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Introduction Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. Methods We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. Results PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. Conclusion As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

Interest in gastrointestinal dysfunction in Parkinson’s disease has blossomed over the past 30 years and has generated a wealth of investigation into this non-motor aspect of the disorder, research that has encompassed its pathophysiology, its clinical features, and its impact on quality of life. The question of gastrointestinal dysfunction in the other synucleinopathies has not received nearly as much attention, but information and knowledge are growing. In this review, the current knowledge, controversies, and gaps in our understanding of the pathophysiology of gastrointestinal dysfunction in Parkinson’s disease and the other synucleinopathies will be addressed, and extended focus will be directed toward the clinical problems involving saliva management, swallowing, gastric emptying, small intestinal function, and bowel function that are so problematic in these disorders.

Recognition of the importance of nonmotor dysfunction as a component of Parkinson’s disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson’s disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson’s disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00897-4) contains supplementary material, which is available to authorized users.

There has been exponential growth in the awareness and understanding of gastrointestinal (GI) dysfunction in Parkinson's disease (PD) over the past 3 decades. The clinical features of GI dysfunction in PD have been clearly identified and innovative research has demonstrated the presence of pathology within the enteric nervous system (ENS) in individuals with PD, leading to suggestions that the GI system may be ground zero for the genesis and the portal of entry of PD pathology, which then ascends via the vagus nerve to the central nervous system (CNS). This theory, as well as the more recent recognition of the association of PD with dysbiosis within the gut microbiota, has been the object of intense study and scrutiny. Since most PD medications are absorbed through the GI system, the need for better understanding of changes within the GI tract that may potentially affect the pattern of response to medications has become evident. In this review, current knowledge of the pathophysiology of changes within the GI tract and the gut microbiome of individuals with PD, including changes that occur with progression of the disease, will be addressed. We focus on common clinical GI problems in PD that can arise from different segments of the GI tract. Relevant diagnostic evaluations and treatment options for each of these problems will be reviewed.

Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. Objective To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. Methods A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. Results Eighty-five papers were used to inform the Panel’s statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. Conclusions The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with delayed peak levodopa plasma levels and increased incidence of motor fluctuations. Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.

Just as gastrointestinal dysfunction may develop in the setting of neurologic disease, neurologic dysfunction may become evident in the setting of gastrointestinal disease. This article describes the range of neurologic features that have been described in three primary gastrointestinal diseases: celiac disease and gluten-related disorders, inflammatory bowel disease, and Whipple disease. Particular emphasis is placed on the controversial and evolving clinical picture of neurologic dysfunction in disorders of gluten sensitivity.Gluten-related disorders, including both the traditional autoimmune-based celiac disease and the more recently recognized nonautoimmune, nonallergic gluten sensitivity, have been the source of much attention in both medical and lay publications. The possible association between Crohn disease and neurologic disorders also is receiving attention. The recognition that, although Whipple disease is an exceedingly rare disorder, a surprising percentage of the population may be asymptomatic stool carriers of the causative organism makes it important to always be cognizant of the disorder.The range of neurologic dysfunction in gastrointestinal diseases is broad and spans the spectrum from peripheral to central processes. Peripheral neuropathy, myopathy, myelopathy, cerebrovascular events, epilepsy, encephalopathy, and cerebellar dysfunction have all been described. Neurologists should be aware of the possibility that an underlying gastrointestinal disease process may be present in and responsible for the neurologic dysfunction that has prompted referral of an individual for evaluation.

