Yasuhiko Baba

Parkinson disease Handedness predicts asymmetry

Objective: To determine the proportion of individuals in a clinic-based setting that present with asymmetric Parkinson disease (PD) and identify predictive factors associated with asymmetric symptoms. Methods: The authors examined right vs left difference scores on the Unified Parkinson Disease Rating Scale motor subscale in a consecutive clinical series of 1,277 individuals diagnosed with PD. Predictors of asymmetry included sex, symptomatic disease duration, age at onset, initial motor symptom laterality, handedness, and medical history variables (e.g., family history of PD). Results: Nearly half the sample (46%) met criteria for asymmetric disease based on a right vs left difference score of ≥5 points, and 12% of the sample had a difference score of ≥10 (difference score: mean = 4, SD = 3.4). All three cardinal features of PD showed characteristics of asymmetric disease presentation. Multiple regression analyses showed that an increased discrepancy between right- and left-sided symptoms was significantly associated with a shorter disease duration, younger age at symptomatic onset, asymmetric initial symptom onset, hand dominance, and a positive self-reported family history of “other” neurodegenerative disorder. Hand dominance was related to the side of asymmetric disease such that left-handed individuals tended to have more severe disease on the left side of the body. Conclusion: Asymmetric presentation of Parkinson disease features was a common occurrence in the clinical cohort. Asymmetry was reliably predicted by several clinical characteristics, although the moderate level of explained variance (i.e., between 16 and 23%) highlighted the need for additional research examining predictive models of asymmetric disease. Recommendations for the classification and measurement of asymmetric disease are discussed.

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not αB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with αB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and αB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Gender and the Parkinson’s disease phenotype

AbstractObjectivesTo determine whether there are gender differences in the Parkinson’s disease (PD) phenotype using a large clinic–based cohort.MethodsWe examined gender differences in demographic, historical and clinical characteristics in a consecutive clinical series of 1264 individuals diagnosed with PD.ResultsThe majority of individuals in the sample were male (67 %). Comparative analyses showed males and females were not significantly different on most demographic and historical characteristics. For both genders, the mean age and the mean age at symptomatic onset were about 70 and 63 years, respectively and, thus, disease duration was not significantly different between genders. The proportion of individuals with a positive family history of PD (15 %) was similar for both genders. A positive history of depression was significantly higher in females (35 % vs. 24 %). The UPDRS instability score was significantly worse among females, whereas the rigidity score was significantly worse for males. Females showed significantly worse ADL capacity and a more advanced H&Y stage. The proportion of individuals receiving antiparkinsonian medication (about 66 %) and time between the last dose and the clinical evaluation (about 4 hours) was similar for both genders. There was a trend for lower daily levodopa equivalence dosage and more severe dyskinesia score among females but these differences did not reach statistical significance after Bonferroni correction.ConclusionsThe majority of comparisons tended to highlight the commonalities in the PD phenotype between genders, particularly in reference to historical and early disease stage characteristics. However, gender may be an important factor related to the expression of PD features during the symptomatic disease course.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder, which has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996. The prevalence and incidence remain unknown but FTDP-17 is an extremely rare condition. It is caused by mutations in the tau gene, which encodes a microtubule-binding protein. Over 100 families with 38 different mutations in the tau gene have been identified worldwide. The phenotype of FTDP-17 varies not only between families carrying different mutations but also between and within families carrying the same mutations. The pathogenetic mechanisms underlying the disorder are thought to be related to the altered proportion of tau isoforms or to the ability of tau to bind microtubules and to promote microtubule assembly. Definitive diagnosis of FTDP-17 requires a combination of characteristic clinical and pathological features and molecular genetic analysis. Genetic counseling should be offered to affected and at-risk individuals; for most subtypes, penetrance is incomplete. Currently, treatment for FTDP-17 is only symptomatic and supportive. The prognosis and rate of the diseases progression vary considerably among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades.

Heredofamilial Brain Calcinosis Syndrome

Brain calcinosis syndrome (BCS) usually is defined as bilateral calcium accumulation in the brain parenchyma, primarily in the basal ganglia. More than 50 reported clinical conditions have been associated with BCS. We reviewed clinical, radiological, and genetic features of heredofamilial BCS accompanying all conditions associated with calcium accumulation in the brain reported in English between 1962 and 2003 in MEDLINE. The location, extent, and degree of calcification in the brain show diversity not only among the various disorders but also among patients sharing the same condition. The pathogenesis of BCS is uncertain. More complicated mechanisms may be Involved when brain calcinosis is present but calcium, phosphorus, and parathyroid hormone metabolism abnormalities are absent. We review conditions associated with heredofamilial BCS in which brain calcinosis is nearly uniformly present because such information may be Important to the clinician pursuing an investigative strategy.

ATP-binding cassette transporter G4 is highly expressed in microglia in Alzheimer's brain.

Apolipoprotein E epsilon4 is an independent risk factor for Alzheimers disease (AD) and is the main constituent of high-density lipoprotein (HDL) as a source of cholesterol in the brain. ATP-binding cassette transporter G4 (ABCG4) is one of the membrane cholesterol transporter which is implicated in HDL-mediated cholesterol efflux, but its precise localization and function in the brain has been unclear. In AD brain, ABCG4 protein was highly expressed in microglial cell that was closely located to senile plaques, whereas in non-neurological cases positive cells were not seen in cortical and nigral tissues. As well as the ABCG4 protein, ABCG4 mRNA signal was detected in microglial cell closely located to senile plaque of AD brain by in situ hybridization histochemistry. These results suggest that upregulated ABCG4 in microglia may accelerate the lipidation of apoE and HDL in the AD brain. This is the first report to show that ABCG4 is highly expressed in microglia on AD brain.

Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation

SummaryIn 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.

Magnetic resonance imaging of thoracic epidural venous dilation in Hirayama disease.

Hirayama disease is a nonprogressive, asymmetric amyotrophy of the hands and forearms, possibly caused by compression of the lower cervical cord on neck flexion. The authors used phase-contrast MR angiography to study a patient with this disorder and observed abnormal spinal epidural venous dilation on neck flexion. In addition to mechanical compression of the lower cervical cord, venous congestion in the spinal canal may have a role in promoting anterior horn damage.

Autosomal dominant dystonia-plus with cerebral calcifications

Objective: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. Methods: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. Results: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D1- and D2-receptor binding and reduced uptake of 6-[18F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. Conclusions: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.

Cardiac papillary fibroelastoma as a cause of recurrent ischemic strokes: The diagnostic value of serial transesophageal echocardiography

Introduction Cardiac papillary fibroelastoma is a rare tumor that attaches to an endocardial surface and is often diagnosed only at postmortem examination. It is thought to be a benign tumor, accounting for 8% of primary cardiac tumors [1]. Occasionally, if it is located close to the mitral or aortic valve, papillary fibroelastoma can be a cause of cerebral infarction and transient ischemic attack. Transesophageal echocardiography (TEE) may be more sensitive for detecting intracardiac tumors than transthoracic echocardiography (TTE). We report a case of recurrent ischemic strokes caused by a papillary fibroelastoma located on the anterior leaflet of the mitral valve. The lesion was detected only after repeated TEE. Case Report In March 1996, a previously healthy 44-year-old man experienced a sudden onset of language difficulties. Blood pressure on admission was 134/76 mm Hg, and the pulse was regular with 66 beats per minute. Cardiac auscultation was unremarkable. He was alert and had fluent aphasia without dysarthria, paresis, or sensory signs. He had no family history of stroke. Magnetic resonance imaging, performed the following day, showed a cortical ischemic lesion in the left posterior temporal lobe. Routine blood chemistry and coagulation were normal. No source of embolus was detected by electrocardiogram or by TEE or TTE. The patient was treated with warfarin. He had six subsequent episodes of transient ischemic attacks and cerebral infarctions. In the course of his illness, TEE was again performed in June 1997 and May 1998, but no abnormalities were detected. In May 1999, the patient suddenly had difficulty in finding words. On admission, he could speak fluently but had some problems with word finding, and there was a mild impairment of comprehension. He showed some difficulty with complex calculations, reading, and writing. There was no cardiac murmur, and respiratory sounds were clear. He was afebrile, and the blood chemistry was normal. The international normalized ratio for prothrombin time was 1.5. Immunoglobulin, antinuclear antibody, complement, anticardiolipin antibody, and protein C and S activities were within normal limits. No cardiomegaly was seen on chest x-ray. The electrocardiogram was normal. Ambulatory electrocardiography showed normal sinus rhythm with premature ventricular beats. Head magnetic resonance