Yasushi Osaki

Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

BACKGROUND Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Postural Dysregulation in Systolic Blood Pressure Is Associated With Worsened Scoring on Neurobehavioral Function Tests and Leukoaraiosis in the Older Elderly Living in a Community

BACKGROUND AND PURPOSE Postural hypotension, which occurs frequently in community-living, apparently healthy elderly adults, is usually asymptomatic. However, the relation between postural changes in blood pressure and quantitative higher cerebral function or silent brain lesions remains unclear. We examined the association of exaggerated postural changes in systolic blood pressure with cognitive and quantitative neurobehavioral functions and with brain lesions on MRI in the community-dwelling older elderly. METHODS The study population consisted of 334 community-dwelling elderly adults, aged 75 years or older (mean age, 80 years). Postural changes in systolic blood pressure (SBP) were assessed using an autosphygmomanometer (BP-203 I). By the difference between the mean of two measurements of SBP at standing and at supine position (dSBP = SBP at upright-SBP at supine position), we divided the subjects into three groups: (1) 20 subjects with postural hypotension (d-SBP < or = -20 mm Hg), (2) 29 subjects with postural hypertension (dSBP > or = 20 mm Hg), and (3) 285 subjects with postural normotension (20 < dSBP < 20 mm Hg). We defined the former two groups as the postural dysregulation group. Scores in four neurobehavioral function tests (Mini-Mental State Exam. Hasegawa Dementia Scale Revised, computer-assisted visuospatial cognitive performance score, and the Up and Go Test) and activities of daily living were compared among the three groups. Brain lesions on MRI, including number of lacunes and periventricular hyperintense lesions, were compared among 15 age- and sex-matched control subjects with postural hypotension, 15 with postural hypertension, and 30 with postural normotension. RESULTS Twenty subjects (6.0%) exhibited postural hypotension and 29 (8.7%) postural hypertension. Scores in neurobehavioral functions and activities of daily living were significantly lower in the postural dysregulation group (both postural hypotension and hypertension groups) than in the postural normotension group. The postural dysregulation group exhibited significantly more advanced periventricular hyperintensities than the normotension group. CONCLUSIONS Asymptomatic community dwelling elderly individuals with postural hypotension as well as those with postural hypertension had poorer scores on neurobehavioral function tests and more advanced leukoaraiosis demonstrated on MRI than those without exaggerated postural changes in SBP.

Accuracy of clinical diagnosis of progressive supranuclear palsy

We assessed the accuracy of clinical diagnosis of progressive supranuclear palsy (PSP, Steele‐Richardson‐Olszewski disease) and the validity of existing sets of clinical diagnostic criteria for PSP (see Appendix ) using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. Diagnosis of PSP was made by 40 different physicians, and 60 cases clinically diagnosed as PSP when last assessed in life were studied. In 47 cases (78%), the diagnosis of PSP was confirmed pathologically. False‐positive diagnoses included Parkinsons disease with significant additional cortical Lewy body (n = 3) or Alzheimer (n = 1) pathology, multiple system atrophy (n = 4), and corticobasal degeneration, Picks disease, motor neurone disease, cerebrovascular disease, and a sporadic case of frontotemporal dementia and parkinsonism linked to chromosome 17 (1 case each). Most cases of PSP were diagnosed accurately by neurologists at the final assessment. Although application of National Institute of Neurological Disorders and the Society for PSP possible category marginally improved the accuracy of initial clinical diagnosis, none of the existing operational criteria could significantly improve accuracy of the final clinical diagnosis.

Do published criteria improve clinical diagnostic accuracy in multiple system atrophy

Objective: To assess the accuracy of a clinical diagnosis of multiple system atrophy (MSA) and compare it to the Quinn and Consensus criteria for MSA using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. Methods: Fifty-nine cases with a neurologic diagnosis of MSA when last assessed prior to death were studied. Results: In 51 (86%) of these cases, the diagnosis of MSA was confirmed pathologically. False positive diagnoses included PD (n = 6), progressive supranuclear palsy (n = 1), and cerebrovascular disease (n = 1). When applying either set of diagnostic criteria, a diagnosis of probable MSA gave lower sensitivity but higher positive predictive value than one of possible MSA. Application of either set of diagnostic criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by the last clinic visit. Conclusions: This study shows a high diagnostic accuracy for the clinical diagnosis of MSA by neurologists, with PD accounting for most of the false positive diagnoses. Application of either Quinn or Consensus criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by last clinic visit.

THE TIMED “UP & GO” TEST IS A USEFUL PREDICTOR OF FALLS IN COMMUNITY-DWELLING OLDER PEOPLE

ratio.3 Fihn et al. concluded that “age did not appear to be an important determinant of risk for bleeding in patients receiving warfarin, with the possible exception of age 80 years or older.” These investigators reported that life-threatening or fatal bleeding complications occurred more often among the oldest patients; the incidence of these events was 0.75 per 100 patient-years in patients younger than SO years of age and 3.38 in patients 80 years of age and older (relative risk 4.50; 95% confidence interval, 1.315.6).4 We agree with Dr. Portnoi that the decision-making process regarding the use of warfarin therapy in the management of older patients with atrial fibrillation should engage patients and, when appropriate, their families. In addition, therapeutic management with regard to warfarin therapy does not end with the initiation of treatment. Continued reevaluation of treatment appropriateness, adequate patient surveillance, and maintenance of the patient in the appropriate therapeutic range are essential. In our study, more than one-quarter of the physicians surveyed responded that they preferred a target therapeutic range with a lower INR limit less than 2 for their older patients with atrial fibrillation who are residents in nursing homes.’ More widespread use of specialized clinics to manage warfarin therapy in the long-term care setting may provide a mechanism to address some of these important issues.

A U-shaped association between home systolic blood pressure and four-year mortality in community-dwelling older men.

BACKGROUND: Several studies in older people have found a U‐shaped or J‐shaped association of blood pressure with mortality. The increased mortality associated with the lowest levels of blood pressure in older people have been explained by concurrent illnesses and frailty, but previous studies used blood pressure measured on a single occasion. Such a casual value is different from the long‐term average of blood pressure. We investigated the relation between the average level of 5‐day consecutive home blood pressure and mortality in older people while adjusting for potential confounding factors including morbidity and frailty at baseline.

Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP

The authors describe a case of clinically diagnosed young onset progressive supranuclear palsy (PSP) with symptom onset at 40 years of age and no family history of neurodegenerative disease. There was no history of falls during the first year of symptoms. Genetic analysis identified this patient as having a tau exon 10 +16 mutation (MAPT, IVS10, C-U, +16). Neuropathologic examination confirmed the genetic diagnosis of frontotemporal dementia. An age at onset younger than 50 years combined with the absence of early falls may indicate the possibility of a tau mutation in clinically diagnosed PSP.

Quality of life of old people living in the community

Vol 350 • November 22, 1997 1521 reported to be expressed specifically in the brain based on northern studies, our ability to detect necdin transcripts in the liver suggests a lower, but detectable level of expression in peripheral tissues. We further examined necdin imprinting by testing expression by RT-PCR with RNA from cultured fibroblasts derived from a normal control and three patients with PWS and three with Angelman syndrome (AS), each with a documented 15q11-q13 deletion (figure B). This analysis likewise revealed imprinted expression, with necdin mRNA detectable in normal and AS samples, but not in PWS samples. The overall level of expression in cultured fibroblast cells may be quite low, given a less robust PCR product than that seen in the liver. These results show that necdin is imprinted with paternal-specific transcription in multiple tissues, including brain, which is the predominant site of its expression, and are consistent with another report indicating imprinted expression of necdin in newborn mouse brain and human fibroblasts. Necdin was initially identified as a mRNA specific to postmitotic, differentiated neuron from embryonal carcinoma cells, and found in the mouse to be expressed only in the central nervous system by northern analysis. In mouse development, necdin is expressed abundantly during periods of neural generation and differentiation, and expression is detected throughout the brain of the adult mouse, with the highest expression in the hypothalamus and midbrain. This Imprinting analysis of the human necdin gene RT-PCR on RNA from brain and liver controls and a PWS patient with a 15q11-q13 deletion (A), and RNA from cultured fibroblast cell lines from a control, three deletion PWS patients and three deletion AS patients (B). Expression of a second gene not on chromosome 15 (LDL receptor) was used as a control for RNA quality, and –RT controls are shown for necdin, whose product is colinear with genomic DNA. Details of RNA preparation and RT-PCR can be obtained from the author. Quality of life of old people living in the community

A validation exercise on the new consensus criteria for multiple system atrophy.

The revised (new) consensus clinical diagnostic criteria for multiple system atrophy (MSA) were published in 2008. To validate these criteria, we utilized the same cohort that we reported previously, which included 59 patients with a clinical diagnosis of MSA that was confirmed neuropathologically in 51 of them at the Queen Square Brain Bank for Neurological Disorders. At the first clinic visit, sensitivity with new consensus possible category was higher, and PPV marginally higher, than for clinical diagnosis and old consensus possible category. New consensus probable category showed marginally higher sensitivity than, and the same PPV as, old consensus probable category. At the last clinic visit, new consensus possible category had exactly the same sensitivity and only marginally higher PPV compared with old consensus possible category. New consensus probable category showed the same sensitivity and PPV as old consensus probable category. Our data indicate that in this case material the new consensus criteria for possible MSA could improve diagnostic accuracy at first neurological evaluation compared with the old consensus criteria. Prospective clinicopathological validation studies of the new consensus criteria, particularly incorporating in vivo structural and functional imaging results, are required to extend the current findings.

Variants associated with Gaucher disease in multiple system atrophy

Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.