyrus (STG) (voxel-level P<0.001, cluster-level PFWE<0.05).ConclusionsIn patients with PD-PA, brain regions associated with brain iron deposition were mainly located in the “mesocorticolimbic loop” (SFGmed and ACC), as well as the STG and thalamus. The present study suggested that abnormal iron deposition in these core brain regions may be associated with abnormal top-down and bottom-up neuroregulation and involved in the mechanism of PD apathy. The present study provides new insights into the pathophysiologic mechanism of PD-PA.

Traditionally, apathy has been viewed as a symptom indicating loss of interest or emotions. This paper evaluates evidence that neuropsychiatric disorders also produce a syndrome of apathy. Both the symptom and the syndrome of apathy are of conceptual interest because they signify loss of motivation. An apathy syndrome is defined as a syndrome of primary motivational loss, that is, loss of motivation not attributable to emotional distress, intellectual impairment, or diminished level of consciousness. Loss of motivation due to disturbance of intellect, emotion, or level of consciousness defines the symptom of apathy. Neuropsychiatric literature dealing with apathy is reviewed within the framework of three approaches to defining the concept of a syndrome. Clinical and investigative approaches for evaluating apathy when it occurs in association with other syndromes are described.

Introduction: Although apathy is a common psychiatric symptom of Parkinson’s disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD. Methods: Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups—apathetic or non-apathetic—based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters. Results: Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p < .004]; modified Hoehn & Yahr stage [p = .039]; Unified Parkinson’s Disease Rating Scale part III [p < .001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales. Conclusion: Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.

ObjectiveApathy has been reported as a possible adverse effect of deep brain stimulation of the subthalamic nucleus (STN-DBS). We investigated the prevalence and severity of apathy in 22 patients with...

Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored. To investigate the association between vascular risk burden, and brain white matter integrity, across five neurodegenerative conditions. Cross-sectional study including 520 participants from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) cohorts: 126 with amnestic Mild Cognitive Impairment/Alzheimer's Disease (MCI/AD), 53 with Frontotemporal Dementia (FTD), 161 with Cerebrovascular Disease (CVD), 140 with Parkinson's Disease (PD), and 40 with Amyotrophic Lateral Sclerosis (ALS), along with 41 cognitively healthy controls. A vascular risk index (VRI, range 0-5) assessed hypertension, diabetes, dyslipidemia, obesity (BMI ≥ 30), and smoking history. Macro (WMH volume) and micro (Diffusion tensor imaging) white matter integrity were evaluated using 3-Tesla MRI. Associations were analyzed using multinomial logistic regression and ANCOVA, adjusting for age, sex, education, and APOE ε4 allele status. Vascular risk factors, particularly hypertension and hypercholesterolemia, were more prevalent in the disease cohorts than controls. A higher VRI was significantly associated with MCI/AD (1.5-fold, p = 0.05), FTD (1.7-fold, p =0 .02), and CVD (2.6-fold, p < 0.005) cohorts. High VRI was associated with reduced macro and microstructural white matter integrity in the pooled sample (macro: p = 0.005; micro: p = 0.003), and separately in CVD (macro: p = 0.04; micro: p = 0.002). APOE ε4 status only mildly attenuated these associations. Vascular risk burden is prevalent in neurocognitive syndromes including MCI/AD, FTD and CVD, and impacts white matter integrity. Future studies are needed to explore if vascular risk management may mitigate the consequences of neurodegeneration in these clinical groups.

