Parkinson Disease: Duda JE

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Kranick SM, Duda JE. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Neurosignals. · Pubmed #18097158 No free full text.

Abstract: Prior to the onset of the cardinal motor features of idiopathic Parkinson's disease (PD), other manifestations of neurodegeneration such as olfactory dysfunction are often apparent. Characterizing these potential biomarkers of preclinical PD is particularly important in identifying individuals who will go on to develop disabling symptoms, and thus be good candidates for new neuroprotective strategies. As shown by the Braak neuropathologic staging of PD, the olfactory system is among the first neuronal populations to display Lewy body pathology. Clinically, loss of smell can be easily tested in the office using several validated techniques and is often helpful to the physician in distinguishing idiopathic PD from other forms of parkinsonism. Recent findings have indicated that a decline in olfaction may be observed in selected at-risk patients, which has significant implications for identifying potential study populations. Ongoing studies of olfactory dysfunction may also reveal potential for use as a medication-independent biomarker of disease progression in addition to use as a biomarker for the diagnosis of PD.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Weintraub D, Morales KH, Moberg PJ, Bilker WB, Balderston C, Duda JE, Katz IR, Stern MB. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Mov Disord. · Pubmed #15954137 links to  free full text

Abstract: The objective of this study was to determine effect sizes for both antidepressant treatment and placebo for depression in Parkinson's disease (PD), and to compare the findings with those reported in elderly depressed patients without PD. Recent reviews have concluded that there is little empiric evidence to support the use of antidepressants in PD; however, available data has not been analyzed to determine the effect size for antidepressant treatment in PD depression. A literature review identified antidepressant studies in PD. Suitable studies were analyzed using meta-analytic techniques, and effect sizes were compared with those from antidepressant studies in elderly patients without PD. Large effect sizes were found for both active treatment and placebo in PD, but there was no difference between the two groups. In contrast, active treatment was superior to placebo in depressed elderly patients without PD. In PD, increasing age and a diagnosis of major depression were associated with better treatment response. Results also suggest that newer antidepressants are well tolerated in PD. Despite the high prevalence of depression and antidepressant use in PD, controlled treatment research has been almost nonexistent. Meta-analysis results suggest a large but nonspecific effect for depression treatment in PD. In addition, PD patients may benefit less from antidepressant treatment, particularly selective serotonin reuptake inhibitors, than do elderly patients without PD.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Weintraub D, Taraborelli D, Morales KH, Duda JE, Katz IR, Stern MB. · University of Pennsylvania School of Medicine, Pennsylvania, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #16963587 links to  free full text

Abstract: 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.

Weintraub D, Newberg AB, Cary MS, Siderowf AD, Moberg PJ, Kleiner-Fisman G, Duda JE, Stern MB, Mozley D, Katz IR. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Nucl Med. · Pubmed #15695780 links to  free full text

Abstract: We studied the correlation of striatal dopamine transporter (DAT) imaging with anxiety and depression symptoms in Parkinson's disease (PD). METHODS: Patients with idiopathic PD (n = 76) and age-matched healthy volunteers (n = 46) underwent SPECT brain scans with (99m)Tc-TRODAT-1, a radiolabeled tropane that selectively binds to the DAT. TRODAT-1 distribution volume ratios, a reflection of DAT availability, were calculated from the SPECT scan data for 6 regions of interest (ROIs) in the caudate and putamen. The association between neuropsychiatric symptoms (anxiety, depression, and fatigue) and DAT availability was explored for both subject groups, and the impact of disease severity on this association was examined in the PD group. RESULTS: PD patients showed lower DAT availability than did healthy volunteers in all examined regions (for all ROIs, P < 0.001). In PD patients, higher individual affective measures (for anxiety, r = -0.30 and P = 0.01; and for depression, r = -0.24 and P = 0.05) and total affect scores (r = -0.31; P = 0.01) were associated with diminished left anterior putamen DAT availability. The association between total affect scores and DAT availability was present only in the subset of patients with less severe PD (r = -0.35; P = 0.04), but subjects with the highest DAT availability did not show high total affect scores. No association between neuropsychiatric measures and DAT availability was found in the controls. CONCLUSION: These preliminary findings suggest that decreased DAT availability may be necessary for but not invariably associated with the development of affective symptoms in PD. This suggestion is consistent with previous research showing a link between depression and basal ganglia impairment, particularly involving the left hemisphere, and extends this finding to include anxiety.

Weintraub D, Moberg PJ, Culbertson WC, Duda JE, Stern MB. · Parkinson's Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Cogn Behav Neurol. · Pubmed #15622014 No free full text.

Abstract: OBJECTIVE: The purpose of the study was to determine whether patients with Parkinson disease (PD) demonstrate different memory profiles. Specifically, we sought to ascertain whether the memory performance of PD patients can be categorized as fitting an unimpaired, an impaired retrieval, or an impaired encoding memory profile. BACKGROUND: Cognitive impairment in PD is usually described as subcortical-frontal in nature. However, neuropathophysiological changes consistent with diffuse cortical disease are also reported. Establishing memory subtypes in PD could potentially assist in reducing the observed heterogeneity of disease presentation, establishing prognosis, making clinical decisions, and defining endpoints in clinical trials. METHODS:: A sample of 63 PD patients was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R). Cluster analysis was used to classify patients into three memory subgroups based on performance on free recall, intrusion errors, and recall enhancement with recognition. Subgroup comparisons were made for demographic and clinical characteristics. RESULTS: An "unimpaired" group (n = 30) demonstrated intact free recall and few intrusion errors. "Impaired retrieval" (n = 22) and "impaired encoding" (n = 11) subgroups with similar impairment on free recall were also identified, but the impaired retrieval group demonstrated greater memory improvement with recognition (P < 0.001) and had fewer intrusion errors (P < 0.001) than the impaired encoding group. CONCLUSIONS: A majority of PD patients demonstrate memory impairment, which can be categorized as either a primary retrieval or a primary encoding deficit. Further research is needed to confirm memory subtypes in PD and determine their diagnostic, prognostic, and therapeutic significance.

Nazem S, Siderowf AD, Duda JE, Have TT, Colcher A, Horn SS, Moberg PJ, Wilkinson JR, Hurtig HI, Stern MB, Weintraub D. · Department of Psychiatry, University of Pennsyvania, Philadelphia, USA. · J Am Geriatr Soc. · Pubmed #19170786 No free full text.

Abstract: OBJECTIVES: 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. DESIGN: A cross-sectional comparison of the MoCA and the MMSE. SETTING: Two movement disorders centers at the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: A convenience sample of 131 patients with idiopathic PD who were screened for cognitive and psychiatric complications. MEASUREMENTS: 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). RESULTS: 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. CONCLUSION: 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.

Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD, Anonymous00097. · Hines VA Hospital, Center for Management of Complex Chronic Care, Hines, Illinois 60141, USA. · JAMA. · Pubmed #19126811 links to  free full text

Abstract: CONTEXT: 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. OBJECTIVE: 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 > or = 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 > or = 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. INTERVENTION: 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. RESULTS: 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 (> or = 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. CONCLUSION: 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: clinicaltrials.gov Identifier: NCT00056563.

Nazem S, Siderowf AD, Duda JE, Brown GK, Ten Have T, Stern MB, Weintraub D. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Mov Disord. · Pubmed #18618660 links to  free full text

Abstract: 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.

Mamikonyan E, Moberg PJ, Siderowf A, Duda JE, Have TT, Hurtig HI, Stern MB, Weintraub D. · Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. · Parkinsonism Relat Disord. · Pubmed #18595765 links to  free full text

Abstract: PURPOSE: 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. METHODS: 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., >or=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). RESULTS: 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. CONCLUSIONS: 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.

Mamikonyan E, Siderowf AD, Duda JE, Potenza MN, Horn S, Stern MB, Weintraub D. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Mov Disord. · Pubmed #17960796 links to  free full text

Abstract: 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.

Moberg PJ, Balderston CC, Rick JH, Roalf DR, Weintraub D, Kleiner-Fisman G, Stern MB, Duda JE. · Parkinson's Disease Research, Education, and Clinical Center, Philadelphia Veterans Affairs Medical Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Cogn Behav Neurol. · Pubmed #17846512 No free full text.

Abstract: OBJECTIVE: To examine phenylthiocarbamide (PTC) sensitivity in Parkinson disease (PD) patients and healthy volunteers to determine whether taster status represented a simple vulnerability marker for PD. BACKGROUND: The inability to taste PTC has been associated with a number of medical illnesses not typically associated with taste impairment. Abnormalities in the function/expression of G protein-signaling pathways have been implicated in PTC perception and also in dopamine expression and regulation in PD. No study has yet probed whether PTC tasting is disrupted in PD. METHOD: PTC sensitivity was assessed in a small sample of 36 male PD patients and 20 healthy male comparison subjects using a standardized psychophysical method. RESULTS: A higher proportion of nontasters were found in patients relative to healthy comparison subjects. These differences were not explained by alterations in perception of basic taste intensity or age. Among patients, nontasters and tasters of PTC did not differ with regard to duration of illness, age of onset, severity of motor symptoms, or overall illness severity. CONCLUSIONS: These data suggest an increase in the frequency of PTC nontaster status in PD. As phenotypic variation in PTC sensitivity is genetic in origin, this may represent a surrogate risk factor for the development of PD.

Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP/Maloney 3rd Floor, Philadelphia, PA 19104-4283, USA. · Acta Neuropathol. · Pubmed #17653732 No free full text.

Abstract: Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE, Moberg PJ, Stern MB. · Department of Psychiatry, University of Pennsylvania, and Parkinson's Disease Research, Education, and Clinical Center, USA. · Arch Neurol. · Pubmed #16831966 links to  free full text

Abstract: OBJECTIVE: To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson disease (PD). DESIGN: An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients. SETTING: Two university-affiliated movement disorders centers. PARTICIPANTS: 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. RESULTS: Eighteen patients (6.6%) with PD 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 symptoms 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). CONCLUSIONS: Patients with PD treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. Because dopamine agonists are increasingly being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations.

Weintraub D, Morales KH, Duda JE, Moberg PJ, Stern MB. · Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. · Parkinsonism Relat Disord. · Pubmed #16797214 links to  free full text

Abstract: 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.

Weintraub D, Moberg PJ, Culbertson WC, Duda JE, Katz IR, Stern MB. · Parkinson's Disease Research, Education and Clinical Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. · Dement Geriatr Cogn Disord. · Pubmed #16020942 No free full text.

Abstract: BACKGROUND: Executive impairment is common in Parkinson's disease (PD). However, it is unknown which dimensions of executive function are assessed by commonly used neuropsychological instruments and if clinical correlates of specific dimensions exist. METHOD: A convenience sample of 46 PD patients was evaluated with three executive function tests: the Tower of London-Drexel, the Trail-Making Test and the Stroop Color-Word Test. Factor analysis was used to probe for dimensions of executive control, and linear regression models were used to explore the association between the generated factors and other clinical features. RESULTS: Factor analysis revealed two executive factors, one related to planning (eigenvalue=4.2) and the other to inhibitory control (eigenvalue=1.8), together accounting for 75% of the variance in scores. In linear regression models, poorer planning was associated with increasing severity of apathy (t=2.11, p=0.041), and diminished inhibitory control was associated with increasing severity of parkinsonism (t=2.78, p=0.008) and lower educational level (t=-2.23, p=0.032). Conclusions: Planning deficits and diminished inhibitory control are two dimensions of executive impairment in PD, the former associated with decreased motivation and the latter with increased motor slowing. Similar performance on both executive and non-executive components of these instruments suggests that results of executive testing in PD may be confounded by non-executive deficits.

Siderowf A, Newberg A, Chou KL, Lloyd M, Colcher A, Hurtig HI, Stern MB, Doty RL, Mozley PD, Wintering N, Duda JE, Weintraub D, Moberg PJ. · Parkinson Disease and Movement Disorders Center, Department of Neurology, University of Pennsylvania, Philadelphia, USA. · Neurology. · Pubmed #15911797 No free full text.

Abstract: BACKGROUND: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD). OBJECTIVE: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD. METHODS: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated. RESULTS: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant. CONCLUSIONS: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.

Liang TW, Forman MS, Duda JE, McCluskey L, Trojanowski JQ, Siderowf A. · Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15654043 links to  free full text

Abstract: A woman presenting with levodopa responsive Parkinsonism developed rapidly progressive bulbar signs, quadriparesis, and upper and lower motor neurone signs. At necropsy, she was found to have three pathological diagnoses: amyotrophic lateral sclerosis, Parkinson's disease, and abundant tau-positive argyrophilic neuritic pathology, known as argyrophilic grain disease. This case raises the possibility that three distinct neuropathological diagnoses share a common aetiology.

Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. · Parkinson's Disease Research, Education and Clinical Center, Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA. · J Am Geriatr Soc. · Pubmed #15086662 No free full text.

Abstract: OBJECTIVES: To examine the effect of depression and other nonmotor symptoms on functional ability in Parkinson's disease (PD). DESIGN: A cross-sectional study of a convenience sample of PD patients receiving specialty care. SETTING: The Parkinson's Disease Research, Education and Clinical Center at the Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: One hundred fourteen community-dwelling patients with idiopathic PD. MEASUREMENTS: The Unified Parkinson's Disease Rating Scale (UPDRS); Hoehn and Yahr Stage; Mini-Mental State Examination; Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, depression module; probes for psychotic symptoms; Hamilton Depression Rating Scale; Geriatric Depression Scale-Short Form; Apathy Scale; and Epworth Sleepiness Scale. Disability was rated using the UPDRS activity of daily living (ADL) score and the Schwab and England ADL score. Multivariate analysis determined effect of depression and other nonmotor symptoms on disability. RESULTS: The presence of psychosis, depressive disorder, increasing depression severity, age, duration of PD, cognitive impairment, apathy, sleepiness, motor impairment, and percentage of time with dyskinesias were related to greater disability in bivariate analyses. Entering these factors into two multiple regression analyses, only the increasing severity of depression and worsening cognition were associated with greater disability using the UPDRS ADL score, accounting for 37% of the variance in disability (P<.001). These two factors plus increasing severity of PD accounted for 54% of the variance in disability using the Schwab and England ADL score (P<.001). CONCLUSION: Results support and extend previous findings that psychiatric and other nonmotor symptoms contribute significantly to disability in PD. Screening for nonmotor symptoms in PD is necessary to more fully explain functional limitations. Further study is required to determine whether identifying and treating these symptoms will improve function and quality of life.

Culbertson WC, Moberg PJ, Duda JE, Stern MB, Weintraub D. · Drexel University, Neuropsychology Program, Philadelphia, PA 19104, USA. · Assessment. · Pubmed #14994951 No free full text.

Abstract: The aim of the study was to investigate the utility of the Tower of London-Drexel (TOLDX) in assessing the executive deficits associated with Parkinson's disease (PD). We sought to determine whether the TOLDX would differentiate between (a) patients with PD and healthy control participants (HCP), (b) demented and nondemented patients, and (c) depressed and nondepressed patients. A new TOLDX score, stimulus bound, was introduced to assess utilization behaviors. Furthermore, the convergent and divergent validity of the TOLDX was examined. The TOLDX total move, rule and time violation, and stimulus-bound scores of patients with PD significantly differed from the HCP. Demented and nondemented patients also differed significantly in their TOLDX performance, with the stimulus-bound score being the most significantly differentiating score. However, the depressed and nondepressed patients did not differ in their TOLDX performance. Support was found for the convergent and divergent validity of the TOLDX. The clinical and theoretical implications of the findings are discussed.

Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. · Parkinson's Disease Research, Education and Clinical Center, Philadelphia Veterans Affairs Medical Center, USA. · J Geriatr Psychiatry Neurol. · Pubmed #12967062 No free full text.

Abstract: Depression in Parkinson's disease (PD) is common, but little is known about its recognition and treatment. The authors report the antidepressant experience (N = 100) and outcome of depression assessment (n = 77) of a convenience sample of patients at a PD center. Subjects were assessed with a psychiatric and neurological battery, and information was gathered on depression treatment. One third (34%) of subjects met criteria for a depressive disorder, and two thirds (65%) of them were not currently receiving antidepressant treatment. Approximately one quarter (23%) of subjects were taking an antidepressant, but almost half (47%) of them still met criteria for a depressive disorder. Few antidepressant users with persistent depression had received either antidepressant treatment at dosages within the highest recommended range (11%) or more than 1 antidepressant trial (33%). Most depressed patients are untreated, and half of antidepressant users remain depressed, suggesting that even when delivered, treatment is often inadequate or ineffective.

Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ. · Parkinson's Disease Research, Education and Clinical Center, Philadelphia Veterans Affairs Medical Center, Pennsylvania, USA. · Acta Neuropathol. · Pubmed #12070658 No free full text.

Abstract: Previous genetic analysis of the familial Parkinson's disease Contursi kindred led to the identification of an Ala53Thr pathogenic mutation in the alpha-synuclein gene. We have re-examined one of the original brains from this kindred using new immunohistochemical reagents, thioflavin S staining and immunoelectron microscopy. Surprisingly, we uncovered a dense burden of alpha-synuclein neuritic pathology and rare Lewy bodies. Immunoelectron microscopy demonstrated fibrillar alpha-synuclein-immunoreactive aggregates. Unexpected tau neuritic and less frequent perikaryal inclusions were also observed. Some inclusions were comprised of both proteins with almost complete spatial disparity. We suggest that it is important to recognize that the neurodegenerative process caused by the Ala53Thr mutation in alpha-synuclein is not identical to that seen in typical idiopathic Parkinson's disease brains.

Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Science. · Pubmed #11062131 links to  free full text

Abstract: Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.