Background Bradykinesia and reduced neuromuscular force exist in Parkinson disease. The interpolated twitch technique has been used to evaluate central versus peripheral manifestations of neuromuscular strength in healthy, aging, and athletic populations, as well as moderate to advanced Parkinson disease, but this method has not been used in mild Parkinson disease. This study aimed to evaluate quadriceps femoris rate of force development and quantify potential central and peripheral activation deficits in individuals with Parkinson disease. Methods Nine persons with mild Parkinson Disease (Hoehn & Yahr ≤ 2, Unified Parkinson Disease Rating Scale total score = mean 19.1 (SD 5.0)) and eight age-matched controls were recruited in a cross-sectional investigation. Quadriceps femoris voluntary and stimulated maximal force and rate of force development were evaluated using the interpolated twitch technique. Findings Thirteen participants satisfactorily completed the protocol. Individuals with early Parkinson disease (n = 7) had significantly slower voluntary rate of force development (p = 0.008; d = 1.97) and rate of force development ratio (p = 0.004; d = 2.18) than controls (n = 6). No significant differences were found between groups for all other variables. Interpretations Persons with mild-to-moderate Parkinson disease display disparities in rate of force development, even without deficits in maximal force. The inability to produce force at a rate comparable to controls is likely a downstream effect of central dysfunction of the motor pathway in Parkinson disease.

Autonomic dysfunction is a frequent and important nonmotor feature of Parkinson's disease (PD). Autonomic dysfunction in PD spans a broad clinical spectrum. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both the patient and the partner. Alterations in sweating and body temperature are not widely recognized, but often are present. The presence of effective treatment for at least some aspects of autonomic dysfunction makes it vitally important that the assessment of autonomic dysfunction be a regular component of the neurologic history and examination for individuals with PD.

Introduction. Antos et al. [7] have reported a case of suspected uniparental disomy leading to an initial erroneous diagnosis of Wilson’s Disease on the basis of genetic testing. They discuss the usefulness of the 64Cu radioactive copper incorporation test as an often-overlooked diagnostic aid. Clinical reflections. Wilson’s Disease is difficult to diagnose because of its rarity, diverse clinical presentations, and the absence of a single fail-safe diagnostic test. The identification of mutations in the ATP7B gene has been an invaluable aid in the diagnosis, but genetic testing alone is not infallible, and should not be used as the sole diagnostic test in arriving at a diagnosis of Wilson’s Disease. Clinical implications. The diagnosis of Wilson’s Disease must be based on a combination of findings that includes clinical history, clinical examination, and diagnostic testing. Genetic testing alone is insufficient.

Dysphagia is frequently present in individuals with Parkinson’s disease (PD). Abnormalities may be localized to the oral, pharyngeal, or esophageal level and may be evident even in the early stages of the disease. Individuals with dysphagia have an increased risk for aspiration, and silent aspiration may be present in up to one-third of patients with PD. The modified barium swallow (MBS) study is the standard screening test for dysphagia in PD, but it is important to remember that esophageal abnormalities may not be visualized on the MBS and a barium esophagram should be considered if the MBS is negative. Surgical treatment may be curative for structural abnormalities such as a Zenker’s diverticulum, but when the problem is due to oropharyngeal or esophageal dysmotility, speech/swallowing therapy is the most effective treatment.

This article reviews the clinical features of Wilson disease, focusing on the neurologic and psychiatric abnormalities, and addresses the diagnostic workup and treatment approaches to managing the disease.The list of known mutations causing Wilson disease continues to grow, but advances in genetic testing may soon make it feasible to routinely perform genetic testing on individuals suspected of having Wilson disease.Wilson disease is a rare genetic disorder with protean manifestations that should be considered in the differential diagnosis of any individual presenting with unexplained neurologic, psychiatric, or hepatic dysfunction. Appropriate diagnostic testing should be expeditiously performed and treatment promptly initiated and maintained since failure to diagnose and treat Wilson disease will result in progressive and ultimately irreversible damage to the neurologic and other systems.

With the growing awareness of the presence of non-motor symptoms in Parkinson's disease (PD) has come the realization that these non-motor features play a tremendously important, and sometimes dominant, role in the management and even the diagnosis of the disorder. Despite this, a reluctance to formally address and treat the non-motor symptoms of PD remains and quality of life for PD patients suffers. This review provides an overview of the impact non-motor symptoms have on persons with PD, along with a brief description of some of the more common non-motor features of PD.

Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus Claviceps purpurea and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony’s fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by Claviceps purpurea. This was the cultural background and scientific foundation on which bromocriptine was discovered.

