The effect of speed-accuracy strategy on response interference control in Parkinson's disease.

Studies that used conflict paradigms such as the Eriksen Flanker task show that many individuals with Parkinson's disease (PD) have pronounced difficulty resolving the conflict that arises from the simultaneous activation of mutually exclusive responses. This finding fits well with contemporary views that postulate a key role for the basal ganglia in action selection. The present experiment aims to specify the cognitive processes that underlie action selection deficits among PD patients in the context of variations in speed-accuracy strategy. PD patients (n=28) and healthy controls (n=17) performed an arrow version of the flanker task under task instructions that either emphasized speed or accuracy of responses. Reaction time (RT) and accuracy rates decreased with speed compared to accuracy instructions, although to a lesser extent for the PD group. Differences in flanker interference effects among PD and healthy controls depended on speed-accuracy strategy. Compared to the healthy controls, PD patients showed larger flanker interference effects under speed stress. RT distribution analyses suggested that PD patients have greater difficulty suppressing incorrect response activation when pressing for speed. These initial findings point to an important interaction between strategic and computational aspects of interference control in accounting for cognitive impairments of PD. The results are also compatible with recent brain imaging studies that demonstrate basal ganglia activity to co-vary with speed-accuracy adjustments.

Autosomal dominant subcortical gliosis presenting as frontotemporal dementia.

OBJECTIVE: To describe a multigenerational kindred with a frontotemporal dementia clinical syndrome (FTDS), extensive subcortical gliosis pathology, and autosomal dominant genetics. METHODS: Clinical, imaging, and pathologic evaluations of multiple family members. RESULTS: Symptom onset commonly occurred in the fifth or sixth decade, although some kindred members did not develop obvious symptoms until their eighth decade. White matter changes were prominent on both MRI and CT imaging. Results from six brain autopsy evaluations showed consistent but varying degrees of pathology that, while unique, share some histologic similarities with leukodystrophies. These brains were notably devoid of both tau- and ubiquitin-containing inclusions. CONCLUSIONS: Subcortical gliosis in this kindred arises from mutation of a novel gene or else represents a unique frontotemporal dementia clinical syndrome variant caused by mutation of an already known gene. Clinical relevance and research implications are discussed.

The effect of Parkinson's disease on interference control during action selection.

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.

Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study.

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 GenePD 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 GenePD 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.

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

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 GenePD 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.

Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

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.

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

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.

Are men at greater risk for Parkinson's disease than women?

Parkinson's disease seems to occur more commonly in men than women based primarily on studies of death rates and prevalence. In recent years, several population based incidence studies of Parkinson's disease that included sex data have been conducted in a variety of populations around the world. To investigate whether these incidence studies suggest an increased risk of Parkinson's disease in men, a meta-analysis was performed of the differences in incidence of Parkinson's disease between men and women reported in seven studies that met the inclusion criteria. A significantly higher incidence rate of Parkinson's disease was found among men with the relative risk being 1.5 times greater in men than women. Possible reasons for this increased risk of Parkinson's disease in men are toxicant exposure, head trauma, neuroprotection by oestrogen, mitochondrial dysfunction, or X linkage of genetic risk factors.

A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study.

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.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.

OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Segregation analysis of Parkinson disease revealing evidence for a major causative gene.

The role of genetics in Parkinson disease (PD) continues to be an area of considerable interest and controversy. We collected information involving the nuclear families of 948 consecutively ascertained PD index cases from the University of Virginia (UVA) Health System, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson (RWJ) School of Medicine, and Boston University (BU) School of Medicine. We performed a segregation analysis to assess evidence for the presence of a Mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the three sites. While most of the index cases were male, modestly more of the reported affected relatives were female. These analyses support the presence of a rare major Mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provides evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. We also found evidence for a Mendelian gene influencing susceptibility to the disease. It is not evident whether these two analyses are modeling the same gene or different genes with different effects on PD. The finding of significant genes influencing penetrance for PD raises the question of whether these may interact with environmental factors or other genes to increase the risk for PD. Such gene environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disease.

Epidemiologic study of 203 sibling pairs with Parkinson's disease: the GenePD study.

OBJECTIVE: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. METHODS: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. RESULTS: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). CONCLUSIONS: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome.

Sex-linked male deafness and dystonia (Mohr-Tranebjaerg syndrome) arises from mutation of the deafness/dystonia peptide (DDP) gene. We describe a novel guanine deletion at nucleotide 108 of the DDP gene in a family with Mohr-Tranebjaerg syndrome, which terminates this 97-amino acid protein at codon 25. Unlike previously reported kindreds, carrier females in this family also manifest dystonias, including torticollis and writer's cramp. A family history of male deafness should alert clinicians to the possibility of DDP mutation in women with focal dystonias.

Genome-wide scan for Parkinson's disease: the GenePD Study.

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.

Anatomy and function of dopamine receptors: understanding the pathophysiology of fluctuations in Parkinson's disease.

The principal dopamine (DA) receptors mediating the antiparkinson effects of levodopa are D1 and D2, which are anatomically and functionally segregated. We hypothesize that DA receptor-mediated effects are critical for the development of treatment-related fluctuations in Parkinson's disease (PD). We suggest that two sequential processes occur to permit the emergence of the so-called short duration response and dyskinesias: (1) functional uncoupling of D1 and D2 receptor-mediated effects with shift to the left of the dose-response curve; and, (2) sensitization of the D1-mediated striatal output due to repetitive, primarily D1 receptor stimulation by DA. These mechanisms result in excessive, pathological inhibition of basal ganglia output neurons in the GPi producing dyskinesias and the short duration response.

Prospective study of hallucinations and delusions in Parkinson's disease.

OBJECTIVE: This study was undertaken to determine the prevalence of hallucinations and delusions in Parkinson's disease, to describe such symptoms phenomenologically, and possibly to determine factors associated with their development. In addition, the role of the visual system in relation to visual hallucinations was examined. METHOD: 102 consecutive patients diagnosed with strictly defined Parkinson's disease were examined for the presence of hallucinations and delusions and assessed for visual acuity, cognition, depression using the geriatric depression scale, disease severity as measured by the UPDRS, and other clinical variables. RESULTS: Of 102 consecutive patients, 29.4% (n=30) had hallucinations or delusions, four (3.9%) were determined to be psychotic due solely to delirium and were excluded from further analysis. Of the 98 remaining patients, 26.5% (n=26) had visual hallucinations. Among these, one patient also had delusions, two had auditory hallucinations, and one had gustatory hallucinations. Visual hallucinations were significantly associated with worse visual acuity, lower cognitive score, higher depression score, and worse disease severity. Hallucinations were not associated with history of psychiatric disease, dose or duration of levodopa or other antiparkinsonian medication treatment, or duration of illness. CONCLUSIONS: Visual hallucinations are common symptoms in Parkinson's disease and are most likely of multifactorial origin. Although higher doses of levodopa are known to be related clinically to hallucinations in individual patients, the results suggest that several underlying characteristics of patients with Parkinson's disease (disease severity, dementia, depression, worse visual acuity) may be more important determinants of which patients experience hallucinations. The data also provide preliminary evidence that abnormality of the visual system may be related to visual hallucinations in Parkinson's disease, as has been found in other disorders with visual hallucinations.