Predictors of anxiety in Parkinson's disease: results from a 3-year longitudinal cohort study.

INTRODUCTION: Anxiety symptoms are the most common neuropsychiatric manifestation of Parkinson's disease (PD), contributing to decreased quality of life. Few longitudinal studies in PD samples have examined correlates of anxiety symptoms over time. Understanding predictor variables may help to identify novel targets for reducing anxiety in PD. The aim of this study was to identify predictors of anxiety symptoms over 3 years in a clinic-based PD cohort. METHODS: Our cohort included patients with PD at an academic medical center in the Southeastern United States (n = 105). Visits included assessment of motor, psychiatric, and cognitive features, including neuropsychological testing. For our multivariate model, we selected 11 predictor variables with the most existing evidence or theoretical support for an association with anxiety symptoms in PD. Multivariate linear mixed model regression was performed to determine which variables were significantly associated with anxiety symptoms over time. RESULTS: Over half of participants (57%) met the screening threshold for an anxiety disorder at some point during the study. Independent predictors of anxiety symptoms over time included symptoms of REM sleep behavior disorder (RBD) and dysautonomia. DISCUSSION: In this PD sample, RBD and dysautonomia symptoms were significantly associated with anxiety symptoms over time. Each of these relationships has been reported in one of two prior longitudinal studies. Unlike prior studies, cognitive impairment was not a significant predictor of anxiety symptoms in our sample. Future research should confirm the direction and mechanisms underlying these relationships, including the potential for anxiety symptom reduction through treatment for RBD and dysautonomia.

Cholinergic nucleus 4 grey matter density is associated with apathy in Parkinson's disease.

Objective: The generation and maintenance of goal-directed behavior is subserved by multiple brain regions that receive cholinergic inputs from the cholinergic nucleus 4 (Ch4). It is unknown if Ch4 degeneration contributes to apathy in Parkinson's disease (PD). Method: We analyzed data from 106 pre-surgical patients with PD who had brain MRIs and completed the Frontal Systems Behavior Scales (FrSBe). Eighty-eight patients also completed the Beck Depression Inventory-2nd Edition. Cholinergic basal forebrain grey matter densities (GMD) were measured by applying probabilistic maps to T1 MPRAGE sequences processed using voxel-based morphometry methods. We used linear and hierarchical regression modelling to examine the association between Ch4 GMD and the FrSBe Apathy subscale scores. We used similar methods to assess the specificity of this association and potential associations between Ch4 target regions and apathy. Results: Ch4 GMD (p = .021) and Ch123 GMD (p = .032) were significantly associated with Apathy subscale scores on univariate analysis. Ch4 GMD, but not Ch123 GMD, remained significantly associated with apathy when adjusting for age, sex, levodopa equivalent doses, and disease duration. Centromedial amygdala GMD, which receives cholinergic inputs from Ch4, was also associated with apathy. Ch4 GMD was not associated with depression or disinhibition, nor was it associated with executive dysfunction when adjusting for clinical and demographic variables. Conclusions: Ch4 GMD is specifically associated with apathy in PD. Ch4 degeneration results in cholinergic denervation of multiple cortical and limbic regions, which may contribute to the cognitive and emotional-affective processing deficits that underlie the behavioral symptoms of apathy.

Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease.

INTRODUCTION: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD. METHODS: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions. RESULTS: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (߈slope= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (߈slope= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time. CONCLUSION: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.

The Effect of Education on Symptom Onset and Severity of Huntington's Disease.

BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Little is known about the effects of environmental factors on HD symptom onset and severity. OBJECTIVE: To evaluate the relationship between education level and age of diagnosis, symptom onset, and symptom severity in HD. METHODS: This study evaluated 4537 adult-onset, motor-manifest HD participants from the Enroll-HD global registry. Education level was assessed using International Standard Classification of Education categories, stratified into three education groups corresponding to pre-secondary, secondary, and post-secondary educational attainment. Motor and behavioral symptoms of HD, cognition, and functional capacity were measured using baseline Unified Huntington's Disease Rating Scale (UHDRS), Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), verbal fluency, and Stroop assessments. RESULTS: After adjusting for CAG repeats, higher level of education predicted lower age of onset of motor symptoms, depression, irritability, and cognitive impairment (all P-values < 0.001). After adjusting for age of enrollment and CAG repeats, the highest education level predicted the lowest UHDRS motor scores, higher UHDRS total functional capacity and functional assessment scores, and higher SDMT, MMSE, verbal fluency, and Stroop assessment scores (all P-values < 0.001). CONCLUSIONS: HD participants with higher education levels have earlier age of diagnosis and age of symptom onset, but lower motor exam scores and higher functional assessment scores. Earlier recognition of symptoms in more highly educated participants may explain earlier symptom onset and diagnosis. Better performance on motor and functional assessments may be explained by higher cognitive reserve in those with greater education.

Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease.