Objective To systematically evaluate the clinical efficacy and safety of nimodipine in treating vascular dementia (VaD). Methods Taking "nimodipine AND vascular dementia" as search terms, retrieve in databases such as PubMed, Cochrane Library, EMBASE/SCOPUS, Science Citation Index (SCI), China National Knowledge Infrastructure (CNKI), VIP and Wanfang Data (January 1995-March 2015). Annual searching was applied to retrieve partial periodical literatures and unpublished studies. Google Scholar was used for randomized controlled trials (RCTs) about nimodipine in treating VaD. Jadad scale was used to evaluate the quality of literature, and Meta-analyses were performed by using RevMan 5.3 software. Results Eleven literatures met inclusion criteria, including 10 clinical studies (1333 patients). All 10 studies were RCTs, including 4 nimodipine vs placebo, 5 nimodipine vs donepezil and one nimodipne vs hydergine, but only 2 described randomization methods. The results of Meta-analysis showed: nimodipine had better Mini-Mental State Examination (MMSE) score than before treatment and placebo group (3 studies, MD = 0.270, 95%CI: 0.070—0.460, P = 0.007); one study of blank control, MD = 2.950, 95% CI: 1.670—4.200, P = 0.000). Patients treated with nimodipne had no significantly improved Activities of Daily Living (ADL) score than placebo group [one study of ADL, MD = 5.800, 95%CI: 2.480—9.120, P = 0.000; one study of ADL Index, MD = -0.040, 95%CI: -0.110—0.030, P = 0.230; one study of instrumental ADL (IADL), MD = -0.080, 95%CI: -0.110—0.000, P = 0.060]. Both nimodipine and donepezil can improve MMSE and ADL scores, but the efficacy of nimodipine was not superior to donepezil [4 studies of MMSE (12-week observation), MD = -4.400, 95% CI: -4.870— -3.920, P = 0.000; one study of MMSE (24-week observation), MD = -8.800, 95% CI: -8.970— -7.430, P = 0.000; 2 studies of ADL, MD = 1.800, 95% CI: 1.360 — 2.230, P = 0.000]. Compared with hydergine, nimodipine had better scores in MMSE ( MD = 2.170, 95%CI: 0.890—3.450, P = 0.001) and ADL ( MD = -5.160, 95%CI: -7.480— -2.840, P = 0.000) in one study. The main side effects of nimodipine were cardio-cerebrovascular diseases, neuropsychiatric symptoms, abnormal skin reaction, gastrointestinal reactions and joint edema, et al. Conclusions Current study shows that the effect of nimodipine in the treatment of VaD may be superior to placebo and hydergine, but not better than donepezil. The results of systematic review still need more high-quality, multi-center and large-sample RCTs to further prove. DOI: 10.3969/j.issn.1672-6731.2015.07.008

Apathy is a common feature of Parkinson's disease (PD) that can manifest independently of depression, but little is known about its natural progression in medically managed patients. The present study sought to characterize and compare trajectories of apathy, depression, and motor symptoms in PD over 18 months. Data from a sample of 186 PD patients (mean disease duration of 8.2 years) followed by the University of Florida Movement Disorders Center were obtained from a clinical research database. Scores on the Unified Parkinson's disease Rating Scale (motor portion), Apathy Scale, and Beck Depression Inventory at three time-points (baseline, 6 months, 18 months) were analyzed in a structural equation modeling framework. A multivariate growth model controlling for age, sex, education, and disease duration identified linear worsening of both apathy (slope estimate = 0.73; p < .001) and motor symptoms (slope estimate = 1.51; p < .001), and quadratic changes in depression (slope estimate = 1.18; p = .07). All symptoms were positively correlated. Higher education was associated with lower apathy, depression, and motor severity. Advanced age was associated with greater motor and apathy severity. Female sex and longer disease duration were associated with attenuated motor worsening. Antidepressant use was associated only with depression scores. These longitudinal results support the differentiation of apathy and depression in PD. Like motor progression, apathy progression may be linked at least partially to dopaminergic neurodegeneration. Empirically supported treatments for apathy in PD are needed.

Anosognosia and apathy are among the most common behavioral and psychological disorders of Alzheimer's disease and are significantly associated in cross-sectional studies. The aim for this study was to carry out for the first time a longitudinal assessment of this association with the aim of clarifying the predictive role between anosognosia and apathy in Alzheimer's disease. A consecutive series of 213 patients with probable Alzheimer's disease were assessed for the presence of apathy and anosognosia using a specific neuropsychiatry assessment. One hundred fifty four of the patients (72%) had a follow-up assessment between 1 and 4 years after the baseline evaluation. Patients with anosognosia at baseline had a significant increase in apathy scores during follow-up relative to patients without anosognosia at both assessments. Conversely, patients with or without apathy had an increase of similar magnitude in anosognosia scores. In conclusion, anosognosia is a significant predictor of apathy in Alzheimer's disease. This may be related to a specific pattern of progression of neuropathology and/or to poor adjustment of Alzheimer's disease patients with poor insight into their functional deficits.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).