Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies.

Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated alpha-synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that alpha-synuclein is nitrated in pathological lesions. The widespread presence of nitrated alpha-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.

Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy.

Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn.

Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.

Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation--preliminary experience.

PURPOSE: To evaluate the temporal evolution and appearance of a radiosurgical lesion at magnetic resonance (MR) imaging and the clinical response in patients undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma knife. MATERIALS AND METHODS: Seventeen patients with medically refractory movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or thalamotomy (n = 15). A single dose of 120-140 Gy was administered to a target in the globus pallidus interna or ventralis intermedius thalamic nucleus. Postprocedure gadolinium-enhanced MR imaging and clinical assessment were performed at 1 month and 3 months. RESULTS: At 3 months, the radiosurgical lesion most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in diameter surrounded by vasogenic edema that extended less than 7 mm in radius beyond the target. Five patients had ring-enhancing lesions 7 mm or more in diameter; four of these developed symptomatic perilesional edema at 3 (n = 2) or 8 (n = 2) months after the procedure. Onset of therapeutic effect began approximately 4 weeks after treatment. In the 15 patients with tremor, there was a mean decline of 2.1 on the Tremor Rating Scale. CONCLUSION: Findings in this pilot study suggest that radiosurgical thalamotomy is a promising treatment for medically refractory tremor. Three-month follow-up MR studies show a ring-enhancing lesion surrounded by a variable amount of vasogenic edema. Visualization of the radiosurgical lesion and the clinical response are delayed compared to that with radio-frequency procedures.

Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson's disease.

Decreased olfactory function is among the first signs of idiopathic Parkinson's disease (PD). Whether such dysfunction is present to the same degree on both sides of the nose, however, is unknown. Furthermore, whether the deficit results from or is influenced by anti-Parkinsonian medications has not been definitely established. Odour identification ability was evaluated on the left and right sides of the nose in 20 early-stage untreated PD patients, 20 early-stage treated PD patients, and 20 controls. In all cases, the PD related olfactory dysfunction was bilateral and no difference was observed between the test scores of patients taking or not taking drugs for PD. Although asymmetries of unsystematic direction were present in the test scores of some PD patients, similar asymmetries were observed in the controls and the asymmetries were not related to the side of the major motor dysfunction. As in earlier work, no relation was present between the olfactory test scores and the degree of tremor, rigidity, bradykinesia, or gait disturbance at the time of testing. These findings indicate that the olfactory dysfunction of early stage PD is robust, typically of the same general magnitude on both sides of the nose, and uninfluenced by anti-Parkinsonian medications.

Transient dystonia as a complication of varicella.

A case of transient post-varicella lingual-mandibular dystonia is presented. This case was compared with the eight previously reported instances of involuntary movement disorders which rarely follow varicella infection.

Low-dose, slow-increase bromocriptine in patients with progressive Parkinson's disease and complications of levodopa therapy.

We studied the effect of adding low-dose bromocriptine to levodopa/carbidopa (Sinemet) in 26 patients suffering from progressive Parkinson's disease with loss of levodopa effectiveness or levodopa-induced fluctuations. Despite the high incidence of drug intolerance and low response rates, a significant proportion of patients with the wearing-off effect and dystonia improved. Low-dose, slow-increase bromocriptine is warranted as adjunctive therapy in these patient subgroups.