BACKGROUND: There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed. OBJECTIVES: The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients. METHODS: We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex. RESULTS: Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021). CONCLUSIONS: Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.

Comparison of Parkinson's Disease Patients' Characteristics by Indication for Deep Brain Stimulation: Men Are More Likely to Have DBS for Tremor.

Background: We investigated whether the characteristics of Parkinson's disease (PD) patients differ based on the primary indication for deep brain stimulation (DBS). Methods: We reviewed data for 149 consecutive PD patients who underwent DBS at the University of Virginia. Patients were categorized based on primary surgical indication, and clinical characteristics were compared between groups. Results: Twenty-nine (93.5%) of 31 PD patients who underwent DBS for medication refractory tremor were men, and 66 (62.3%) of 106 PD patients who underwent DBS for motor fluctuations were men (p = 0.001). Other primary indications for DBS were tremor and fluctuations (n = 5), medication intolerance (n = 5), and dystonia (n = 2). Discussion: Patients who underwent DBS for medication refractory tremor were predominantly men, while patients who had DBS for motor fluctuations approximated the gender distribution of PD. Possible explanations are that men with PD are more likely to develop medication refractory tremor or undergo surgery for medication refractory tremor in PD compared to women.

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

OBJECTIVE: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD. METHODS: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models. RESULTS: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (ß=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (ß=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (ß=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (ß=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (ß=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (ß=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (ß=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls. CONCLUSION: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.

Predictors of health-related quality of life in Parkinson's disease.

BACKGROUND: Health-related quality of life in Parkinson's disease may be affected by a wide range of motor and non-motor symptoms. Identifying which symptoms are significant predictors of health-related quality of life in Parkinson's disease prioritizes symptoms for treatment, therapeutic development, and clinical outcomes. OBJECTIVES: To determine predictors of health-related quality of life in patients with Parkinson's disease. METHODS: We recruited 102 subjects into a prospective study to investigate neuropsychiatric symptoms in Parkinson's disease. Health-related quality of life was measured with the 39-item Parkinson's Disease Questionnaire. Subjects completed the Movement Disorder Society Unified Parkinson's Disease Rating Scale Parts I-IV as well as validated scales to assess anxiety, depression, apathy, cognition, psychosis, impulsive-compulsive disorder, autonomic dysfunction, sleep quality, excessive daytime sleepiness, and rapid eye movement sleep behavior disorder. We used univariate analyses to select clinical predictors to construct a multivariate regression model to determine which predictors were independently associated with worse health-related quality of life. RESULTS: In a multivariate linear regression model adjusted for age and gender, higher scores for the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale part II as well more severe symptoms of depression, anxiety, apathy, and excessive daytime sleepiness were associated with worse health-related quality of life. The model explained 78% of the variance of health-related quality of life, and the non-motor symptoms explained 49% of the variance. CONCLUSIONS: Anxiety, depression, excessive daytime sleepiness, apathy, and impairment in activities of daily living related to motor symptoms were independently associated with worse health-related quality of life.

Clinical and demographic correlates of apathy in Parkinson's disease.

OBJECTIVE: To better understand the demographic, neuropsychiatric, cognitive, and motor predictors of apathy in Parkinson's disease (PD). METHOD: 112 participants (Mage = 68.53 years; Mdisease duration = 6.17 years) were administered the Apathy Scale (AS), Beck Depression Inventory-II (BDI-II), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Trail Making Test (TMT), Wechsler Adult Intelligence Scale-IV Matrix Reasoning subtest, letter (F-A-S) and category (Animals) fluency, and Hopkins Verbal Learning Test-Revised. Psychosis was assessed. A stepwise logistic regression analysis was performed to investigate the ability of demographic factors and clinical assessments to predict nonapathetic (AS ≤ 13) versus apathetic (AS > 13) group membership. RESULTS: The regression analysis yielded a robust model in which older age, less education, elevated BDI-II, current psychosis, higher MDS-UPDRS Part III (motor score), and slower TMT-B performance predicted membership in the apathetic group, with a correct classification rate of 77.5% (Nagelkerke R2 = 0.48, p < .001). Depression (OR = 9.20, p < .001) and education (OR = 0.66, p = 0.002) contributed significantly to the overall model. A linear regression with AS score as the outcome variable was similar, but TMT-B additionally contributed significantly (p = 0.02) to the overall model, F(6, 86) = 12.02, p < .001, adjusted R2 = 0.42. CONCLUSIONS: Of the factors examined, depression, education, and executive functioning were the strongest correlates of apathy in PD. These results support the idea that common underlying frontosubcortical disruptions in this population contribute to apathy, depression, and executive dysfunction.

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. In-vivo human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients (N = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients (N = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects (N = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are "higher" in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.

Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia.

INTRODUCTION: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia. METHODS: 101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied. RESULTS: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis. CONCLUSION: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.

Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

BACKGROUND: Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. OBJECTIVE: The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). METHODS: Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. RESULTS: In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects > 70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. CONCLUSIONS: Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.