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1.  Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson’s disease 
Hyposmia, psychiatric disorders and cognitive problems are common non-motor manifestations in Parkinson's Disease but how they are related remains unclear.
To investigate the relationship between olfactory dysfunction and neuropsychiatric manifestations we performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London-Drexel and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification test.
There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%, p<0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean(standard deviation) 6.2(3.2) vs. 8.4(2.8), p<0.001) and executive performance (Tower of London total moves, 52(38) vs. 34(21), p<0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex and disease characteristics in logistic regression models.
The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common non-motor symptoms.
PMCID: PMC3168697  PMID: 21611985
Parkinson's Disease; olfaction; non-motor symptoms; psychiatric symptoms; cognitive symptoms
2.  Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease 
Neurology  2012;79(24):2307-2314.
To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD).
We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed.
Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD.
These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.
PMCID: PMC3578379  PMID: 23152586
3.  Neuropathologic substrates of Parkinson’s disease dementia 
Annals of neurology  2012;72(4):587-598.
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
140 patients with a clinical diagnosis of PD and either normal cognition or onset of dementia two or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded.
Autopsy records of genetic data and semi-quantitative scores for the burden of neurofibrillary tangles (NFTs), senile plaques (SPs), Lewy body (LB/LN) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of co-morbid Alzheimer’s disease (PDD+AD) were also examined.
92 PD patients developed dementia and 48 remained cognitively normal. Severity of cortical LB/LN (CLB/LN) pathology was positively associated with dementia (p<0.001), with an odds-ratio (OR) of 4.06 (CI95%1.87–8.81), as was Apolipoprotein E4 (APOE4) genotype (p=0.018,OR4.19 CI95% 1.28–13.75). 28.6% of all PD cases had sufficient pathology for co-morbid AD, of which 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p=0.001,OR1.12 CI95%1.04–1.21), higher CLB/LN burden (p=0.037,OR 2.48 CI95%1.06–5.82), and cerebral amyloid angiopathy severity (p=0.032, OR4.16 CI95%1.13–15.30).
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or Aβ could potentially improve cognitive performance in PD.
PMCID: PMC3484250  PMID: 23037886
4.  Brain Organochlorines and Lewy Pathology: The Honolulu-Asia Aging Study 
Although organochlorines have been reported more frequently in Parkinson’s disease (PD) brains than controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during mid-life, represent a population well suited to determine the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS.
Study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites.
With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found to be present in at least one brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. Prevalence of Lewy pathology was 75% (6/8) among brains with any 2 of the 3 compounds, 48.8% (79/162) among those with 1, and 32.7% (18/55) for those with neither (P=0.007 test for trend). While findings persisted after removing cases with PD and dementia with Lewy bodies, and when adjustments were made for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (p=0.013), results were insignificant when correcting for multiple testing.
While consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.
PMCID: PMC3474594  PMID: 22976848
Parkinson’s disease; epidemiology; Lewy body; organochlorines; pesticides
5.  Daytime sleepiness is associated with falls in Parkinson’s disease 
Journal of Parkinson's disease  2013;3(3):387-391.
Falls are frequent in Parkinson’s disease (PD), and may be influenced by daytime sleepiness. We reviewed the records of 120 men with PD. Mean Epworth Sleepiness Scale (ESS) values were significantly different between non-fallers and fallers (6.0 vs. 9.7, p<0.01). In multivariate analysis, ESS remained significantly associated with falls (OR 1.2, 95% CI 1.1–1.4, p=0.02), along with cognitive impairment (OR 4.4 95% CI 1.0–18.7, p=0.04) and postural instability/gait dysfunction (OR 1.6 95% CI 1.0–2.4, p=0.03) in non-depressed patients. In conclusion, non-depressed PD patients are 20% more likely to fall for every one unit increase in the ESS measure of sleepiness.
PMCID: PMC3772981  PMID: 23948992
Parkinson’s disease; falls; sleepiness; depression; cognitive impairment
6.  Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease 
Brain  2011;135(1):170-180.
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
PMCID: PMC3316476  PMID: 22108576
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
7.  Involuntary emotional expression disorder (IEED) in Parkinson’s disease 
Parkinsonism & related disorders  2009;15(7):511-515.