Background Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS). Methods The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. Results Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). Conclusions First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society

DYT6 dystonia is an autosomal dominant primary dystonia causally-associated with sequence variants in THAP1 which encodes the DNA-binding transcription factor THAP1.1–3 DYT6 dystonia shows reduced penetrance and variable expressivity.2–8 In contrast to DYT1 dystonia, DYT6 more commonly remains focal in distribution and often affects the cervical and laryngeal musculature.1,4,5 Over 30 sequence variants have been localized to the coding regions of THAP1 and associated with focal, segmental, multi-focal or generalized dystonia with age of onset ranging from 2 to 62 years.1–8 In addition, several asymptomatic carriers have been identified in the relatives of probands. The genetic and phenotypic heterogeneity of DYT6 dystonia, and variable penetrance of known coding variants suggest that non-coding variants in THAP1 could contribute to the risk of developing adult-onset primary dystonia.4,5,7 Given that THAP1 is a transcriptional repressor, it is conceivable that non-coding variants which cause minor quantitative changes in the temporal or spatial patterns of THAP1 expression could have broad effects on the transcriptome. Djarmati and colleagues4 identified a non-coding sequence variant (c.-237_236GA>TT) near the transcriptional start site of THAP1 that might increase the risk of developing primary dystonia. The relative frequency of this polymorphism in their subjects with dystonia (20/320) relative to controls (7/355) was noteworthy (P = 0.0054). Extrapolation of their findings to a broad population of late-onset primary dystonia is problematic given that the subjects with dystonia were relatively young (mean age of onset = 38.5 years) and predominantly Northern German whereas the control group was composed of Caucasian individuals of more diverse European ancestry. Another, relatively small case-control study with heterogeneous control and dystonia populations did not find an association between the TT allele and risk for dystonia.7 Herein, we present the results of a large case-control study of c.-237_236GA>TT in primary, mainly adult-onset, dystonia. All subjects were Caucasians. Moreover, the effects of the TT variant on overall gene expression (transcript) were interrogated in leukocytes, and replicated in lymphoblastoid cell lines (transcript and protein) derived from distinct cohorts of cases and controls. Although RNA derived from peripheral blood has been used to study DYT1 dystonia9 and other movement disorders, analysis of gene expression in lymphoblastoid cell lines limits potential exogenous confounds including the effects of medications, nutrient intake, and concomitant infectious and inflammatory medical conditions.

Background Antidepressants have appeared to be more effective than placebo treatment in treating depressive syndromes in patients with Parkinson's disease (PD). Objective To identify factors that predict improvement in depressive symptoms during antidepressant treatment in depressed PD patients. Methods A secondary analysis was performed on the dataset of the Randomized Placebo-controlled Study of Antidepressants in PD (SAD-PD), in which 76 patients received active treatment with either paroxetine or venlafaxine extended release (XR), and 39 patients received placebo treatment. Backward stepwise regression analyses were conducted with change in 24-item Hamilton Depression Rating Scale (HAMD-24) score between assessments at baseline and week 12 as the main outcome measure, and sex, age, baseline HAMD-24 score, Unified Parkinson's Disease Rating Scale section III (UPDRS-III) score, Mini-Mental State Examination (MMSE), and the Clinical Anxiety Scale (CAS) as independent variables. Results In both the active treatment and placebo groups, higher baseline HAMD-24 score and lower UPDRS-III score were associated with greater reduction in HAMD-24 score. Higher anxiety scores predicted less response in the active treatment group. Higher MMSE scores predicted greater response only in the placebo-treated group. Sex and age were no predictors of response. Conclusions Higher pre-treatment depression scores and lower pre-treatment anxiety scores are the two most important predictors for improvement during antidepressant treatment in depressed PD patients, which is in line with those found in treatment studies of depressed non-PD patients. Furthermore, our results indicate the requirement for different or more intensive treatment for depressed PD patients with more severe anxiety symptoms.

