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The purpose of this paper is to describe neuropsychological outcomes in people with Parkinson’s disease (PD) following their participation in an NIH-sponsored, randomized-controlled trial of cognitive-behavioral treatment for depression. Improvements in mood were associated with modest gains in verbal memory and executive functioning, over the 10-week treatment period, and accounted for greater variance in neuropsychological outcomes at the end-of-treatment, than other known correlates of cognitive functioning in PD, such as disease severity, age, and education. Baseline working memory and executive skills were also associated with depression improvement over time.

Objective Parkinson's disease (PD) is frequently complicated by depression and there is a paucity of controlled research that can inform the management of this disabling nonmotor complaint. A randomized controlled trial of nortriptyline, paroxetine, and placebo for the treatment of depression in PD (dPD) was recently completed. The purpose of this article is to describe the baseline pattern of depressive symptom presentation in PD, the specific symptoms of dPD that improve with pharmacotherapy, and the residual symptoms that remain in patients who meet a priori criteria for response or remission after acute treatment (8 weeks). Setting The Departments of Psychiatry and Neurology at Robert Wood Johnson Medical School, New Jersey. Participants Fifty-two depressed patients (major depression or dysthymia based on Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria ) with Parkinson's disease ( by research criteria ). Design/Intervention A randomized controlled trial of nortriptyline, paroxetine, and placebo. Measurement The four subscales (core mood, anxiety, insomnia, and somatic) and individual items from the Hamilton Rating Scale for Depression-17 were the focus of this study. These measures were assessed at baseline and Week 8. Results Baseline depressive symptoms were unrelated to motor functioning. Treatment response was associated with significant improvements in the core mood, anxiety, insomnia, and somatic symptoms seen in dPD. Residual symptoms, such as sadness and loss of interest, persisted in treatment responders in a milder form than was initially present. Conclusions Antidepressants may influence all symptoms of dPD, including those that share great overlap with the physical disease process. Additional research regarding adjunctive interventions is needed to help optimize the management of dPD. (Am J Geriatr Psychiatry 2011; 19:222–229)

Background Parkinson's disease (PD) affects patients' lives with more than just physical impairment. Many of the non-motor aspects of PD, such as cognitive impairment, depression, and sleep disturbances, are common and are associated with a variety of poor outcomes. However, at present, the pathophysiology and clinical management of these symptoms are poorly understood. Objective The authors sought to determine the associations between various illness-associated cytokines, cortisol, and the non-motor symptoms of PD. Method The authors examined a panel of cytokines (IL-1 β , IL-6, IL-10, TNF- α ) and cortisol in a cohort of 52 PD patients with depression. Results There were a number of significant correlations between the non-motor symptoms and TNF- α . Specifically, the authors found that TNF- α (but not IL-1 β , IL-6, IL-10, or cortisol) was significantly correlated with measures of cognition, depression, and disability. In regression analyses accounting for all variables, TNF- α was consistently significant in explaining variance in cognition, depression, sleep, and disability. Conclusion These data are consistent with a growing body of literature that implicates inflammatory cytokines in neural and behavioral processes and further suggests that TNF- α may be involved in the production and/or maintenance of non-motor symptoms in PD.

Parkinson's disease (PD) is a common neurodegenerative disease affecting up to one million individuals in the United States. Depression is found in 40 to 50% of these patients and is associated with a variety of poor outcomes for both patients and their families. Despite this, there are few evidence-based data to guide clinical care. This was an NIH-funded, randomized, controlled trial of paroxetine, nortriptyline, and placebo. It included an 8 week acute phase and a 16 week blind extension phase. This report details the impact of depression treatment on quality of life (QoL) and disability in the acute and extension phase of this study. Secondary outcomes included relapse, tolerability, safety, and the impact of depression treatment on PD physical functioning. Patients who had improvement in depression, compared with those who did not, had significant gains in measures of QoL and disability (PDQ-8, P = 0.0001; SF-36, P = 0.0001) at 8 weeks and maintained their gains in the extension phase. Patients who were on active drug were significantly less likely to relapse in the extension phase than those on placebo (P = 0.041). Though relatively modest in size, this trial provides the first controlled data on the impact of treatment of depression on QoL and disability in PD. It suggests that successfully treating depression in PD leads to important, sustained improvements in these outcomes and that patients who improve on antidepressants are less likely to relapse than are patients who initially improve on placebo.

