Arch Neurol
· 2012 Oct · PMID 22869155
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OBJECTIVE: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-lengt...OBJECTIVE: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN: Conditional logistic regression models and survival analysis. SETTING: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. PARTICIPANTS: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. MAIN OUTCOME MEASURES: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. RESULTS: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects. CONCLUSIONS: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
Arch Neurol
· 2012 Nov · PMID 22869065
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BACKGROUND: Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pat...BACKGROUND: Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI). OBJECTIVE: To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI. DESIGN: Randomized,double-blind,placebo-controlled trial. SETTING: Clinical Research Center, University of Washington School of Medicine in Seattle. PARTICIPANTS: A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study. INTERVENTION: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc),a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout(week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition. MAIN OUTCOME MEASURES: Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference,Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test,and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample. RESULTS: The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults.The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory(P=.08). Treatment with GHRH increased insulin like growth factor 1 levels by 117 %(P.001), which remained within the physiological range, and reduced percent body fat by 7.4%(P.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35%in adults with MCI (P.001) but not in healthy adults. Adverse events were mild and were reported by 68%of GHRH treated adults and 36% of those who received placebo. CONCLUSIONS: Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.” TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00257712
Siepmann T, Gibbons CH, Illigens BM
… +3 more, Lafo JA, Brown CM, Freeman R
Arch Neurol
· 2012 Nov · PMID 22868966
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BACKGROUND: Cutaneous autonomic function can be quantified by the assessment of sudomotor and vasomotor responses. Although piloerector muscles are innervated by the sympathetic nervous system, there are at present no me...BACKGROUND: Cutaneous autonomic function can be quantified by the assessment of sudomotor and vasomotor responses. Although piloerector muscles are innervated by the sympathetic nervous system, there are at present no methods to quantify pilomotor function. OBJECTIVE: To quantify piloerection using phenylephrine hydrochloride in humans. DESIGN: Pilot study. SETTING: Hospital-based study. PARTICIPANTS: Twenty-two healthy volunteers (18 males,4 females) aged 24 to 48 years participated in 6 studies. INTERVENTIONS: Piloerection was stimulated by iontophoresis of 1% phenylephrine. Silicone impressions of piloerection were quantified by number and area. The direct and indirect responses to phenylephrine iontophoresis were compared on both forearms after pre treatment to topical and subcutaneous lidocaine and iontophoresis of normal saline. RESULTS: Iontophoresis of phenylephrine induced piloerection in both the direct and axon reflex–mediated regions, with similar responses in both arms. Topical lidocaine blocked axon reflex–mediated piloerection post-iontophoresis (mean [SD], 66.6 [19.2] for control impressions vs 7.2 [4.3] for lidocaine impressions;P.001). Subcutaneous lidocaine completely blocked piloerection.The area of axon reflex–mediated piloerection was also attenuated in the lidocaine-treated region postiontophoresis (mean [SD], 46.2 [16.1]cm2 vs 7.2 [3.9]cm2; P.001). Piloerection was delayed in the axon reflex region compared with the direct region. Normal saline did not cause piloerection. CONCLUSIONS: Phenylephrine provoked piloerection directly and indirectly through an axon reflex–mediated response that is attenuated by lidocaine. Piloerection is not stimulated by iontophoresis of normal saline alone.The quantitative pilomotor axon reflex test (QPART) may complement other measures of cutaneous autonomic nerve fiber function.
OBJECTIVE: To investigate the white matter (WM) microstructure using diffusion tensor imaging in patients with vascular parkinsonism (VP) and specific fiber tract involvement with respect to clinical severity. DESIGN: Di...OBJECTIVE: To investigate the white matter (WM) microstructure using diffusion tensor imaging in patients with vascular parkinsonism (VP) and specific fiber tract involvement with respect to clinical severity. DESIGN: Diffusion measures (fractional anisotropy and mean diffusivity) were calculated from diffusion tensor images of patients with VP and control subjects. We performed global-, voxel-, and tract-based analyses to compare WM microstructural properties between groups.We further correlated findings with Unified Parkinson's Disease Rating Scale scores and modified postural instability gait difficulty (PIGD) scores to identify most relevant tract involvement. SETTING: Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. PARTICIPANTS: Twelve patients with VP and 12 age-matched healthy controls without VP. RESULTS: In the VP group, the left thalamus, right frontal subcortical WM, and left anterior limb of the internal capsule had a significantly lower regional fractional anisotropy compared with the control group. The bilateral frontal subcortical WM showed a significantly higher regional mean diffusivity. The diffusion metrics in these regions were significantly correlated with the modified PIGD score part III, and the sum of modified PIGD scores parts II and III. Tract-based analysis showed a group difference in mean fractional anisotropy and mean diffusivity for multiple fiber bundles, but only diffusion measures of fiber tracts from the bilateral frontal lobe that pass through the anterior limb of internal capsule and tracts of the genu of the corpus callosum showed significant correlation with these scores. CONCLUSIONS: Disruption of the microstructural organization of frontal lobe WM is associated with the severity of VP. Our findings are in accordance with the frontal lobe disconnection hypothesis for gait problems and reinforce the paradigm that the involvement of fibers related to the prefrontal cortex is crucial for the core features of VP.
Arch Neurol
· 2012 Oct · PMID 22825369
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OBJECTIVE: To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD). DESIGN: Autopsied patients were analyzed from February 24, 20...OBJECTIVE: To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD). DESIGN: Autopsied patients were analyzed from February 24, 2005, through July 25, 2010, to determine the distribution and severity of individual pathologic protein deposits (α-synuclein, Aβ, and tau) using routine protocols for histologic and immunohistochemical analysis and established neuropathologic staging criteria. Clinical data were extracted from an electronic medical record system used for all patients with PD. PATIENTS: Thirty-two consecutive autopsied patients treated at the Washington University Movement Disorders Center who had neuropathologic confirmation of PD and a history of dementia, regardless of the timing of the onset of dementia with respect to motor symptoms. RESULTS: Three pathologic subgroups of dementia associated with PD were identified: (1) predominant synucleinopathy (Braak Lewy body stages 5-6) (12 [38%]), (2) predominant synucleinopathy with Aβ deposition (Braak amyloid stages B-C) but minimal or no cortical tau deposition (19 [59%]), and (3) synucleinopathy and Aβ deposition with at least moderate neocortical tauopathy (Braak tau stages 5-6; 1 [3%]). Kaplan-Meier and Cox regression analyses revealed that patients with synucleinopathy plus Aβ deposition had significantly shorter survival (years from PD onset until death and years from dementia onset until death) than patients with synucleinopathy only. CONCLUSIONS: Dementia associated with PD has 2 major pathologic subgroups: neocortical synucleinopathy and neocortical synucleinopathy with Aβ deposition. Alzheimer disease with neocortical Aβ and tau deposition does not commonly cause dementia with PD. Furthermore, accumulation of Aβ is associated with lower survival rates in PD patients with dementia. Additional studies are needed to prospectively determine the association between α-synuclein and Aβ accumulation and the role of Aβ in the development and progression of cognitive impairment in PD.
Honig LS, Kang MS, Schupf N
… +2 more, Lee JH, Mayeux R
Arch Neurol
· 2012 Oct · PMID 22825311
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BACKGROUND: Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. OBJECTIVE: To determine wh...BACKGROUND: Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. OBJECTIVE: To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality. DESIGN: We studied available stored leukocyte DNA from a community-based study of aging using realtime polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence. SETTING: A multiethnic community-based study of aging and dementia. PARTICIPANTS: One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia. RESULTS: The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P.001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P=.05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only. CONCLUSION: Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging.
Wagner SL, Tanzi RE, Mobley WC
… +1 more, Galasko D
Arch Neurol
· 2012 Oct · PMID 22801784
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Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the...Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.
Feng X, Han D, Kilaru BK
… +3 more, Franek BS, Niewold TB, Reder AT
Arch Neurol
· 2012 Oct · PMID 22801747
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OBJECTIVE: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). DESIGN: Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononucle...OBJECTIVE: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). DESIGN: Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. PATIENTS: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. INTERVENTIONS: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. RESULTS: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P < .001), interferon regulatory factor 1 protein by 30% (P=.006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium- dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. CONCLUSIONS: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.
Doecke JD, Laws SM, Faux NG
… +27 more, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL, Martins RN, Alzheimer's Disease Neuroimaging Initiative, Australian Imaging Biomarker and Lifestyle Research Group
Arch Neurol
· 2012 Oct · PMID 22801742
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OBJECTIVE: To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). DESIGN: Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. SETTING: G...OBJECTIVE: To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). DESIGN: Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. SETTING: General community-based, prospective, longitudinal study of aging. PARTICIPANTS: A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. RESULTS: A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, β(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve. CONCLUSIONS: This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.
Soares HD, Potter WZ, Pickering E
… +16 more, Kuhn M, Immermann FW, Shera DM, Ferm M, Dean RA, Simon AJ, Swenson F, Siuciak JA, Kaplow J, Thambisetty M, Zagouras P, Koroshetz WJ, Wan HI, Trojanowski JQ, Shaw LM, Biomarkers Consortium Alzheimer's Disease Plasma Proteomics Project
Arch Neurol
· 2012 Oct · PMID 22801723
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BACKGROUND: A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment. OBJECTIVE: To apply a multiplex immunoassay panel to identify plasma...BACKGROUND: A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment. OBJECTIVE: To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer's Disease Neuroimaging Initiative cohort. DESIGN: Cohort study. SETTING: The Biomarkers Consortium Alzheimer's Disease Plasma Proteomics Project. PARTICIPANTS: Plasma samples at baseline and at 1 year were analyzed from 396 (345 at 1 year) patients with mild cognitive impairment, 112 (97 at 1 year) patients with AD, and 58 (54 at 1 year) healthy control subjects. MAIN OUTCOME MEASURES: Multivariate and univariate statistical analyses were used to examine differences across diagnostic groups and relative to the apolipoprotein E (ApoE) genotype. RESULTS: Increased levels of eotaxin 3, pancreatic polypeptide, and N-terminal protein B-type brain natriuretic peptide were observed in patients, confirming similar changes reported in cerebrospinal fluid samples of patients with AD and MCI. Increases in tenascin C levels and decreases in IgM and ApoE levels were also observed. All participants with Apo ε3/ε4 or ε4/ε4 alleles showed a distinct biochemical profile characterized by low C-reactive protein and ApoE levels and by high cortisol, interleukin 13, apolipoprotein B, and gamma interferon levels. The use of plasma biomarkers improved specificity in differentiating patients with AD from controls, and ApoE plasma levels were lowest in patients whose mild cognitive impairment had progressed to dementia. CONCLUSIONS: Plasma biomarker results confirm cerebrospinal fluid studies reporting increased levels of pancreatic polypeptide and N-terminal protein B-type brain natriuretic peptide in patients with AD and mild cognitive impairment. Incorporation of plasma biomarkers yielded high sensitivity with improved specificity, supporting their usefulness as a screening tool. The ApoE genotype was associated with a unique biochemical profile irrespective of diagnosis, highlighting the importance of genotype on blood protein profiles.
Kumar KR, Weissbach A, Heldmann M
… +13 more, Kasten M, Tunc S, Sue CM, Svetel M, Kostić VS, Segura-Aguilar J, Ramirez A, Simon DK, Vieregge P, Münte TF, Hagenah J, Klein C, Lohmann K
OBJECTIVE: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample. DESIGN: Genetic analysis by DNA sequencing an...OBJECTIVE: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample. DESIGN: Genetic analysis by DNA sequencing and detailed clinical and neuropsychiatric assessment as well as neuroimaging in mutation carriers. SETTING: Tertiary referral centers in Germany, Serbia, Chile, and the United States. PATIENTS: One thousand seven hundred seventy-four patients with PD. MAIN OUTCOME MEASURE: Frequency of the p.D620N mutation. RESULTS: A single mutation carrier was identified. The mutation carrier was a 60-year-old German man who had tremor-dominant PD since the age of 45 years. Longitudinal follow-up over 13 years revealed a disease progression from Hoehn and Yahr stage 1 to 3. There was evidence of mild cognitive impairment on the Montreal Cognitive Assessment. No abnormalities were observed by multimodal neuroimaging. He had a family history consistent with autosomal dominant inheritance. An affected paternal aunt and 3 reportedly unaffected siblings were also found to be mutation carriers. CONCLUSION: VPS35 mutations are a rare cause of PD in different populations. The clinical phenotype may be indistinguishable from idiopathic PD with the possible exception of an earlier age at onset. Genetic analysis of the extended family revealed incomplete penetrance of the p.D620N mutation.
Gutiérrez Ríos P, Kalra AA, Wilson JD
… +5 more, Tanji K, Akman HO, Area Gómez E, Schon EA, DiMauro S
Arch Neurol
· 2012 May · PMID 22782513
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OBJECTIVES: To describe the first American patient with a congenital muscle dystrophy characterized by the presence in muscle of gigantic mitochondria displaced to the periphery of the fibers and to stress the potential...OBJECTIVES: To describe the first American patient with a congenital muscle dystrophy characterized by the presence in muscle of gigantic mitochondria displaced to the periphery of the fibers and to stress the potential origin and effects of the mitochondrial changes. DESIGN: Case report and documentation of a novel mutation in the gene encoding choline kinase beta (CHKB). SETTING: Collaboration between 2 tertiary care academic institutions. PATIENT: A 2-year-old African American boy with weakness and psychomotor delay. INTERVENTIONS: Detailed clinical and laboratory studies, including muscle biopsy, biochemical analysis of the mitochondrial respiratory chain, and sequencing of the CHKB gene. MAIN OUTCOME MEASURES: Definition of unique mitochondrial changes in muscle. RESULTS: This patient had the same clinical and laboratory features reported in the first cohort of patients, but he harbored a novel CHKB mutation and had isolated cytochrome c oxidase deficiency in muscle. CONCLUSIONS: Besides confirming the phenotype of CHKB mutations, we propose that this disorder affects the mitochondria-associated membrane and the impaired phospholipid metabolism in the mitochondria-associated membrane causes both the abnormal size and displacement of muscle mitochondria.
Chen YZ, Matsushita MM, Robertson P
… +8 more, Rieder M, Girirajan S, Antonacci F, Lipe H, Eichler EE, Nickerson DA, Bird TD, Raskind WH
Arch Neurol
· 2012 May · PMID 22782511
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BACKGROUND: Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21...BACKGROUND: Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21-3q21. The 72.5-Mb linkage region was too large for traditional positional mutation identification. OBJECTIVE: To identify the gene responsible for FDFM by exome resequencing of a single affected individual. PARTICIPANTS: We performed whole exome sequencing in 1 affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or the 1000 Genomes Project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in 3 generations. MAIN OUTCOME MEASURES: Unique DNA variants in the linkage region that co-segregate with FDFM. RESULTS: The exome contained 23 428 single-nucleotide variants, of which 9391 were missense, nonsense, or splice site alterations. The critical region contained 323 variants, 5 of which were not present in 1 of the sequence databases. Adenylyl cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control white exomes. This residue is highly conserved, and the change is nonconservative and predicted to be damaging. CONCLUSIONS: ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence combined with linkage information to identify causative genes for rare autosomal dominant mendelian diseases.
Arch Neurol
· 2012 May · PMID 22782510
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OBJECTIVE: To determine whether magnetic resonance imaging measurements observed in the Alzheimer Disease Neuroimaging Initiative (ADNI) convenience sample differ from those observed in the Mayo Clinic Study of Aging (MC...OBJECTIVE: To determine whether magnetic resonance imaging measurements observed in the Alzheimer Disease Neuroimaging Initiative (ADNI) convenience sample differ from those observed in the Mayo Clinic Study of Aging (MCSA) population-based sample. DESIGN: Comparison of 2 samples. SETTING: Fifty-nine recruiting sites for the ADNI in the United States and Canada and the MCSA, a population-based cohort in Olmsted County, Minnesota. PATIENTS: Cognitively normal subjects and amnestic subjects with mild cognitive impairment were selected from the ADNI convenience cohort and MCSA population-based cohort. A simple random sample of subjects from both cohorts in the same age range was selected, and a second sample applied matching for age, sex, educational level, apolipoprotein E genotype, and Mini-Mental State Examination score. MAIN OUTCOME MEASURES: Baseline hippocampal volumes and annual percentage of decline in hippocampal volume. RESULTS: In the population-based sample, MCSA subjects were older, had less education, performed worse on the Mini-Mental State Examination, and had a family history of Alzheimer disease less often than did ADNI subjects. Baseline hippocampal volumes were larger in ADNI compared with MCSA cognitively normal subjects in the random sample, although no differences were observed after matching. Rates of decline in hippocampal volume were greater in the ADNI compared with the MCSA for cognitively normal subjects and those with amnestic mild cognitive impairment, even after matching. CONCLUSIONS: Rates of decline in hippocampal volume suggest that ADNI subjects have a more aggressive brain pathologic process than MCSA subjects and hence may not be representative of the general population. These findings have implications for treatment trials that use ADNI-like recruitment mechanisms and for studies validating new diagnostic criteria for Alzheimer disease in its various stages.