To estimate the frequency and correlates of involuntary emotional expression disorder (IEED) in Parkinson’s disease (PD) using the Center for Neurologic Study-Lability Scale (CNS-LS) and recently-proposed diagnostic criteria for IEED.
IEED is characterized by uncontrollable emotional episodes, typically unrelated to or in excess of the underlying mood, and occurring with minimal or no stimulus. IEED has been reported to occur in many neurological disorders and neurodegenerative diseases, but its prevalence and correlates in PD have not been well studied. Additionally, there is no published research using recently-proposed IEED diagnostic criteria in any population.
193 patients with idiopathic PD were assessed with a neuropsychiatric battery, including the CNS-LS and the 15-item Geriatric Depression Scale (GDS-15). A subset (N =100) was also administered a diagnostic interview by a blinded rater that applied criteria for both IEED and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) depressive disorders.
Applying formal diagnostic criteria, 7.0% of patients were diagnosed with IEED, and an additional 7.0% had subsyndromal IEED symptoms. Applying recommended CNS-LS cutoff scores from other populations, either 42.5% (cutoff ≥13) or 16.6% (cutoff ≥17) screened positive for IEED. Depressive symptoms were associated with higher CNS-LS scores (B[SE] =0.27[.08], P =.001) but not with a diagnosis of IEED (odds ratio =1.1, [95% CI =1.0–1.3], P =.16). The CNS-LS had poor discriminant validity for an IEED diagnosis (AUC =.79, no cutoff value with sensitivity and specificity both >60%).
IEED and depression are overlapping but distinct disorders in PD. IEED symptoms may occur in up to 15% of PD patients, but a disorder occurs in only half of those, suggesting that often IEED symptoms are not clinically significant in this population. The CNS-LS does not appear to be a good screening instrument for IEED in PD, in part due to its high correlation with depressive symptoms.
PMCID: PMC3524499  PMID: 19181560
Involuntary emotional expression disorder; Pseudobulbar affect; Emotional lability; Depression; Parkinson’s disease
8.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
PMCID: PMC3290902  PMID: 22159053
9.  Delayed Parkinson's Disease Diagnosis among African-Americans: The Role of Reporting of Disability 
Neuroepidemiology  2011;36(3):150-154.
Racial differences in the observed prevalence of Parkinson's disease (PD) may be due to delayed diagnosis among African-Americans. We sought to compare the stage at which African-American and white PD patients present for healthcare, and determine whether perception of disability accounts for racial differences.
Using records of veterans with newly diagnosed PD at the Philadelphia Veterans Affairs Medical Center, we calculated differences in reporting of symptoms as the difference in z-scores on the Unified Parkinson Disease Rating Scale part 2 (disability) and part 3 (motor impairment). Ordinal logistic regression was used to determine predictors of stage at diagnosis.
African-American (n = 16) and white (n = 58) veterans with a mean age of 70.1 years were identified. African-Americans presented at a later PD stage than whites (median Hoehn + Yahr stage 2.5 vs. 2.0, p = 0.02) and were more likely to under-report disability relative to motor impairment (81 vs. 40%, p < 0.01). Multivariate analysis showed that under-reporting of disability accounted for much of the effect of race on stage of diagnosis.
Under-reporting of disability among African-Americans may account for later stages of PD diagnosis than whites. This study begins to explain the mechanisms underlying observed racial disparities in PD.
PMCID: PMC3095837  PMID: 21508648
African-American; Delay; Diagnosis; Health services; Parkinsonism; Race
10.  Subcortical TDP-43 pathology occurs infrequently in multiple system atrophy 
Aims and Methods
The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological TDP-43 or FUS aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients.
TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe structures and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions.
The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.
PMCID: PMC3030620  PMID: 20942898
Multiple system atrophy; 43-kDa transactivating responsive sequence DNA-binding protein
11.  Patient versus informant reporting of ICD symptoms in Parkinson’s disease using the QUIP: Validity and variability☆ 
Parkinsonism & related disorders  2010;17(3):153-155.
Questions exist regarding the validity of patient-reporting of psychiatric symptoms in Parkinson’s disease (PD). We assessed observer variability and validity in reporting of impulse control disorder (ICD) symptoms in PD by using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP). PD patients and their informants (71 pairs) completed the QUIP to assess four ICDs (compulsive gambling, buying, sexual behavior, and eating) in patients. Trained raters then administered a diagnostic interview. Sensitivity of the QUIP for a diagnosed ICD was 100% for both patient- and informant-completed instruments, and specificity was 75% for both raters. Approximately 40% of patients without an ICD diagnosis had a positive QUIP, suggesting that many PD patients experience subsyndromal ICD symptoms that require ongoing monitoring. Agreement between patient- and informant-reporting of any ICD behaviors on the QUIP was moderate (kappa = 0.408), and for individual ICDs was highest for gambling (kappa = 0.550). Overall, a negative QUIP from either the patient or informant rules out the possibility of an ICD, while a positive QUIP requires a follow-up diagnostic interview and ongoing monitoring to determine if symptoms currently are, or in the future become, clinically significant.
PMCID: PMC3073062  PMID: 21186135
Impulse control disorders; Parkinson’s disease; QUIP
Lewy body dementia (LBD) is a common cause of dementia but to date, little is known about caregiver burden. The Lewy Body Dementia Association ( conducted a web-based survey of 962 caregivers (mean age 56y; 88% women). The most common initial symptoms were cognitive (48%), motor (39%), or both (13%). Caregivers expressed concerns about fear of future (77%), feeling stressed (54%), loss of social life (52%) and uncertainty about what to do next (50%). Caregivers reported moderate to severe burden; 80% felt the people around them did not understand their burden and 54% reported feelings of isolation with spousal caregivers reporting more burden than non-spousal caregivers. Only 29% hired in-home assistance while less than 40% used respite or adult day care, geriatric case managers or attended a support group meeting. Lack of service utilization occurred despite two-thirds of caregivers reporting medical crises requiring emergency services, psychiatric care or law enforcement. Caregivers reported preferences for web-based information, directories of LBD expert providers, information on LBD research and location of local support groups. These findings highlight significant unmet needs for LBD caregivers and provide targets for intervention to reduce caregiver burden. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers.
PMCID: PMC2879080  PMID: 20505434
Lewy body dementia; caregiver burden; stress
Parkinsonism & related disorders  2010;16(6):388-392.
Lewy body dementia (LBD) is the second most common cause of dementia, however, little is known about how the clinical diagnosis of LBD is obtained in the community or the caregiver experience while seeking the diagnosis.
The Lewy Body Dementia Association ( conducted a web-based survey of 962 caregivers over a 6-month period.
The mean age of respondents was 55.9y; 88% were female and 64% had daily contact with patients. The mean age of LBD patients was 75.4y; 62% were male and 46% lived with a caregiver. The most common presentation of symptoms as reported by LBD caregivers was cognitive (48%), motor (39%) or both (13%). The first diagnoses given to the patients were Parkinson disease or other movement disorder (39%), Alzheimer disease or other cognitive disorder (36%), or mental illness (24%). Fifty percent of patients saw >3 doctors for more than 10 visits over the course of 1 year before an LBD diagnosis was established. Neurologists diagnosed most cases (62%), while primary care-providers diagnosed only 6% of cases. No differences were found between the presentation of disease and the number of physicians, number of office visits, length of time to establish diagnosis, or type of doctor who finally made an LBD diagnosis. Caregivers viewed physicians as knowledgeable about disease manifestations and treatment options, but not about disease course/prognosis and available community resources and referrals.
These data highlight a need for increasing physician awareness and knowledge of LBD, which will facilitate accurate diagnosis and treatment. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers.
PMCID: PMC2916037  PMID: 20434939
Lewy body dementia; caregiver experiences; diagnosis
14.  Use of Latent Variable Modeling to Delineate Psychiatric and Cognitive Profiles in Parkinson’s Disease 
A range of psychiatric symptoms and cognitive deficits occur in Parkinson’s disease (PD), and symptom overlap and co-morbidity complicate the classification of non-motor symptoms. The objective of this study was to use analytic-based approaches to classify psychiatric and cognitive symptoms in PD.
Cross-sectional evaluation of a convenience sample of patients in specialty care.
Two outpatient movement disorders centers at the University of Pennsylvania and Philadelphia Veterans Affairs Medical Center.
177 patients with mild-moderate idiopathic PD and without significant global cognitive impairment.
Subjects were assessed with an extensive psychiatric, neuropsychological, and neurological battery. Latent class analysis (LCA) was used to statistically delineate group-level symptom profiles across measures of psychiatric and cognitive functioning. Predictors of class membership were also examined.
Results from the LCA indicated that a four-class solution best fit the data. 32.3% of the sample had good psychiatric and normal cognitive functioning, 17.5% had significant psychiatric co-morbidity but normal cognition, 26.0% had few psychiatric symptoms but had poorer cognitive functioning across a range of cognitive domains, and 24.3% had both significant psychiatric co-morbidity and poorer cognitive functioning. Age, disease severity, and medication use predicted class membership.
LCA delineates four classes of patients in mild-moderate PD, three of which experience significant non-motor impairments and comprise over two-thirds of patients. Neuropsychiatric symptoms and cognitive deficits follow distinct patterns in PD, and further study is needed to determine if these classes are generalizable, stable, predict function, quality of life and long-term outcomes, and are amenable to treatment at a class level.
PMCID: PMC2848973  PMID: 19855199
Parkinson’s disease; neuropsychology; psychiatry; cognition; depression
15.  Validation of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) 
As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson’s disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD.
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored.
The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling=0.95, sexual behavior=0.97, buying=0.87, eating=0.88, punding=0.78, hobbyism=0.93, walkabout=0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling=0.95, sexual behavior=0.96, buying=0.87, eating=0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96% and 94%, respectively.
Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.
PMCID: PMC2848971  PMID: 19452562
Parkinson’s disease; impulse control disorders; dopamine dysregulation syndrome; punding; pathological gambling
16.  Mild cognitive impairment is common in Parkinson’s disease patients with normal Mini-Mental State Examination (MMSE) scores 
Parkinsonism & related disorders  2008;15(3):226-231.
Cognitive impairment occurs in the majority of Parkinson’s disease (PD) patients, but little is known about detection of mild cognitive impairment (MCI) in this population. We report on the frequency and characteristics of cognitive deficits in PD patients with intact global cognition based on Mini-Mental State Examination (MMSE) performance.
One hundred and six PD patients with normal age- and education-adjusted MMSE scores (mean [SD] score = 29.1 [1.1]) were administered standardized neuropsychological tests assessing memory, executive function, and attention. Impairment on a cognitive domain was a low score (i.e., ≥1.5 SD below the published normative mean) on at least two measures or tests (for memory and executive abilities) or a single measure (for attention).
Mild cognitive impairment was found in 29.2% of PD patients, with 17.9% demonstrating single domain and 11.3% multiple domain impairment. Memory and attention impairment were most common (15.1% and 17.0%, respectively), followed by executive impairment (8.5%). Depending on the measure of disease severity chosen, increasing age and disease severity, anti-anxiety medication use, and a suggestion for increasing severity of daytime sleepiness were independent predictors of cognitive impairment.
Cognitive deficits are common in PD patients with “normal” cognition based on MMSE performance, suggesting that MCI is under-recognized in clinical practice due to routine use of insensitive screening instruments. In contrast with some previous reports, early memory impairment may be as common as either executive or attentional deficits in PD. In addition, psychiatric medication use and daytime sleepiness may be reversible or treatable contributors to cognitive impairment.
PMCID: PMC2668811  PMID: 18595765
Mild cognitive impairment; Parkinson’s disease; Mini-Mental State Examination; Neuropsychology
17.  Bilateral Deep Brain Stimulation vs Best Medical Therapy for Patients With Advanced Parkinson Disease 
Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients.
To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy.
Design, Setting, and Patients
Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (<70 years vs ≥70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage ≥2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006.
Bilateral deep brain stimulation of the subthalamic nucleus (n=60) or globus pallidus (n=61). Patients receiving best medical therapy (n=134) were actively managed by movement disorder neurologists.
Main Outcome Measures
The primary outcome was time spent in the “on” state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events.
Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P<.001). Motor function improved significantly (P<.001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (≥5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P<.001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P<.001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage.
In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.
Trial Registration Identifier: NCT00056563
PMCID: PMC2814800  PMID: 19126811
18.  Montreal Cognitive Assessment Performance in Patients with Parkinson’s Disease with “Normal” Global Cognition According to Mini-Mental State Examination Score 
To examine Montreal Cognitive Assessment (MoCA) performance in patients with Parkinson’s disease (PD) with “normal” global cognition according to Mini-Mental State Examination (MMSE) score.
A cross-sectional comparison of the MoCA and the MMSE.
Two movement disorders centers at the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center.
A convenience sample of 131 patients with idiopathic PD who were screened for cognitive and psychiatric complications.
Subjects were administered the MoCA and MMSE, and only subjects defined as having a normal age- and education-adjusted MMSE score were included in the analyses (N = 100). As previously recommended in patients without PD, a MoCA score less than 26 was used to indicate the presence of at least mild cognitive impairment (MCI).
Mean MMSE and MoCA scores ± standard deviation were 28.8 ± 1.1 and 24.9 ± 3.1, respectively. More than half (52.0%) of subjects with normal MMSE scores had cognitive impairment according to their MoCA score. Impairments were seen in numerous cognitive domains, including memory, visuospatial and executive abilities, attention, and language. Predictors of cognitive impairment on the MoCA using univariate analyses were male sex, older age, lower educational level, and greater disease severity; older age was the only predictor in a multivariate model.
Approximately half of patients with PD with a normal MMSE score have cognitive impairment based on the recommended MoCA cutoff score. These results suggest that MCI is common in PD and that the MoCA is a more sensitive instrument than the MMSE for its detection.
PMCID: PMC2754699  PMID: 19170786
cognitive impairment; Parkinson’s disease; Mini-Mental State Examination; Montreal Cognitive Assessment; neuropsychology
19.  Evaluation of α-synuclein immunohistochemical methods used by invited experts 
Acta neuropathologica  2008;116(3):277-288.
The use of α-synuclein immunohistochemistry has altered our concepts of the cellular pathology, anatomical distribution and prevalence of Lewy body disorders. However, the diversity of methodology between laboratories has led to some inconsistencies in the literature. Adoption of uniformly sensitive methods may resolve some of these differences. Eight different immunohistochemical methods for demonstrating α-synuclein pathology, developed in eight separate expert laboratories, were evaluated for their sensitivity for neuronal elements affected by human Lewy body disorders. Identical test sets of formalin-fixed, paraffin-embedded sections from subjects diagnosed neuropathologically with or without Lewy body disorders were stained with the eight methods and graded by three observers for specific and nonspecific staining. The methods did not differ significantly in terms of Lewy body counts, but varied considerably in their ability to reveal neuropil elements such as fibers and dots. One method was clearly superior for revealing these neuropil elements and the critical factor contributing to its high sensitivity was considered to be its use of proteinase K as an epitope retrieval method. Some methods, however, achieved relatively high sensitivities with optimized formic acid protocols combined with a hydrolytic step. One method was developed that allows high sensitivity with commercially available reagents.
PMCID: PMC2708176  PMID: 18626651
20.  Characterization of antibodies that selectively detect α-synuclein in pathological inclusions 
Acta neuropathologica  2008;116(1):37-46.
Sensitive detection of α-synuclein (α-syn) pathology is important in the diagnosis of disorders like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy and in providing better insights into the etiology of these diseases. Several monoclonal antibodies that selectively react with aggregated α-syn in pathological inclusions and reveal extensive and underappreciated α-syn pathology in the brains of diseased patients were previously reported by Duda et al. (Ann Neurol 52:205-210, 2002). We sought to characterize the specificity of some of these antibodies (Syn 505, Syn 506 and Syn 514); using C-terminal and N-terminal truncations of α-syn, all three antibodies were determined to require N-terminal epitopes that minimally comprise amino acids 2-4, but possibly extend to amino acid 12 of α-syn. The selectivity of these antibodies was further assessed using biochemical analysis of human brains and reactivity to altered recombinant α-syn proteins with duplication variants of amino acids 1-12. In addition, by expressing wild-type or a double mutant (E46K/A53T) of α-syn in cultured cells and by comparing their immunoreactivities to another antibody (SNL-4), which has a similar primary epitope, it was determined that Syn 505, Syn 506 and Syn 514 recognize conformational variants of α-syn that is enhanced by the presence of the double mutations. These studies indicate that antibodies Syn 505, Syn 506 and Syn 514 preferentially recognize N-terminal epitopes in complex conformations, consistent with the dramatic conformational change associated with the polymerization of α-synuclein into amyloid fibrils that form pathological inclusions.
PMCID: PMC2664556  PMID: 18414880
α-Synuclein; Antibodies; Fibrillization; Lewy bodies; Parkinson's disease
21.  Long-Term Follow-Up of Impulse Control Disorders in Parkinson’s Disease 
Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson’s disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = -3.1, P = 0.002) and a higher daily levodopa dosage (Z = -1.9, P = 0.05), but a similar total LEDD dosage (Z = -0.47, P = 0.64) with no changes in Unified Parkinson’s Disease Rating Scale motor score (Z = -1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.
PMCID: PMC2651355  PMID: 17960796
dopamine agonist; gambling; impulse control disorders; Parkinson’s disease
22.  Suicidal and Death Ideation in Parkinson’s Disease 
Parkinson’s disease (PD) is a chronic, disabling illness affecting primarily the elderly and is associated with a high prevalence of depression. Although these are known risk factors for suicidal and death ideation, little is known about the prevalence and correlates of such ideation in PD. A convenience sample of 116 outpatients with idiopathic PD at two movement disorders centers were administered a modified Paykel Scale for suicidal and death ideation, as well as an extensive psychiatric, neuropsychological, and neurological battery. Univariate and multivariate logistic regression models were used to determine the correlates of suicidal or death ideation. Current death ideation (28%) or suicide ideation (11%) were present in 30% of the sample, and 4% had a lifetime suicide attempt. On univariate logistic regression analysis, increasing severity of depression (odds ratio = 2.92, 95% CI 2.01-4.24, P < 0.001), impulse control disorder (ICD) behaviors sometime during PD (odds ratio = 6.08, 95% CI 1.90-19.49, P = 0.002), and psychosis (odds ratio = 2.45, 95% CI 1.05-5.69, P = 0.04) were associated with either ideation. On multivariate logistic regression analysis, only increasing severity of depressive symptoms (odds ratio = 2.76, 95% CI 1.88-4.07, P < 0.001) predicted suicidal or death ideation. In conclusion, active suicidal or death ideation occurs in up to one-third of PD patients. Comorbid psychiatric disorders, more than PD-related disease variables, are associated with this ideation, highlighting the need for a comprehensive approach to the clinical care of PD patients.
PMCID: PMC2635951  PMID: 18618660
Parkinson’s disease; suicide; depression
23.  Dopamine Agonist Use is Associated with Impulse Control Disorders in Parkinson’s Disease 
Archives of neurology  2006;63(7):969-973.
To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson’s disease (PD).
An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients.
Two university-affiliated movement disorders centers.
A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications.
Main Outcome Measures
Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview.
Eighteen (6.6%) PD patients met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptomatology prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001).
PD patients treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. As dopamine agonists are increasing being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations.
PMCID: PMC1761054  PMID: 16831966
24.  Escitalopram for Major Depression in Parkinson’s Disease: An Open-Label, Flexible-Dosage Study 
Depression and antidepressant use are common in Parkinson’s disease, but the benefit of selective serotonin reuptake inhibitor (SSRI) treatment in this population has not been established. The authors treated 14 Parkinson’s disease patients with major depression with escitalopram in an open-label study. Although treatment was well tolerated and correlated with a significant decrease in Inventory of Depressive Symptomatology score, response and remission rates were only 21% and 14%, respectively. However, half of the subjects met Clinical Global Impression-Improvement criteria for response. In Parkinson’s disease, either SSRIs may have limited antidepressant effects, or the use of existing depression diagnostic and rating instruments may be problematic.
PMCID: PMC1761053  PMID: 16963587
25.  Frequency and correlates of co-morbid psychosis and depression in Parkinson’s disease 
Parkinsonism & related disorders  2006;12(7):427-431.
Though both psychosis and depression are common in Parkinson’s disease (PD), it is not clear if an association between the two disorders exists. One hundred and thirty PD patients were divided into four groups based on a comprehensive psychiatric assessment: (1) no depression or psychosis (47.7%); (2) psychosis only (16.2%); (3) depression only (26.2%); and (4) psychosis and depression (10.0%). Co-morbid psychosis and depression did not occur more frequently than expected by chance (P = .77). Psychosis was associated with dopamine agonist use (P = .02), depression with mild-cognitive impairment (P = .03), and their co-occurrence with higher daily levodopa dosages (P<.01). These results suggest that psychosis and depression in PD are distinct neurobehavioral disorders.
PMCID: PMC1992517  PMID: 16797214
Parkinson’s disease; Depression; Psychosis; Co-morbidity

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