Background: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care. Methods: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks. Results: Nortriptyline was superior to placebo for the change in HAM-D ( p p p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR ( p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated. Conclusions: Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors. ARR = absolute risk reduction; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAM-A = Hamilton Anxiety Scale; HAM-D = Hamilton Depression Rating Scale; MMSE = Mini-Mental State Examination; NNT = number needed to treat; PD = Parkinson disease; PDQ = Parkinson’s Disease Questionnaire; PSQI = Pittsburgh Sleep Quality Index; SCID = Structured Clinical Interview; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; UPDRS = Unified Parkinson’s Disease Rating Scale.

Patients with psychogenic parkinsonism (PP), like those with Parkinson's disease (PD), may have tremor, bradykinesia, rigidity, and gait disturbances. Unusual features predominate in PP, but clear psychogenic signs may not be obvious. Because PP may be difficult to diagnose, identifying a wider spectrum of disease manifestations that point toward psychogenic rather than organic parkinsonism could be useful for clinicians.We retrospectively reviewed the charts and clinical data for all patients referred for parkinsonism to a single physician at our movement disorders clinic from 1980 to 2012.Patients with PP represented 1.5% of all patients referred for parkinsonism. Among 36 patients with PP, the most common complaints were tremor (31), gait disturbance (18), fatigue (12), and diminished balance (10). Neurologic examination revealed 12 patients with unusual (functional) postures, 5 with a normal exam, and none with micrographia, hypophonia, or hypomimia. Seven of 36 patients improved, 6 of these with antidepressant therapy.PP is not rare in a movement disorders practice. Leg tremor is more likely in PP than in PD, whereas falls are rare. Unusual (nonphysiologic) postures may be present. The outcome generally is not favorable, although antidepressants are beneficial in some patients with disease duration of2 years. The presence of micrographia, hypophonia, or hypomimia strongly suggests an organic cause of parkinsonism rather than PP.

Background: Polymorphisms in the glutathione S-transferase pi gene ( GSTP1 ), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the Gene PD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. Methods: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. Results: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. Conclusions: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

We report four patients with Parkinson's disease who had an unusual pattern of severe chorea and dystonia in the evenings only. The temporal pattern of abnormal movements and simultaneous monitoring of plasma levodopa and clinical state were consistent with dyskinesias associated with subtherapeutic (low dopa dyskinesias) rather than peak concentrations of levodopa (high dopa dyskinesias). In two patients, addition of a direct-acting dopamine receptor agonist was helpful in ameliorating this complication of antiparkinson therapy.

Depression in Parkinson's disease (PD) is associated with faster progression of physical symptoms, greater decline in cognitive skills, and greater decline in the ability to care for oneself. The depression in these patients is also frequently comorbid with anxiety. There are no trials that provide data on the impact of depression treatment on anxiety, disability, and cognition in these patients. In this prospective, 8-week, open label trial, 10 patients with PD and major depression, without dementia, were given flexible doses of citalopram. Depression improved significantly and was associated with significant improvements in anxiety symptoms and functional impairment. The drug was well tolerated. This is the first study that provides data suggesting that treating depression in patients with PD may lead to improvements in anxiety and functional capacity. As with all nonrandomized, open-label trials at tertiary research centers, many nonspecific factors may have influenced the results.

Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders. We report here the immunohistochemical, biochemical and ultrastructural characterization of alpha-syn neuropathology in a case of familial PD with the A53T alpha-syn gene mutation. Insoluble filamentous alpha-syn lesions were detected in almost all brain regions examined and as in sporadic PD, we observed the accumulation of insoluble nitrated alpha-syn in this familial disorder. Significant accumulations of filamentous insoluble tau protein also were detected in some brain regions of this patient, suggesting a role for A53T mutant alpha-syn in tau fibrillization. Indeed, in vitro studies of tau and alpha-syn fibrillization showed that the A53T mutation accelerated alpha-syn fibril formation, initiated tau assembly into filaments and synergistically enhanced fibrillization of both tau and alpha-syn. Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset ( p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) ( SPR ) gene, rs1876487 ( p = 0.02) and rs1150500 ( p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394 . The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age ( p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD ( p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

The clinical features of the genetically determined forms of familial Parkinson’s disease (PD) have been described in multiple reports, but there have been few comparative neuropathologic studies. Five familial PD cases, with mutations in SNCA, were matched for age, sex, and Alzheimer type pathology with sporadic PD cases. Immunohistochemistry for phospho-tau and α-synuclein was performed in 8 brain regions. The frequency of tau pathology and the morphologic features of α-synuclein pathology in familial PD were compared with sporadic PD using semi-quantitative methods. In familial PD, there were significantly more tau positive extra-perikaryal spheroid-like and thread-like lesions than in the sporadic PD. There was no significant difference in the amount of α-synuclein positive neuronal perikaryal pathology between familial PD and sporadic PD, but α-synuclein positive oligodendroglial and neuritic lesions were significantly greater in familial PD compared to sporadic PD. In the substantia nigra, familial PD had more marked neuronal loss and fewer residential neurons with Lewy bodies than the sporadic PD, suggesting a close relationship between the severity of neuronal loss and Lewy body formation. The results show a diversity of pathological features of genetically determined familial PD, and they draw attention to the possible role of tau protein in neurodegeneration. Moreover, the presence of oligodendroglial inclusions at the light and electron microscopic levels in familial PD suggests that PD and multiple system atrophy form a continuum of α-synuclein pathology.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

We report three cases of autopsy-proven Binswanger's disease (subcortical arteriosclerotic encephalopathy) with unusual clinical features. Two patients had supranuclear gaze disturbances, early gait dysfunction, and speech disorders suggestive of progressive supranuclear palsy. One of these patients was not demented at the time of death. The third patient had features typical of Parkinson's disease. All three patients were responsive to treatment with levodopa. The clinical spectrum of Binswanger's disease should be expanded to include levodopa-responsive parkinsonism.

In a study of 104 patients with Parkinson's disease (PD) and 61 control subjects with equal disability scores, PD patients had higher depression scores (P < 0.001) than control subjects. Functional disability was correlated with depression in PD and, in a regression analysis, explained 9% of the variance in depression (P < 0.001). Depression was not correlated with novelty seeking, a personality trait related to dopaminergic pleasure and reward systems. Harm avoidance, a trait related to central serotonergic systems, was, however, correlated with depression (P < 0.001) and explained 31% of the variance in depression scores. Results support the hypotheses that both physiologic and psychologic factors contribute to depression seen in these patients and that serotonergic function plays a more critical role than dopaminergic function.

Despite the negative effects of depression in Parkinson's disease, there is currently no evidence-based standard of care. The purpose of this study was to examine the efficacy of individually administered cognitive-behavioral therapy (CBT), relative to clinical monitoring (with no new treatment), for depression in this medical population.Eighty depressed (based on DSM-IV criteria) patients with Parkinson's disease participated in a randomized, controlled trial of CBT relative to clinical monitoring (1:1 ratio) in an academic medical center from April 2007 to July 2010. All patients continued to maintain stable medication regimens under the care of their personal physicians. The 17-item Hamilton Depression Rating Scale (HAM-D) total score was the primary outcome. CBT was modified to meet the unique needs of the Parkinson's disease population and provided for 10 weeks. Assessments were completed by blind raters at baseline and 5 (midpoint), 10 (end of treatment), and 14 weeks (follow-up evaluation) postrandomization.The CBT group reported greater reductions in depression (change in HAM-D score) than the clinical monitoring group. At week 10, the mean HAM-D score change was 7.35 for CBT relative to 0.05 for clinical monitoring. CBT was also superior to clinical monitoring on several secondary outcomes (i.e., Beck Depression Inventory scores, anxiety, quality of life, coping, Parkinson's disease symptom ratings). There were more treatment responders in the CBT group than the clinical monitoring group (56% versus 8%, respectively).CBT may be a viable approach for the treatment of depression in Parkinson's disease. Further research is needed to replicate and extend these findings.

Depression is associated with more rapid cognitive decline in Parkinson's disease. The goal of this study was to examine the impact of the acute (8-week) and longer-term (24-week) antidepressant treatment on cognition in Parkinson's disease and to detail cognitive predictors of treatment response. Fifty-two depressed Parkinson's disease patients were enrolled in an NIH-funded randomized, controlled trial of nortriptyline, paroxetine, and placebo. Neuropsychological testing was performed at baseline and weeks 8 and 24. Higher baseline scores on measures of executive functioning, speed of processing, and verbal memory were associated with antidepressant response. Treatment responders did not exhibit larger gains in cognition than nonresponders. Findings warrant replication.

Parkinson’s disease (PD) is a common neurodegenerative disease affecting up to one million individuals in the United States. Depression is found in 40 to 50% of these patients and is associated with a variety of poor outcomes for both patients and their families. Despite this, there are few evidence-based data to guide clinical care. This was an NIH-funded, randomized, controlled trial of paroxetine, nortriptyline, and placebo. It included an 8 week acute phase and a 16 week blind extension phase. This report details the impact of depression treatment on quality of life (QoL) and disability in the acute and extension phase of this study. Secondary outcomes included relapse, tolerability, safety, and the impact of depression treatment on PD physical functioning. Patients who had improvement in depression, compared with those who did not, had significant gains in measures of QoL and disability (PDQ-8, P = 0.0001; SF-36, P = 0.0001) at 8 weeks and maintained their gains in the extension phase. Patients who were on active drug were significantly less likely to relapse in the extension phase than those on placebo (P = 0.041). Though relatively modest in size, this trial provides the first controlled data on the impact of treatment of depression on QoL and disability in PD. It suggests that successfully treating depression in PD leads to important, sustained improvements in these outcomes and that patients who improve on antidepressants are less likely to relapse than are patients who initially improve on placebo.

Udgivelsesdato: 2008-Aug-15 The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.

Background We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. Methods A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. Results Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. Conclusion Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Background: Microtubule-associated protein tau ( MAPT ) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the Gene PD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT , and neighboring genes Saitohin ( STH ) and KIAA1267 , are altered in PD cerebellum. Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the Gene PD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT , STH , and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT . Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT , specifically STH and KIAA1267 , may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

Background The PARK2 gene at 6q26 encodes parkin , whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design Clinical and genetic study. Setting Twenty collaborative clinical sites. Patients Patients with familial PD collected in the Gene PD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 ( D6S305 ) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2 . Main Outcome Measures Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none ( P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation ( P = .04). Conclusions These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

We followed 4 patients with Parkinson's disease and severe, intermittent, drenching sweats. One patient was studied with serial plasma levodopa levels and simultaneous clinical examinations. She was observed during a severe sweating episode; this was associated with subtherapeutic plasma levodopa levels (low dopa state). All 4 patients' sweats responded favorably to the institution of agonist therapy. Drenching sweats should be considered part of the spectrum of off-period levodopa-related fluctuations in Parkinson's disease.

Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders. We report here the immunohistochemical, biochemical and ultrastructural characterization of alpha-syn neuropathology in a case of familial PD with the A53T alpha-syn gene mutation. Insoluble filamentous alpha-syn lesions were detected in almost all brain regions examined and as in sporadic PD, we observed the accumulation of insoluble nitrated alpha-syn in this familial disorder. Significant accumulations of filamentous insoluble tau protein also were detected in some brain regions of this patient, suggesting a role for A53T mutant alpha-syn in tau fibrillization. Indeed, in vitro studies of tau and alpha-syn fibrillization showed that the A53T mutation accelerated alpha-syn fibril formation, initiated tau assembly into filaments and synergistically enhanced fibrillization of both tau and alpha-syn. Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Parkinson's disease (PD) is primarily an α-synucle- inopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis. © 2001 Movement Disorder Society.

Impulse control disorders, including pathological gambling, binge eating, compulsive shopping and hypersexual behaviors, have frequently been reported as a side effect of dopaminergic medications for Parkinson's disease (PD). Here we describe a patient with PD who developed an unusual manifestation of impulsive behaviors, including cigarette smoking, associated with an increase in dopamine agonist medication. We postulate this to be related to an overstimulation of mesolimbic dopamine receptors responsible for reward-seeking behaviors. Further research is needed to examine impulsive cigarette smoking in PD.

We report a 45-year-old woman with a 3-year history of continuous dystonic movements of tongue and palate with intermittent episodes of noticeable worsening lasting 6 to 8 h. The movements began immediately after a viral illness. The only contributory history is that the patient received high doses of prochlorperazine 22 years earlier for hyperemesis gravidarum. The patient appears to have an unusual focal lower cranial dystonia. Proposed etiologies may be idiopathic or related to prior use of a phenothiazine with a viral trigger.

We report our long-term experience using enteral levodopa infusions in 22 patients with Parkinson's disease and severe motor fluctuations. Amelioration of intractable dyskinesias was the most important factor that determined whether patients chose to continue using the infusion pump system. Mechanical and physical problems associated with enteral access were the most common reasons for which patients discontinued pump use. Nearly all patients continued to have dramatically increased on time for the duration of follow up, suggesting that technically less-cumbersome systems that provide continuous dopaminergic stimulation are worthwhile and should be developed.

The cause of progressive supranuclear palsy (PSP) is not known and has been little studied.The one previous controlled epidemiologic survey, performed at our center in 1986, found small-town experience and greater educational attainment as PSP risks, but, in retrospect, these results may have been produced by ascertainment bias. Since that time, several anecdotal reports have implicated heredity and various environmental exposures in the cause of some cases of PSP. To clarify the results of the previous study and to evaluate the more recently implicated candidate factors in a controlled fashion, we mailed a validated 69-item questionnaire to 91 personally examined patients with PSP and 104 unmatched controls with other neurologic conditions for which they had been referred to our tertiary neurologic center. We were able to match 75 subjects from each group by year of birth, sex, and race and subjected them to a separate matched-pair analysis. We allowed surrogates to supply any or all of the responses. Questions concerned hydrocarbon, pesticide, and herbicide exposure; urban/rural living; auto repair and other occupations; head trauma; educational attainment; maternal age; and family history of PSP, parkinsonism, dementia, and other neurologic conditions. A statistically significant finding was that patients with PSP were less likely to have completed at least 12 years of school (matched odds ratio = 0.35, 95% CI = 0.12-0.95, p = 0.022; unmatched odds ratio = 0.44, 95% CI = 0.21-0.89, p = 0.020). We hypothesize that this result may be a proxy for poor early-life nutrition or for occupational or residential exposure to an as-yet unsuspected toxin. Future studies should examine these potential risk factors in PSP.NEUROLOGY 1996;47: 148-154

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathology changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinson's disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.

We report the clinical response of a parkinsonian patient with severe motor fluctuations who was begun on continuous, nighttime-only levodopa infusions accompanied by oral carbidopa/levodopa use during the day. Sleep disturbances improved immediately. There was a gradual reduction in "off" time and severity of dyskinesias during the waking day. Nighttime-only levodopa infusions have a carryover benefit to the waking hours and may be suitable for long-term therapy to reduce daily motor fluctuations in some patients with Parkinson's disease.

The few previously reported patients with familial parkinsonism and Lewy-body pathology in the substantia nigra displayed a variety of clinical and pathologic syndromes. We now describe a family with very slowly progressive Parkinson's disease (PD) that has, in most cases, responded poorly to levodopa and includes subjective visual difficult. Four personally confirmed cases--with onset at ages 35, 25, 16, and 16-have occurred in three generations, and four suspicious cases have occurred in three other generations. There has been a trend toward progressively younger age of onset. One autopsied case showed a distribution of cell loss and Lewy bodies typical of PD. The hereditary pattern is most compatible with autosomal dominance. This kindred's illness shows that a presumably single Mendelian dominant gene can cause the clinical and pathologic features of PD, and further extends the clinical spectrum of pathologically typical Lewy-body PD.

We report two patients with a primarily akinetic form of parkinsonism who were nonresponsive to treatment with levodopa. At autopsy, both patients had many Lewy bodies in brainstem and diencephalic nuclei, with sparse Lewy bodies in association cortices and more numerous Lewy bodies in the limbic cortices, consistent with the transitional form of Lewy body disease. These cases emphasize that (1) Lewy body Parkinson's disease cannot be excluded on the basis of atypical presentation or levodopa nonresponsiveness, and (2) the clinicopathologic spectrum of Lewy body disease is varied.

Immunocytochemistry with antibodies to ubiquitin is currently the most sensitive method for detecting cortical Lewy bodies, which are a sine qua non for the diagnosis of diffuse Lewy body disease (DLBD), an increasingly recognized form of primary degenerative dementia. In the systematic application of ubiquitin immunocytochemistry to sections of hippocampus from control subjects and patients with a wide spectrum of neurodegenerative diseases, we noted the frequent occurrence of ubiquitin-immunoreactive neurites in the CA2-3 region in DLBD. The nature of these neurites was investigated with immunocytochemistry in DLBD, Alzheimer's disease (AD), normal elderly subjects, and Parkinson's disease (PD). Although the number of neurites varied from case to case, they were virtually always detected in DLBD but not in normal, AD, or PD brains. Double immunolabeling studies with anti-ubiquitin demonstrated a small fraction of double-stained neurites with antibodies to neurofilament or Alz-50, but no double staining with an antibody to Alzheimer neurofibrillary tangles. These results are different from those for neurites in AD, which are rarely seen in CA2-3 and which are immunoreactive with all these antibodies. Neuritic degeneration in the CA2-3 region of the hippocampus appears to be a specific histopathologic feature of DLBD.

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for alpha-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactivity was measured in Western blots. Total alpha-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to alpha-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.