The cognitive profile of early onset Parkinson’s disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson’s disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study. (JINS, 2011, 17, 1–10)

Background. Resistance training research has demonstrated positive effects for persons with Parkinson's disease (PD), but the number of acute training variables that can be manipulated makes it difficult to determine the optimal resistance training program.Objective. The purpose of this investigation was to examine the effects of an 8-week resistance training intervention on strength and function in persons with PD.Methods. Eighteen men and women were randomized to training or standard care for the 8-week intervention. The training group performed 3 sets of 5–8 repetitions of the leg press, leg curl, and calf press twice weekly. Tests included leg press strength relative to body mass, timed up-and-go, six-minute walk, and Activities-specific Balance Confidence questionnaire.Results. There was a significant group-by-time effect for maximum leg press strength relative to body mass, with the training group significantly increasing their maximum relative strength (P<.05). No other significant interactions were noted (P>.05).Conclusions. Moderate volume, high-load weight training is effective for increasing lower-body strength in persons with PD.

Previous investigations have demonstrated leg strength deficits in persons with Parkinson's disease (PD) as compared to neurologically-normal adults. However, the exact mode of contraction by which strength is assessed may determine how closely such deficits are related to functional performance. The purpose of this study was to better understand the relationship of strength and functional mobility in persons with PD (n = 17, mean H&Y stage = 2.0) via comparison to a group of similar age healthy controls (n = 10) using a multi-joint isometric test of strength and various measures of functional mobility. Tests included isometric leg press maximum force relative to body mass, the Activities-specific Balance Confidence scale (ABC), postural sway under various unilateral stance and visual conditions, and the timed up and go (TUG). Relative force (p = 0.044) and ABC questionnaire mean scores (p < 0.001), showed controls performing better than PD subjects. The control group performed better than the PD group for length of path of the center of pressure except in the eyes closed positions (p < 0.05 for all). TUG time (p = 0.052) was not significantly different between the PD group and healthy controls. Leg press maximum force relative to body mass was however significantly correlated with TUG time (r = -0.68, p = 0.003) in persons with PD. There were no gender differences for any variables. These results suggest that some balance and functional mobility task performances are more worse for persons with mild-to-moderate PD than for neurologically-normal age-matched controls, which may be influenced by lessened lower extremity multi-joint strength. Strength training of the lower extremity utilizing such multi-joint actions may be beneficial for this population.

Objective: Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD. Methods: We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations. Results: We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at ≤45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at ≤45 years, p = 0.06). Conclusions: Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.

Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.

Objective: A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2 , result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding. Methods: We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD. Results: We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 ( p = 0.28). Conclusions: We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37. GDS = Geriatric Depression Scale; MMSE = Mini-Mental State Examination; NCRAD = National Cell Repository for Alzheimer’s Disease; PD = Parkinson disease; PSG = Parkinson Study Group; UPDRS = Unified Parkinson’s Disease Rating Scale.

The long-term management of Parkinson’s disease is compromised by the development of treatment-related complications that can severely limit the effectiveness of levodopa. Growing evidence implicates intermittent, or pulsatile, stimulation of dopamine receptors as one potential mechanism in their genesis. Continuous administration of medication via the transdermal route offers a potential avenue to circumvent pulsatile drug delivery and, thus, possibly deflect development of dyskinesia and motor fluctuations. The development of an effective transdermal drug preparation for Parkinson’s disease has had a long gestation, but the recent emergence of rotigotine as an effective transdermal therapy provides hope and encouragement that additional advances may also be forthcoming and that our ability to effectively treat this devastating disease will continue to grow.

Wilson's disease is an autosomal-recessive disorder caused by mutation in the ATP7B gene, with resultant impairment of biliary excretion of copper. Subsequent copper accumulation, first in the liver but ultimately in the brain and other tissues, produces protean clinical manifestations that may include hepatic, neurological, psychiatric, ophthalmological, and other derangements. Genetic testing is impractical because of the multitude of mutations that have been identified, so accurate diagnosis relies on judicious use of a battery of laboratory and other diagnostic tests. Lifelong palliative treatment with a growing stable of medications, or with liver transplantation if needed, can successfully ameliorate or prevent the progressive deterioration and eventual death that would otherwise inevitably ensue. This article discusses the epidemiology, genetics, pathophysiology, clinical features, diagnostic testing, and treatment of Wilson's disease.

Contrary to what one may assume, neurology and gastroenterology are similar to each other in many ways. A process found in one system can also affect the other, whether it be gastrointestinal (GI) dysfunction present in neurologic diseases or neurologic dysfunction present in GI diseases. Several disorders from both fields of medicines are highlighted in this review, ranging from stroke, Parkinson disease, and multiple sclerosis (MS) as examples of GI dysfunction in neurologic disease, to celiac disease and inflammatory bowel disease as examples of neurologic dysfunction in GI disease. Rare disorders such as Whipple disease (WhD), chronic acquired hepatocerebral degeneration (CAHD), and Wilson disease (WD) should also be considered for their neurologic dysfunctions as manifested extraintestinally. Tables give an overview of clinical features of the various disorders presented in this review. This module contains ­4 highly rendered figures, 9 tables, 349 references, and 5 MCQs.

Any neurologist—even a movement disorders neurologist, if he or she is honest, will tell you that it can be maddeningly difficult to differentiate between Parkinson's disease (PD) and the atypical parkinsonian syndromes (APS) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), especially during their initial clinical stages. Although the cynic might propose that it does not make much of a difference, since the treatment measures employed are essentially identical, the reality is that accurate diagnosis does, indeed, make a difference to patients and their family members. The likelihood for a meaningful response to medication is markedly less for individuals with one of the APS (even though some individuals with MSA may achieve, at least initially, a noticeable response) and the expectations, prognosis and life expectancy for individuals with one of the APS are significantly bleaker than for individuals with PD. Patients and their family members want and are entitled to know this because it can make a tremendous difference in the counseling they receive and the planning they may make. Accurate diagnosis also is important from a research standpoint. It has been documented that the initial diagnosis of PD is often incorrect. In a recent report comparing clinical diagnosis with neuropathological confirmation, the accuracy rate of general neurologists in diagnosing PD was only 75% (Joutsa et al. 2014) and in another recent report utilizing data from the Arizona Study of Aging and Neurodegenerative Disorders, the diagnostic accuracy of a clinical diagnosis of PD in untreated or poorly treatment-responsive individuals was only 26%, rising to 53% in individuals with suspected early PD responsive to medication and to a greater extent than 85% in individuals with a more long-standing diagnosis responsive to medication (Adler et al. 2014). Diagnostic accuracy in the APS is also notoriously suboptimal (Litvan et al. 1997a,b). Although an accuracy rate of 90% is achieved when the diagnosis is made by neurologists specializing in movement disorders utilizing specific diagnostic criteria (Hughes et al. 2001), much room for improvement still exists. This diagnostic inaccuracy, especially early in the disease course, also has tremendous implications from the standpoint of clinical trials. Much research attention currently is focused on the search for agents that might modify disease progression, which would be most effective if employed early in the course of the disease, even before the appearance of motor dysfunction if possible, since by the time the motor features of PD become evident, approximately 50% of dopaminergic neurons have already been lost (Kordower et al. 2013). It is possible, in fact, that the error rate inherent in the purely clinical diagnosis of PD already has led to the failure to identify effective disease modifying agents because of the inclusion in clinical trials of subjects who later turned out to have one of the APS or other disorders. It is amidst this quandary that an impressive array of approaches toward complementing and improving the accuracy of clinical diagnosis of PD and APS has undergone investigation. Approaches as varied as cerebrospinal fluid markers (Hall et al. 2012; Herbert et al. 2014; Magdalinou et al. 2015), smell testing (Driver-Dunckley et al. 2014), breath analysis (Nakhleh et al. 2015), voice analysis (Hariharan et al. 2014), transcranial ultrasonography (Fernandes Rde and Berg 2015), and others have been studied. However, it is neuroimaging in a variety of permutations that has received the most attention. Radiotracer imaging procedures, such as dopaminergic imaging with both PET and SPECT, and cardiac imaging with MIBG, already have found some usefulness in clinical practice. Advanced magnetic resonance imaging techniques, particularly those focusing on atrophy patterns, are now receiving increasing attention. Magnetic resonance volumetry is performed in a manual or semi-automated fashion that is operator dependent and time consuming; in contrast, voxel-based morphometry is a fully automated approach that is rater-independent and does not require prior identification of regions of interest (Holtbernd and Eidelberg 2014). Yu and colleagues have taken the innovative and important step of submitting information from 39 published voxel-based morphometry articles, encompassing a total of 782 patients with either PD or one of the APS, to whole brain meta-analysis utilizing the modified Anatomic Likelihood Estimation method (Yu et al. 2015) and have identified characteristic patterns of gray matter atrophy, unique to each disorder, to be evident for each of the APS (MSA, PSP, CBD). This information will serve as a vital comparison point and guide for future studies. However, hurdles remain. Although distinctive patterns of gray matter involvement have been identified for the APS with voxel-based morphometry, overlap is present and interpretation cannot currently be performed on individual patients. It also is unclear, as discussed by Yu and colleagues, how effective this method may be in identifying changes in early disease, since atrophy may be a later-occurring phenomenon. Perhaps even more problematic is the fact that in the vast majority of studies utilizing voxel-based morphometry—and in the vast majority of studies evaluating all types of potential biomarkers—the control against which the new techniques or procedures are compared is the clinical diagnosis; a standard which we know is inadequate because of errors in diagnosis, as described above. The “gold standard” of neuropathological confirmation of diagnosis is rarely employed and, thus, the best the various procedures can hope to be is equivalent to an already imperfect standard. Prospective, longitudinal studies that ultimately have neuropathological confirmation of diagnosis are sorely needed to jump this hurdle, but will be very challenging to complete.

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

During the past 25 years, there has been an explosion of information regarding the occurrence of gastrointestinal dysfunction in Parkinson’s disease. In this review, the clinical features of gastrointestinal dysfunction in Parkinson’s disease will be described and information regarding the potential role of the enteric nervous system and the gut microbiome in the genesis of Parkinson’s disease will be addressed. Recognition is growing regarding the role that gastroparesis and small intestinal dysfunction may play in Parkinson’s disease, especially with regard to erratic responses to anti-Parkinson medication. The presence of enteric nervous system involvement in Parkinson’s disease is now well established, but whether the enteric nervous system is the starting point for Parkinson’s disease pathology remains a source of debate. The potential role of the gut microbiome also is beginning to emerge. Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson’s disease and dysfunction can be found along the entire length of the gastrointestinal tract. The enteric nervous system is clearly involved in Parkinson’s disease. Whether it is the initial source of pathology is still a source of controversy. There also is growing recognition of the role that the gut microbiome may play in Parkinson’s disease, but much more research is needed to fully assess this aspect of the disorder.

We present genealogical and longitudinal clinical observations and autopsy findings of a previously reported kindred, Family C (German-American), with late-onset autosomal dominant parkinsonism with evidence for linkage on chromosome 2p13. The clinical phenotype includes the cardinal features of idiopathic Parkinson's disease. In addition, postural tremor and dementia are detected in some individuals. Two members of the kindred, one affected and one unaffected have recently come to autopsy. The unaffected family member was an 82-year-old woman whose brain showed only mild age-related pathology and no evidence of subclinical Lewy body disease. In contrast, the affected family member was an 83-year-old man whose brain had neuronal loss, gliosis and Lewy bodies in the substantia nigra and other monoaminergic brain stem nuclei, as well as the basal forebrain and amygdala. Lewy bodies and Lewy neurites had a distribution typical of cases of idiopathic Parkinson's disease. Thus, the clinical and pathological findings in this family with autosomal dominant parkinsonism are similar to those of sporadic Parkinson's disease.

Background: Autonomic dysfunction occurs in Parkinson's disease (PD), but few studies have addressed it in a comprehensive manner. Methods: Autonomic symptoms were evaluated by a questionnaire in sixty-eight subjects (44 patients and 24 controls). Results: PD patients experienced higher frequency and severity of autonomic dysfunction. When all autonomic symptoms were pooled into an aggregate score, differences between patients and controls were highly statistically significant (p

Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.

It is both ironic and remarkable that now, almost 200 years later, the question of interaction between the gut and the brain in Parkinson’s disease (PD) has resurfaced to become the subject of a veritable tsunami of fascinating and tremendously important research that has potential ramifications not only for understanding the pathophysiology of PD but also for its treatment and even its diagnosis. During the past 30 years, gastrointestinal (GI) dysfunction has gained recognition as one of the more frequent and troublesome nonmotor features of PD [2, 3] and pathology within the enteric nervous system (ENS), including Lewy body formation and alphasynuclein deposition, has been identified as part of the disorder [4–6]. Loss of dopamine neurons within the ENS also has been reported [6]. Braak et al. have proposed that PD actually has its genesis within the ENS and spreads from there via the vagus nerve to the central nervous system (CNS), initially establishing a beach

Many cases of myoclonus-dystonia (M-D) are due to mutations in SGCE (DYT11). For the majority of patients, myoclonus is relatively more severe than dystonia and can lead to significant functional disability. Deep brain stimulation has been chosen as a treatment option in some patients given that M-D often responds poorly to oral pharmacotherapy.Two siblings with M-D due to the same SGCE deletion mutation were evaluated with the Global Dystonia Rating Scale (GDRS), Fahn-Marsden Rating Scale (FM) and Unified Myoclonus Rating Scale (UMRS) on and off tetrabenazine.Both subjects showed marked improvement in myoclonus and mild-to-moderate improvement in dystonia with tetrabenazine. In addition, the response to tetrabenazine has been sustained for years.A therapeutic trial of tetrabenazine should be considered in patients with M-D, especially before consideration of deep brain stimulation. An adequately powered multi-center, double-blind study of tetrabenazine will be required to determine the relative contributions of tetrabenazine therapy to myoclonus, dystonia, quality of life, and activities of daily living in patients with M-D.

Many gastrointestinal diseases have extraintestinal manifestations including neurologic involvement. Malabsorption, which can result from diseases that damage absorptive sites in the small intestine, such as inflammatory bowel disease and tropical sprue, or may develop following bariatric surgical procedures in which absorptive sites may be bypassed or removed, can result in vitamin and other nutrient deficiencies that produce neurologic dysfunction. Disease processes involving immunologic mechanisms, in which both the gastrointestinal and nervous systems are attacked, such as celiac disease, may also produce neurologic symptoms. Neurologic dysfunction in hepatic disease most often is the result of failure of the liver to adequately perform its detoxifying function, but in the case of fulminant hepatic failure cerebral edema is the life-threatening consequence. Prompt recognition of these disorders is vitally important, since many of the neurologic manifestations of gastrointestinal disease are treatable.

Although malabsorption is generally considered to be a gastrointestinal problem, the effects of malabsorption extend far beyond the gastrointestinal tract and can include neurologic dysfunction. Malabsorption may occur by a variety of mechanisms, both genetic and acquired, that interfere with the absorption of basic nutrients, vitamins, minerals, and trace elements. Disorders that interfere with fat absorption can lead to neurologic dysfunction as a consequence of associated impairment of fat-soluble vitamin absorption. Thus, individuals with genetic vitamin E deficiency and the familial hypocholesterolemias may develop symptoms of peripheral neuropathy, cerebellar ataxia, and other neurologic signs and symptoms. Disease processes that damage the enteric mucosa and produce malabsorption can trigger neurologic dysfunction both by immune-related processes, as in celiac disease, and by impairing absorption of essential vitamins and other nutrients, as in tropical sprue. Deficiencies of water-soluble vitamins, such as thiamine and niacin, can also develop in the setting of malabsorption and lead to neurologic dysfunction. Neurologists are aware of the neurologic damage that copper excess can cause in Wilson's disease, but copper deficiency due to malabsorption can also produce neurologic dysfunction in the form of myelopathy. It is vitally important for neurologists to be aware of the potential for malabsorptive processes to produce neurologic dysfunction, because effective treatment for such disorders is often available.

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia.