Howard I Hurtig

William Penn University, Filadelfia, Pennsylvania, United States

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Publications (161)963.83 Total impact

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    ABSTRACT: Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Results: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). Conclusions: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.
    Neurology 09/2015; 85(15). DOI:10.1212/WNL.0000000000002001 · 8.29 Impact Factor
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    ABSTRACT: The aim of this work was to describe the development and psychometric analysis of the Penn Parkinson's Daily Activities Questionnaire. The questionnaire is an item response theory-based tool for rating cognitive instrumental activities of daily living in PD. Candidate items for the Penn Parkinson's Daily Activities Questionnaire were developed through literature review and focus groups of patients and knowledgeable informants. Item selection and calibration of item-response theory parameters were performed using responses from a cohort of PD patients and knowledgeable informants (n = 388). In independent cohorts of PD patients and knowledgeable informants, assessments of test-retest reliability (n = 50), and construct validity (n = 68) of the questionnaire were subsequently performed. Construct validity was assessed by correlating questionnaire scores with measures of motor function, cognition, an existing activities of daily living measure, and directly observed daily function. Fifty items were retained in the final questionnaire item bank. Items were excluded owing to redundancy, difficult reading level, and when item-response theory parameters could not be calculated. Test-retest reliability was high (intraclass correlation coefficient = 0.97; P < 0.001). The questionnaire correlated strongly with cognition (r = 0.68; P < 0.001) and directly observed daily function (r = 0.87; P < 0.001), but not with motor impairment (r = 0.08; P = 0.53). The questionnaire score accurately discriminated between PD patients with and without dementia (receiver operating characteristic curve = 0.91; 95% confidence interval: 0.85-0.97). The Penn Parkinson's Daily Activities Questionnaire shows strong evidence of reliability and validity. Item response theory-based psychometric analysis suggests that this questionnaire can discriminate across a range of daily functions. © 2015 International Parkinson and Movement Disorder Society. © 2015 Movement Disorder Society.
    Movement Disorders 08/2015; DOI:10.1002/mds.26339 · 5.68 Impact Factor
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    ABSTRACT: Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
    Nature Communications 06/2015; 6. DOI:10.1038/ncomms8247 · 11.47 Impact Factor
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    ABSTRACT: Apathy is a common, troublesome symptom in Parkinson's disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson's Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. Of 132 PD patients 12.1% (N = 16) scored in the apathetic range at baseline. A total of 19.6% (N = 26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR = 3.56; 95% CI = 1.09-11.62; p = 0.04). A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 06/2015; 21(8). DOI:10.1016/j.parkreldis.2015.06.009 · 3.97 Impact Factor
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    ABSTRACT: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD. © 2015 American Academy of Neurology.
    Neurology 02/2015; 84(10). DOI:10.1212/WNL.0000000000001332 · 8.29 Impact Factor
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    ABSTRACT: Since brain stem regions associated with early Parkinson's disease (PD) pathology encroach upon those involved in taste function, the ability to taste may be compromised in PD. However, studies on this point have been contradictory. We administered well-validated whole-mouth and regional taste tests that incorporated multiple concentrations of sucrose, citric acid, caffeine, and sodium chloride to 29 early stage PD patients and 29 age-, sex-, and race-matched controls. Electrogustometry was also performed on the anterior tongue. The PD cohort was tested both on and off dopamine-related medications in counterbalanced test sessions. While whole-mouth taste identification test scores for all stimuli were, on average, nominally lower for the PD patients than for the controls, a trend in the opposite direction was noted for the intensity ratings at the lower stimulus concentrations for all stimuli except caffeine. Moreover, regional testing found that PD subjects tended to rate the stimuli, relative to the controls, as more intense on the anterior tongue and less intense on the posterior tongue. No significant associations were evident between taste test scores and UPDRS scores, L-DOPA medication equivalency values, or [(99m)Tc]TRODAT-1 SPECT imaging of dopamine transporter uptake within the striatum and associated regions. Our findings suggest that suprathreshold measures of taste function are influenced by PD and that this disease differentially influences taste function on anterior (CN VII) and posterior (CN IX) tongue regions. Conceivably PD-related damage to CN IX releases central inhibition on CN VII at the level of the brainstem, resulting in enhanced taste intensity on the anterior tongue.
    Journal of Neurology 12/2014; 262(3). DOI:10.1007/s00415-014-7589-z · 3.38 Impact Factor
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    ABSTRACT: Importance Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD.Observations We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs.Conclusions and Relevance To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.
