Dorothée G, Bottlaender M, Moukari E
… +10 more, de Souza LC, Maroy R, Corlier F, Colliot O, Chupin M, Lamari F, Lehéricy S, Dubois B, Sarazin M, Aucouturier P
OBJECTIVE: To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy...OBJECTIVE: To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS: The class and subclass levels of serum anti-Aβ antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Aβ40/42 and any cross-reacting antigen. RESULTS: Anti-Aβ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Aβ42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS: Serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants.
Arch Neurol
· 2012 Sep · PMID 22710333
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OBJECTIVES: To determine if prevalent and incident diabetes mellitus (DM) increase risk of cognitive decline and if, among elderly adults with DM, poor glucose control is related to worse cognitive performance. DESIGN Pr...OBJECTIVES: To determine if prevalent and incident diabetes mellitus (DM) increase risk of cognitive decline and if, among elderly adults with DM, poor glucose control is related to worse cognitive performance. DESIGN Prospective cohort study. SETTING: Health, Aging, and Body Composition Study at 2 community clinics. PARTICIPANTS: A total of 3069 elderly adults (mean age, 74.2 years; 42% black; 52% female). MAIN OUTCOME MEASURES: Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. Diabetes mellitus status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c level was measured at years 1 (baseline), 4, 6, and 10 from fasting whole blood. RESULTS: At baseline, 717 participants (23.4%) had prevalent DM and 2352 (76.6%) were without DM, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs 90.9; DSST: 32.5 vs 36.3, respectively; t = 6.09; P = .001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: -6.0- vs -4.5-point decline; t = 2.66; P = .008; DSST: -7.9- vs -5.7-point decline; t = 3.69; P = .001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other 2 groups but were not statistically different from the group without DM. Multivariate adjustment for demographics and medical comorbidities produced similar results. Among participants with prevalent DM, glycosylated hemoglobin A1c level was associated with lower average mean cognitive scores (3MS: F = 8.2; P for overall = .003; DSST: F = 3.4; P for overall = .04), even after multivariate adjustment. CONCLUSION: Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests that severity of DM may contribute to accelerated cognitive aging.
Arch Neurol
· 2012 Jun · PMID 22689192
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OBJECTIVE: To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels. DESIGN: Cross-sectional comparison of plasma levels of 77 proteins measured using multipl...OBJECTIVE: To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels. DESIGN: Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays. SETTING: A tertiary referral dementia research center. PARTICIPANTS: Thirty-three persons from families harboring PSEN1 or APP mutations, aged 19 to 59 years. MAIN OUTCOME MEASURES: Protein levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs) and among APOE genotype groups, using multiple linear regression models. RESULTS: Twenty-one participants were FAD MCs and 12 were NCs. Six had the APOE ε2/3, 6 had the ε3/4, and 21 had the ε3/3 genotype. Levels of 17 proteins differed among APOE genotype groups, and there were significant interactions between age and APOE genotype for 12 proteins. Plasma levels of apolipoprotein E and superoxide dismutase 1 were highest in the ε2 carriers, lowest in ε4 carriers, and intermediate in the ε3 carriers. Levels of multiple interleukins showed the opposite pattern and, among the ε4 carriers, demonstrated significant negative correlations with age. Although there were no significant differences between FAD MCs and NCs, there were interactions between mutation status and APOE genotype for 13 proteins. CONCLUSIONS: We found different patterns of inflammatory markers in young and middle-aged persons among APOE genotype groups. The APOE ε4 carriers had the lowest levels of apolipoprotein E. Young ε4 carriers have increased inflammatory markers that diminish with age. We demonstrated altered inflammatory responses in young and middle adulthood in ε4 carriers that may relate to AD risk later in life.
Arch Neurol
· 2012 Jun · PMID 22689191
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As epidemiologic studies continue to note a striking increase in rates of autism spectrum disorder (ASD) diagnosis around the world, the lack of identified causative agents in most cases remains a major hindrance to the...As epidemiologic studies continue to note a striking increase in rates of autism spectrum disorder (ASD) diagnosis around the world, the lack of identified causative agents in most cases remains a major hindrance to the development of treatment and prevention strategies. Published observations of immune system abnormalities in ASD have increased recently, with several groups identifying fetal protein reactive IgG antibodies in plasma from mothers of children with autism. Furthermore, other gestational immune parameters, including maternal infection and dysregulated cytokine signaling, have been found to be associated with ASD in some cases. While detailed pathogenic mechanisms remain to be determined, the hypothesis that some cases of ASD may be influenced, or even caused, by maternal fetal brain-reactive antibodies or other in utero immune-related exposures is an active area of investigation. This article reviews the current literature in this area and proposes several directions for future research.
BACKGROUND: Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously "seronegative" (SN) generalized myasthenia gravis (GMG), but their presence in p...BACKGROUND: Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously "seronegative" (SN) generalized myasthenia gravis (GMG), but their presence in patients with ocular MG (OMG) and their pathogenicity in vivo are unknown. OBJECTIVE: To test the presence of clustered AChR-Abs and their pathophysiologic properties in patients with SNMG. DESIGN: Screening and diagnostic tests. SETTING: Regional specialist myasthenia center and clinical laboratory. PATIENTS: Serum samples from 16 patients with SN and OMG were tested for binding to clustered AChRs. Results from 28 further SN patients (14 OMG) were correlated with their single fiber electromyography values. MAIN OUTCOME MEASURES: Presence, complement-fixation capacity, correlation with neurophysiologic changes, and in vivo pathogenicity of clustered AChR-Abs. RESULTS: Up to 50% of patients with previous SN-OMG had complement-fixing IgG1 clustered AChR-Abs. IgG binding (n = 28) and complement deposition (n = 21) each correlated with the mean consecutive difference (jitter) on single-fiber electromyography. Injection of purified IgG from 2 patients with clustered AChR-Abs into wild-type or complement regulator-deficient mice reduced miniature end plate potential amplitudes to an extent similar to that found with AChR-Abs, and complement was deposited at the end plates. A trend was noted toward an increase in the number of packets of acetylcholine released (quantal content). CONCLUSIONS: A proportion of patients with SN-GMG or OMG have clustered AChR-Abs that correlate with their electrophysiologic features. Clustered AChR-Abs can passively transfer disease to mice, demonstrating their pathogenicity, and the mechanisms seem similar to those of patients with typical AChR-Abs.
Savica R, Adeli A, Vemuri P
… +9 more, Knopman DS, Dejesus-Hernandez M, Rademakers R, Fields JA, Whitwell J, Jack CR, Lowe V, Petersen RC, Boeve BF
Arch Neurol
· 2012 Sep · PMID 22637471
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BACKGROUND: The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophi...BACKGROUND: The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum. OBJECTIVE: To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. DESIGN: Clinical series. SETTING: Tertiary care academic medical center. PATIENTS The members of a family affected by the mutation with features of FTD and/or ALS. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, and neuroimaging assessments. RESULTS: All 3 examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and 1 had ALS. Magnetic resonance imaging showed symmetric bilateral frontal, temporal, insular, and cingulate atrophy. CONCLUSIONS: This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuroimaging-neuropathologic correlations.
BACKGROUND: In the Kii peninsula of Japan, high prevalences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex have been reported. There are 2 major foci with a high prevalence, which include the so...BACKGROUND: In the Kii peninsula of Japan, high prevalences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex have been reported. There are 2 major foci with a high prevalence, which include the southernmost region neighboring the Koza River (Kozagawa and Kushimoto towns in Wakayama prefecture) and the Hohara district (Mie prefecture). OBJECTIVE: To delineate the molecular basis of ALS in the Kii peninsula of Japan, we analyzed hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene, which has recently been identified as a frequent cause of ALS and frontotemporal dementia in the white population. DESIGN: Case series. SETTING: University hospitals. PATIENTS: Twenty-one patients (1 familial patient and 20 sporadic patients) with ALS from Wakayama prefecture, and 16 patients with ALS and 16 patients with parkinsonism-dementia complex originating from Mie prefecture surveyed in 1994 through 2011 were enrolled in the study. In addition, 40 probands with familial ALS and 217 sporadic patients with ALS recruited from other areas of Japan were also enrolled in this study. MAIN OUTCOME MEASURES: After screening by repeat-primed polymerase chain reaction, Southern blot hybridization analysis was performed to confirm the expanded alleles. RESULTS: We identified 3 patients with ALS (20%) with the repeat expansion in 1 of the 2 disease foci. The proportion is significantly higher than those in other regions in Japan. Detailed haplotype analyses revealed an extended shared haplotype in the 3 patients with ALS, suggesting a founder effect. CONCLUSIONS: Our findings indicate that the repeat expansion partly accounts for the high prevalence of ALS in the Kii peninsula.
BACKGROUND: Epileptic seizures are often associated with changes in cardiac autonomic function. Yet atrial fibrillation (AFib) or atrial flutter (AFlu) following epileptic seizures has only rarely been reported in the pa...BACKGROUND: Epileptic seizures are often associated with changes in cardiac autonomic function. Yet atrial fibrillation (AFib) or atrial flutter (AFlu) following epileptic seizures has only rarely been reported in the past. OBJECTIVES: To describe and characterize patients who experienced lone AFib or AFlu as a consequence of epileptic seizures. DESIGN: Case reports. SETTING: University teaching hospital. PATIENTS: We describe 4 patients who developed transient AFib following epileptic seizures and 1 patient who developed transient AFlu following epileptic seizures. RESULTS: In all patients, AFib and AFlu followed a generalized tonic-clonic seizure. The arrhythmia usually lasted a few hours and converted spontaneously to a normal sinus rhythm. In 3 patients, AFib or AFlu developed during the first seizure they experienced, and none of the patients developed drug-resistant epilepsy. Moreover, none of the patients had a known cardiac disease, yet, in 2 patients, the cardiological workup demonstrated mild abnormalities on the cardiac stress test. CONCLUSIONS: Atrial fibrillation is the most common type of arrhythmia, with an estimated prevalence of 1%. Despite the fact that AFib can cause syncope, it is important to consider the possibility of AFib developing secondary to an epileptic seizure in cases of AFib and transient loss of consciousness.
OBJECTIVE: To determine whether vascular endothelial growth factor (VEGF) levels are associated with the presence of cerebral microbleeds (CMBs) in patients after acute ischemic stroke. DESIGN: A cross-sectional study th...OBJECTIVE: To determine whether vascular endothelial growth factor (VEGF) levels are associated with the presence of cerebral microbleeds (CMBs) in patients after acute ischemic stroke. DESIGN: A cross-sectional study that used blood samples obtained within 24 hours of symptom onset from patients who experienced acute stroke to measure VEGF levels by enzyme immunoassay. A validated CMB rating scale was used to analyze acutely acquired magnetic resonance images, with the rater blind to clinical details and VEGF levels. SETTING: Accident and Emergency Department at University College Hospital, London, England. PATIENTS: Twenty patients who experienced acute ischemic stroke. MAIN OUTCOME MEASURES: Presence of CMBs and serum level of VEGF. RESULTS: Five of the 20 patients with acute ischemic stroke (25%) had CMBs. The median VEGF level in the CMB group was significantly higher than that in the group without CMBs (P = .003). CONCLUSION: An increase in vascular permeability secondary to a raised VEGF level may have a role in the genesis of CMBs in patients with acute ischemic stroke.
Dementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies i...Dementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies imply a genetic and mechanistic overlap with Alzheimer disease, Parkinson disease with dementia, and Parkinson disease. In this review, we provide a comprehensive overview of the current studies on dementia with Lewy bodies heritability, genetic etiology, and genetic heterogeneity. We conclude with a critical discussion of the missing heritability in dementia with Lewy bodies and encourage scientists to further explore the underlying mechanisms of this disease.
Orange D, Frank M, Tian S
… +7 more, Dousmanis A, Marmur R, Buckley N, Parveen S, Graber JJ, Blachère N, Darnell RB
Arch Neurol
· 2012 Sep · PMID 22566506
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BACKGROUND Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. OBJECTIVE To evaluate the short-term u...BACKGROUND Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. OBJECTIVE To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted. DESIGN Retrospective single-center case series of patients with PND treated with tacrolimus. SETTING The Rockefeller University Hospital, a research hospital in New York, New York. PATIENTS Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 autoantibodies were enrolled. Patients were referred from Memorial Sloan Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events. INTERVENTIONS Patients were treated with tacrolimus, 0.15-0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone, tapered off during 1 to 4 weeks. MAIN OUTCOME MEASURES The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described. RESULTS Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus. CONCLUSIONS A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378326.
BACKGROUND: The importance of developing unique, neural circuitry-based treatments for the cognitive and neuropsychiatric symptoms of Alzheimer disease (AD) was the impetus for a phase I study of deep brain stimulation (...BACKGROUND: The importance of developing unique, neural circuitry-based treatments for the cognitive and neuropsychiatric symptoms of Alzheimer disease (AD) was the impetus for a phase I study of deep brain stimulation (DBS) in patients with AD that targeted the fornix. OBJECTIVE: To test the hypotheses that DBS would increase cerebral glucose metabolism in cortical and hippocampal circuits and that increased metabolism would be correlated with better clinical outcomes. DESIGN: Open-label trial. SETTING: Academic medical center. PATIENTS: A total of 5 patients with mild, probable AD (1 woman and 4 men, with a mean [SD] age of 62.6 [4.2] years). INTERVENTION: Deep brain stimulation of the fornix. MAIN OUTCOME MEASURES: All patients underwent clinical follow-up and high-resolution positron emission tomography studies of cerebral glucose metabolism after 1 year of DBS. RESULTS: Functional connectivity analyses revealed that 1 year of DBS increased cerebral glucose metabolism in 2 orthogonal networks: a frontal-temporal-parietal-striatal-thalamic network and a frontal-temporal-parietal-occipital-hippocampal network. In similar cortical regions, higher baseline metabolism prior to DBS and increased metabolism after 1 year of DBS were correlated with better outcomes in global cognition, memory, and quality of life. CONCLUSIONS: Increased connectivity after 1 year of DBS is observed, which is in contrast to the decreased connectivity observed over the course of AD. The persistent cortical metabolic increases after 1 year of DBS were associated with better clinical outcomes in this patient sample and are greater in magnitude and more extensive in the effects on cortical circuitry compared with the effects reported for pharmacotherapy over 1 year in AD.