Kathleen M. Shannon

A Double-blind Controlled Trial of Bilateral Fetal Nigral Transplantation in Parkinson's Disease

Thirty‐four patients with advanced Parkinsons disease participated in a prospective 24‐month double‐blind, placebo‐controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinsons Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one‐donor groups deteriorated by 9.4 ± 4.25 and 3.5 ± 4.23 points, respectively, whereas those in the four‐donor group improved by 0.72 ± 4.05 points. Pairwise comparisons were not significant, although the four‐donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty‐six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication (“off”‐medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.Ann Neurol 2003;54:403–414

Prevalence of Parkinsonian Signs and Associated Mortality in a Community Population of Older People

BACKGROUND Older people frequently have signs of parkinsonism, but information about the prevalence of parkinsonism and mortality among those with the condition in the community is limited. METHODS A stratified random sample of 467 residents of East Boston, Massachusetts, 65 years of age or older, were given structured neurologic examinations. Using uniform, specified combinations of parkinsonian signs, we estimated the prevalence of four categories of signs--bradykinesia, gait disturbance, rigidity, and tremor--and of parkinsonism, defined as the presence of two or more categories. We did not study Parkinsons disease because it could not be distinguished from other conditions that can cause parkinsonism. Proportional-hazards models were used to compare the risk of death among people with and those without parkinsonism. RESULTS One hundred fifty-nine persons had parkinsonism, 301 did not, and 7 could not be classified. The overall prevalence estimates were 14.9 percent for people 65 to 74 years of age, 29.5 percent for those 75 to 84, and 52.4 percent for those 85 and older. With a mean follow-up period of 9.2 years, 124 persons with parkinsonism (78 percent) and 146 persons without (49 percent) died. Adjusted for age and sex, the overall risk of death among people with parkinsonism was 2.0 (95 percent confidence interval, 1.6 to 2.6) times that among people without. Among people with parkinsonism, the presence of gait disturbance was associated with an increased risk of death. CONCLUSIONS Parkinsonism is very common among people over the age of 65, and its prevalence increases markedly with age. Parkinsonism is associated with a twofold increase in the risk of death, which is strongly related to the presence of a gait disturbance.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinsons disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.

Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease.

The diagnosis of Parkinsons disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α‐synuclein aggregation, the pathological signature of Parkinsons disease, can be detected in gastrointestinal tract neurons in Parkinsons disease. We studied whether we could demonstrate α‐synuclein pathology in specimens from unprepped flexible sigmoidoscopy of the distal sigmoid colon in early subjects with Parkinsons disease. We also looked for 3‐nitrotyrosine, a marker of oxidative stress. Ten subjects with early Parkinsons disease not treated with dopaminergic agents (7 men; median age, 58.5 years; median disease duration, 1.5 years) underwent unprepped flexible sigmoidoscopy with biopsy of the distal sigmoid colon. Immunohistochemistry studies for α‐synuclein and 3‐nitrotyrosine were performed on biopsy specimens and control specimens from a tissue repository (23 healthy subjects and 23 subjects with inflammatory bowel disease). Nine of 10 Parkinsons disease samples were adequate for study. All showed staining for α‐synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern. A few showed light α‐synuclein staining in round cells. 3‐Nitrotyrosine staining was seen in 87% of Parkinsons disease cases but was not specific for Parkinsons disease. This study suggests a pattern of α‐synuclein staining in Parkinsons disease that was distinct from healthy subjects and those with inflammatory bowel disease. The absence of this pattern in subjects with inflammatory bowel disease suggests it is not a sequel of inflammation or oxidative stress. 3‐Nitrotyrosine immunostaining was common in all groups studied, suggesting oxidative stress in the colonic submucosa.

Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease.

Parkinsons disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. Trial Registration Clinicaltrials.gov NCT01155492

Is alpha‐synuclein in the colon a biomarker for premotor Parkinson's Disease? Evidence from 3 cases

Background: Despite clinicopathological evidence that Parkinsons disease (PD) may begin in peripheral tissues, identification of premotor Parkinsons disease is not yet possible. Alpha‐synuclein aggregation underlies Parkinsons disease pathology, and its presence in peripheral tissues may be a reliable disease biomarker. Objective: We sought evidence of alpha‐synuclein pathology in colonic tissues before the development of characteristic Parkinsons disease motor symptoms. Methods: Old colon biopsy samples were available for three subjects with PD. Biopsies were obtained 2‐5 years before PD onset. We performed immunohistochemistry studies for the presence of alpha‐synuclein and Substance P in these samples. Results: All subjects showed immunostaining for alpha‐synuclein (two, five and two years before first motor Parkinsons disease symptom). No similar alpha‐synuclein immunostaining was seen in 23 healthy controls. Staining of samples for substance P suggested colocalization of alpha‐synuclein and substance P in perikarya and neurites. Conclusions: This is the first demonstration of alpha‐synuclein in colon tissue prior to onset of PD. Additional study is required to determine whether colonic mucosal biopsy may be a biomarker of premotor PD.

Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia

Objective: To directly compare two serotypes of botulinum toxin (BoNTA and BoNTB) in cervical dystonia (CD) using a randomized, double-blind, parallel-arm study design. Methods: Subjects with CD who had a previous response from BoNTA were randomly assigned to BoNTA or BoNTB and evaluated in a blinded fashion at baseline, 4 weeks, 8 weeks, and 2-week intervals thereafter until loss of 80% of clinical effect or completion of 20 weeks of observation. CD severity was measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and adverse events were assessed by structured interview. Statistical analysis included Wilcoxon rank sum test, log rank tests, and Kaplan–Meier survival curves for duration of effect. Results: A total of 139 subjects (BoNTA, n = 74; BoNTB, n = 65) were randomized at 19 study sites. Improvement in TWSTRS score was found at 4 weeks after injection and did not differ between serotypes. Dysphagia and dry mouth were more frequent with BoNTB (dysphagia: BoNTA 19% vs BoNTB 48%, p = 0.0005; dry mouth (BoNTA 41% vs BoNTB 80%, p < 0.0001). In clinical responders, BoNT A had a modestly longer duration of benefit (BoNTA 14 weeks, BoNTB 12.1 weeks, p = 0.033). Conclusion: Both serotypes of botulinum toxin (BoNTA and BoNTB) had equivalent benefit in subjects with cervical dystonia at 4 weeks. BoNTA had fewer adverse events and a marginally longer duration of effect in subjects showing a clinical response.

An R5L τ mutation in a subject with a progressive supranuclear palsy phenotype

MAPT, the gene encoding tau, was screened for mutations in 96 progressive supranuclear palsy subjects. A point mutation (R5L) was identified in a single progressive supranuclear palsy subject that was not in the other progressive supranuclear palsy subjects or in 96 controls. Functionally, this mutation alters the ability of tau to promote microtubule assembly. Analysis of soluble tau from different brain regions indicates that the mutation does not affect the ratio of tau isoforms synthesized. Aggregated insoluble tau from subcortical regions was predominantly four‐repeat tau with no or one amino terminal insert (0N4R and 1N4R). Insoluble tau from cortical regions also contained 1N3R tau. Thus, the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain‐of‐function mechanism.

Colonic bacterial composition in Parkinson's disease

We showed that Parkinsons disease (PD) patients have alpha‐synuclein (α‐Syn) aggregation in their colon with evidence of colonic inflammation. If PD patients have altered colonic microbiota, dysbiosis might be the mechanism of neuroinflammation that leads to α‐Syn misfolding and PD pathology.

Metric properties of nurses' ratings of parkinsonian signs with a modified Unified Parkinson's Disease Rating Scale

We evaluated the ability of nurse clinicians to assess parkinsonian signs in older persons with a modified version of the motor section of the Unified Parkinsons Disease Rating Scale (UPDRS). After completing a structured training protocol, three nurse clinicians and a neurologist with expertise in movement disorders administered a modified UPDRS to 75 older persons. The nurses repeated the assessment about 3 weeks later. Inter-rater agreement and short-term temporal stability were estimated for each item, the total modified UPDRS score, and for summary measures of bradykinesia, postural reflex impairment, rigidity, and tremor, and a global parkinsonian sign score. We performed our assessment in Catholic religious communities in the Chicago area, using consecutive subjects at four communities participating in the Religious Orders Study, a longitudinal, clinical-pathologic study of older persons. Our results showed that nurses were not a significant source of variability, with intraclass correlations exceeding 0.97 for all items, and they showed good to excellent agreement with the neurologist for most modified UPDRS items. Correlations between nurses and neurologist exceeded 0.90 for the total modified UPDRS, ranged from 0.76 to 0.95 for the four parkinsonian domain scores, and exceeded 0.90 for the global parkinsonian sign score. Nurses showed fair to good agreement with themselves over the 3-week interval for most modified UPDRS items. Correlations over the 3-week interval exceeded 0.90 for the total modified UPDRS score, ranged from 0.70 to 0.95 for the four domain scores, and exceeded 0.90 for the global parkinsonian sign score. Ratings of parkinsonian signs by nurse clinicians corresponded closely to those of a neurologist with expertise in movement disorders and showed good inter-rater agreement and temporal stability. With appropriate training, nurse clinicians can reliably administer the modified UPDRS.