    JAMA Neurology 11/2014; 72(1). DOI:10.1001/jamaneurol.2014.2704 · 7.42 Impact Factor
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    ABSTRACT: Cognitive impairment is one of the earliest, most common, and most disabling non-motor symptoms in Parkinson's disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale-2 (DRS-2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS-2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS-2 using equipercentile equating and log-linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 11/2014; 29(14). DOI:10.1002/mds.26062 · 5.68 Impact Factor
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    ABSTRACT: A number of sensory changes occur in the earliest stages of Parkinson's disease (PD), some of which precede the expression of the classic motor phenotype by years (e.g., olfactory dysfunction). Whether point pressure sensitivity (PPS), a cutaneous measure of light touch mediated by myelinated Aβ fibers, is altered in early PD is not clear. Prior studies on this point are contradictory and are based on non-forced-choice threshold tests that confound the sensitivity measure with the response criterion. While α-synuclein pathology, a defining feature of PD, is present in the skin of PD patients, it is restricted to unmyelinated nerve fibers, suggesting PPS may be spared in this disease. We determined PPS thresholds using a state-of-the-art forced-choice staircase threshold test paradigm in 29 early stage PD patients and 29 mathced controls at 11 body sites: the center of the forehead and the left and right forearms, the index fingers, the palms, the medial soles of the feet, and the plantar halluces. The patients were tested, in counterbalanced sessions, both on and off dopamine-related medications (DRMs). PPS was not influenced by PD and did not correlate with DRM l-DOPA equivalents, scores on the Unified Parkinson's Disease Rating Scale, side of the major motor disturbances, or SPECT imaging of the striatal dopamine transporter, as measured by technetium-99 m TRODAT. However, PPS thresholds were lower on the left than on the right side of the body (p = 0.008) and on the upper extremities relative to the toes and feet (ps < 0.0001). Positive correlations were evident among the thresholds obtained across all body sectors, even though disparate regions of the body differed in terms of absolute sensitivity. This study indicates that PPS is not influenced in early stage PD regardless of whether patients are on or off DRMs.
    Physiology & Behavior 10/2014; 138. DOI:10.1016/j.physbeh.2014.09.015 · 2.98 Impact Factor
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    ABSTRACT: The discovery of novel plasma-based biomarkers could lead to new approaches in the treatment of Parkinson's disease (PD). Here, we explore the role of plasma apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels. Plasma ApoA1 and the single-nucleotide polymorphism, rs670, were assayed in a discovery cohort (cohort 1) of 301 PD patients, 80 normal controls (NCs), and 165 subjects with other neurodegenerative diseases, as well as a cohort (cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1,494 PD and 925 NC subjects from both clinical sites. Compared to both normal and disease controls, PD patients have lower plasma ApoA1 (P < 0.001 for both comparisons). Moreover, in PD patients, plasma ApoA1 levels are correlated with genotype at the APOA1 promoter polymorphism, rs670. Specifically, lower plasma ApoA1 levels were found in rs670 major allele (G) homozygotes in both cohort 1 (P = 0.009) and in a replication cohort (cohort 2; n = 158 PD patients; P = 0.024). Finally, evaluating rs670 genotype frequencies in 1,930 PD cases versus 997 NCs, the rs670 GG genotype shows a trend toward association (odds ratio: 1.1; P = 0.10) with PD. Our results are compatible with a model whereby circulating ApoA1 levels may be useful in risk-stratifying subjects for the development of PD, with higher ApoA1 levels suggesting relative protection. Future studies evaluating modulation of ApoA1 as a novel therapeutic strategy in PD are warranted. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 09/2014; 30(6). DOI:10.1002/mds.26022 · 5.68 Impact Factor
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    ABSTRACT: Importance Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.Objective To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.Design, Setting, and Participants We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test–Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.Main Outcomes and Measures Nine variables derived from 7 psychometric tests.Results The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10−6; corrected P [Pc] = 6.0 × 10−5), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10−5; Pc = 9 × 10−5); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.Conclusions and Relevance Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.
    JAMA Neurology 09/2014; 71(11). DOI:10.1001/jamaneurol.2014.1455 · 7.42 Impact Factor
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    ABSTRACT: Background Whether Parkinson's disease (PD) influences suprathreshold changes in perceived odor intensity is unknown. In patients with Alzheimer's disease, patients with schizophrenia, and the elderly, such perception is reportedly normal. If generally true, this could reflect a core element of the olfactory system insulated to some degree from age- and disease-related pathological conditions.Methods Odor intensity ratings for pentyl acetate were obtained from 29 early-stage PD patients when on and off dopamine-related medications (DRMs) and from 29 matched controls.ResultsThe ratings were significantly attenuated at the higher odorant concentrations, with the degree of attenuation associated with overall olfactory dysfunction. Ratings were higher on the right than on the left side of the nose of both patients and controls. No associations with DRMs, Unified Parkinson's Disease Rating Scale (UPDRS) scores, or striatal dopamine transporter imaging were found.Conclusions Parkinson's disease (PD) influences suprathreshold estimates of perceived odor intensity, negating the notion that such perception might be spared in this disease. No association with dopaminergic processes was apparent. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 08/2014; 29(9). DOI:10.1002/mds.25946 · 5.68 Impact Factor
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    ABSTRACT: Impulse control disorders (ICDs) in Parkinson disease (PD) are common and can be difficult to manage. The objective of this study was to determine the efficacy and tolerability of naltrexone, an opioid antagonist, for the treatment of ICDs in PD.METHODS: Patients with PD (n = 50) and an ICD were enrolled in an 8-week, randomized (1:1), double-blind, placebo-controlled study of naltrexone 50-100 mg/d (flexible dosing). The primary outcome measure was response based on the Clinical Global Impression-Change score, and the secondary outcome measure was change in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) ICD score.RESULTS: Forty-five patients (90%) completed the study. The Clinical Global Impression-Change response rate difference favoring naltrexone in completers was 19.8% (95% confidence interval [CI] -8.7% to 44.2%). While this difference was not significant (odds ratio = 1.6, 95% CI 0.5-5.2, Wald χ(2) [df] = 0.5 [1], p = 0.5), naltrexone treatment led to a significantly greater decrease in QUIP-RS ICD score over time compared with placebo (regression coefficient for interaction term in linear mixed-effects model = -7.37, F[df] = 4.3 [1, 49], p = 0.04). The estimated changes in QUIP-RS ICD scores from baseline to week 8 were 14.9 points (95% CI 9.9-19.9) for naltrexone and 7.5 points (95% CI 2.5-12.6) for placebo.CONCLUSIONS: Naltrexone treatment was not efficacious for the treatment of ICDs in PD using a global assessment of response, but findings using a PD-specific ICD rating scale support further evaluation of opioid antagonists for the treatment of ICD symptoms in PD.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with PD and an ICD, naltrexone does not significantly increase the probability of achieving response. However, the study lacked the precision to exclude an important difference in response rates.
    Neurology 07/2014; 83(9). DOI:10.1212/WNL.0000000000000729 · 8.29 Impact Factor
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    ABSTRACT: Dementia in Parkinson's disease (PD) is a serious health issue and a major concern for many patients. In most cases mild cognitive impairment (MCI) is considered a transitional stage between normal cognitive functioning and dementia which is of potential importance in the early identification of patients at risk for dementia. Recently, the Movement Disorder Society (MDS) proposed diagnostic criteria for MCI in PD (PD-MCI). These criteria comprise two operationalizations: Level I (based on an abbreviated assessment) and Level II (based on comprehensive neuropsychological evaluation permitting MCI subtyping). These criteria need to be validated. This paper describes a project aiming to validate the MDS PD-MCI criteria by pooling and analyzing cross-sectional and longitudinal neuropsychological databases comprising ≥5,500 PD patients and ≥1,700 controls. After applying the MDS PD-MCI Level I and Level II criteria, rates of conversion to PD-dementia and predictive variables for conversion to PD-dementia will be established. This study will also assist in identifying whether revisions of the PD-MCI criteria are required.
    12/2013; DOI:10.3233/JPD-130304
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    ABSTRACT: Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2013; 10(4). DOI:10.1016/j.jalz.2013.06.003 · 12.41 Impact Factor
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    ABSTRACT: Objective To identify plasma-based biomarkers for Parkinson disease (PD) risk. Methods In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n=134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging was performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. ResultsOne of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1; p=0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards, p<0.001, hazard ratio=0.742). The association between plasma ApoA1 levels and age at PD onset was replicated in an independent cohort of PD patients (p<0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p=0.037). InterpretationLower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk. ANN NEUROL 2013;74:119-127
    Annals of Neurology 07/2013; 74(1). DOI:10.1002/ana.23872 · 9.98 Impact Factor
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    ABSTRACT: Background Rapid eye movement (REM) sleep behavior disorder (RBD) is present in around 40% of Parkinson's disease (PD) patients. Definitive diagnosis requires a polysomnogram, but that is costly, time intensive, and not practical for large-scale studies. Therefore, we assessed using a questionnaire-based diagnostic approach.Methods The patient-administered RBD questionnaire and bed-partner-administered question 1 of the Mayo questionnaire were prospectively validated.ResultsSeventy-five PD patients (51 male, 68 Hoehn and Yahr stages I and II) participated. Forty-eight had a clinical history of RBD. Sensitivity was 100% (95% CI, 86.3%-100%) when a combination of both questionnaires was compared with the gold standard of polysomnogram-confirmed RBD. Among those who achieved REM sleep (n = 65), specificity was highest for the patient questionnaire used alone, at 82.4% (95% CI, 64.8%-92.6%).ConclusionsA combination of patient and bed-partner questionnaires is a useful tool to detect RBD. © 2013 Movement Disorder Society
    Movement Disorders 07/2013; 28(8). DOI:10.1002/mds.25438 · 5.68 Impact Factor
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    ABSTRACT: Background: Poor nocturnal sleep is common in Parkinson's disease (PD) and negatively impacts quality of life. There is little data on how dopaminergic drugs influence nocturnal sleep in PD, particularly in relation to medication timing. We examined the association between dopaminergic medications and subjective and objective nocturnal sleep in PD. Methods: Individuals with PD were recruited from the outpatient clinic. Demographics and disease information were collected. Patients underwent one-night polysomnography and responded to SCOPA-SLEEP, a self-administered questionnaire which includes a section on nighttime sleep and an overall measure of sleep quality; higher scores indicate worse sleep. Medication intake, including medication timing in relation to bedtime, was obtained and converted to levodopa equivalents. Results: 41 Males and 21 females, median age 63.9 years, participated. Median disease duration was 5 years. After adjusting for age, sex, disease severity, and disease duration, greater total levodopa equivalent intake within 4 h of sleep was associated with higher total SCOPA-nighttime score (p = 0.009) and greater wake time after sleep onset (p = 0.049). Greater dopaminergic medication intake prior to sleep was also associated with less rapid eye movement (REM) sleep as a percent of total sleep time (p = 0.004). Conclusions: Higher amounts of dopaminergic medications taken prior to sleep were associated with poor sleep quality and less REM sleep. Although poor nocturnal sleep in PD is likely multi-factorial in etiology, our findings suggest that timing and dose of medications prior to sleep need to be considered in its management.
    Parkinsonism & Related Disorders 06/2013; 19(10). DOI:10.1016/j.parkreldis.2013.05.009 · 3.97 Impact Factor
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    ABSTRACT: IMPORTANCE Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD). OBJECTIVE To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression. DESIGN AND SETTING Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups. PARTICIPANTS The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA -associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing. MAIN OUTCOME MEASURES Biochemical profiling was available for all 20 GBA -associated PD cases, as well as a subset (87 of 242) of the GBA -negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations. RESULTS Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) and were more likely to demonstrate cognitive dysfunction (P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 (P = .001), monocyte chemotactic protein 1 (P = .008), and macrophage inflammatory protein 1α (P = .005). The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separate cohort of patients having PD with vs without GBA mutations. CONCLUSIONS AND RELEVANCE Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.
    05/2013; 70(7):1-7. DOI:10.1001/jamaneurol.2013.1274
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    ABSTRACT: IMPORTANCE While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING Eleven centers from sites around the world performing genotyping. PARTICIPANTS Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
    04/2013; 70(6):1-9. DOI:10.1001/jamaneurol.2013.1925

Publication Stats

10k Citations
963.83 Total Impact Points


  • 1986-2015
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1984-2015
    • University of Pennsylvania
      • • Department of Neurology
      • • Department of Psychiatry
      Filadelfia, Pennsylvania, United States
  • 2004-2012
    • Parkinson's and Movement Disorders Center Of Maryland
      Maryland, United States
  • 2011
    • Pennsylvania Department of Health
      Harrisburg, Pennsylvania, United States
  • 1989-2011
    • Hospital of the University of Pennsylvania
      • • Department of Neurology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Radiology
      Philadelphia, Pennsylvania, United States
  • 2010
    • Pennsylvania Medical Society
      Filadelfia, Pennsylvania, United States
  • 2009
    • University of Louisville
      • Department of Neurology
      Louisville, Kentucky, United States
  • 2002
    • Northwestern University
      • Parkinson's Disease and Movement Disorders Center
      Evanston, Illinois, United States
  • 1999
    • Beth Israel Medical Center
      New York City, New York, United States
  • 1995
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada