Objectives  To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.

Design  Association study of AD and CLU, PICALM, CR1, and APOE genotypes.

Setting  Academic research institutions in the United States, Canada, and Israel.

Participants  Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals.

Results  Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE 4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE 4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE 4, and an interaction term showed significant interaction between presence or absence of APOE 4 and PICALM.

Conclusions  We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE 4–positive subjects. Thus, APOE and PICALM synergistically interact.

Objective  To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD).

Design  Postmortem observational study.

Setting  University Department of Clinical Neuroscience, Institute of Neurology, University College London.

Subjects  Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains.

Main Outcome Measure  Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of -synuclein, degradation pathways for this protein were studied in a dopaminergic cell line.

Results  The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of -synuclein.

Conclusions  These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation, and suggest that this pathway may be a suitable therapeutic target in PD.

Minocycline is a clinically available antibiotic and anti-inflammatory drug that also demonstrates neuroprotective properties in a variety of experimental models of neurological diseases. There have thus far been more than 300 publications on minocycline neuroprotection including a growing number of human studies. Our objective is to critically review the biological basis and translational potential of this action of minocycline on the nervous system.

Objective  To measure longitudinal use of stroke prevention medications following stroke hospital discharge. We hypothesized that a combination of patient-, provider-, and system-level factors influence medication-taking behavior.

Design  Observational cohort design.

Setting  One hundred six US hospitals participating in the American Heart Association Get With The Guidelines–Stroke program.

Patients  Two thousand eight hundred eighty-eight patients 18 years or older admitted with ischemic stroke or transient ischemic attack.

Main Outcome Measure  Regimen persistence, including use of antiplatelet therapies, warfarin, antihypertensive therapies, lipid-lowering therapies, or diabetes medications, from discharge to 3 months. Reasons for nonpersistence were also ascertained.

Results  Two thousand five hundred ninety-eight patients (90.0%) were eligible for analysis. At 3 months, 75.5% of subjects continued taking all secondary prevention medications prescribed at discharge. Persistence at 3 months was associated with decreasing number of medication classes prescribed, increasing age, medical history, less severe stroke disability, having insurance, working status, understanding why medications are prescribed and how to refill them, increased quality of life, financial hardship, geographic region, and hospital size.

Conclusions  One-quarter of stroke patients reported discontinuing 1 or more of their prescribed regimen of secondary prevention medications within 3 months of hospitalization for an acute stroke. Several modifiable factors associated with regimen persistence were identified and could be targets for improving long-term secondary stroke prevention.

Objectives  To determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia.

Design  Longitudinal study including 3 visits during approximately 41/2 years (2000-2006).

Setting  Northern Manhattan community.

Participants  Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aβ measurements and were dementia free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD.

Main Outcome Measures  General estimating equations tested the association between plasma Aβ (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices).

Results  High baseline plasma Aβ42 (P = .01) and Aβ40 (P = .01) and decreasing/relatively stable Aβ42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (P = .01) and decreasing/relatively stable plasma Aβ42 (P = .01) were associated with faster cognitive decline, primarily in memory.

Conclusions  The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.

Objectives  To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.

Design  Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging–based morphometric analysis.

Setting  Inpatient traumatic brain injury unit.

Patients or Other Participants  Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.

Main Outcome Measure  Changes in global and regional brain volumes between initial and follow-up magnetic resonance imaging were used to assess the spatial distribution of posttraumatic volume loss. The Glasgow Outcome Scale–Extended score was the primary measure of functional outcome.

Results  Patients underwent substantial global atrophy with mean whole-brain parenchymal volume loss of 4.5% (95% confidence interval, 2.7%-6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole-brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.

Conclusion  Traumatic axonal injury leads to substantial posttraumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration–approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.

Objective  To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis.

Design  Case report.

Setting  University hospital.

Patient  A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions.

Interventions  Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids.

Results  After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML.

Conclusions  In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Objectives  To establish whether early electroencephalography (EEG) or later sleep-deprived EEG (SD-EEG) has a higher yield of epileptiform and background abnormalities in children with new-onset seizures, and to use EEG results to assist in diagnosis of electroclinical epilepsy syndromes at presentation.

Design  Prospective analysis blinded to EEG protocol and epilepsy diagnosis.

Setting  Regional service capturing a pediatric population of 121 000.

Patients  Consecutive untreated children aged 2 to 16 years presenting to emergency departments with new-onset seizures (excluding myoclonic and absence seizures).

Intervention  Each child had 2 EEG protocols: an early EEG study (within 24 hours following a seizure) and an SD-EEG study (48 hours to 4 weeks following a seizure). Epilepsy diagnosis was made independently by 2 pediatric epileptologists.

Main Outcome Measures  Rate of epileptiform abnormalities and slowing in the 2 EEG studies. The secondary outcome measure was diagnosis of epilepsy syndrome where possible.

Results  Of 92 children studied, 50 (54%) had a single seizure; 42 (46%) had 2 or more seizures at presentation. Seizures were focal in 61 children (66%) and generalized in 19 (21%). Epileptiform discharges occurred in 56 SD-EEGs (61%) and 52 early EEGs (57%) (P = .27). Background slowing occurred in 26 SD-EEGs (28%) and 42 early EEGs (46%) (P < .001). Parents preferred early EEG (65 parents [71%]) to later SD-EEG (14 parents [15%]) because of availability of earlier results and epilepsy diagnosis. Forty-two of 92 children (46%) were diagnosed with a specific electroclinical syndrome.

Conclusions  Early EEG and SD-EEG studies have a similar yield of epileptiform abnormalities. Background abnormalities are more frequent in early EEGs. The EEG results at presentation in new-onset seizures support epilepsy diagnosis, with electroclinical syndromes diagnosed in almost 50% of children.

Objective  To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status.

Design  Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data.

Setting  The intramuscular interferon beta-1a pivotal trial was a double-blind, placebo-controlled phase 3 study.

Participants  Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postrandomization.

Intervention  Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial.

Main Outcome Measures  Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years. A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up.

Results  Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not. Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit, 8 years after randomization. Other independent predictors were treatment arm assignment and baseline EDSS score.

Conclusion  In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinically significant disability 8 years after randomization into the clinical trial.

Natalizumab (Tysabri) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, 3 patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later reapproved and its use restricted to monotherapy in patients with relapsing forms of MS. Since reapproval in 2006, additional cases of PML were reported in patients with MS receiving natalizumab monotherapy. Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease-modifying or immunosuppressive agents. In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment.

We conducted a systematic review of all studies of status epilepticus (SE) with more than 30 patients published between January 1, 1990, and December 31, 2008, to determine the frequencies of the common underlying causes and the extent to which the underlying causes affect the prognosis of an episode of SE. The frequencies of underlying causes vary among studies and show marked geographic differences, but in most studies, the most common underlying causes were cerebrovascular disease and low antiepileptic drug levels. A relatively good prognosis of SE is found when the underlying cause is associated with low antiepileptic drug levels or alcohol abuse, and a relatively poor outcome occurs when the underlying cause is cerebrovascular disease, particularly in the case of SE due to acute cerebral anoxia, but in most conditions, the reported prognosis is variable. Also, when SE occurs in the context of an acute cerebral insult, such as cerebral infection or cerebrovascular disease, the prognosis of the acute cerebral event is worsened.

Objective  To assess the efficacy of idebenone on neurological function in patients with Friedreich ataxia.

Design  Randomized, double-blind, placebo-controlled intervention trial.

Setting  Children's Hospital of Philadelphia and the University of California at Los Angeles.

Participants  Seventy ambulatory pediatric patients (age, 8-18 years) with a baseline International Cooperative Ataxia Rating Scale (ICARS) score of 10 to 54.

Interventions  Participants were randomized into 1 of 3 treatment arms: 450 or 900 mg of idebenone per day (in those with a body weight ≤ or >45 kg, respectively; n = 22); 1350 or 2250 mg of idebenone per day (n = 24); or placebo (n = 24).

Main Outcome Measures  Mean change from baseline to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale (FARS) score, performance measures, and activities of daily living were the secondary efficacy variables.

Results  Patients who received idebenone improved by 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 points. Patients who took idebenone also improved by 1.6 points on the FARS, while patients taking placebo declined by 0.6 points. For both end points, the difference between the idebenone and placebo groups was not statistically different.

Conclusions  Idebenone did not significantly alter neurological function in Friedreich ataxia during the 6-month study. Larger studies of longer duration may be needed to assess the therapeutic potential of drug candidates on neurological function in Friedreich ataxia.

Trial Registration  clinicaltrials.gov Identifier: NCT00537680

Objective  To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.

Design  Mixture modeling approach.

Setting  Alzheimer's Disease Neuroimaging Initiative database.

Patients or Other Participants  Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment.

Main Outcome Measures  Cerebrospinal fluid–derived β-amyloid protein 1-42, total tau protein, and phosphorylated tau_181P protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed.

Results  Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid β-amyloid protein 1-42/phosphorylated tau_181P biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E 4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD.

Conclusions  The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.

Objective  To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease.

Design  Follow-up case-control association study.

Setting  The Mayo Clinics at Jacksonville, Florida, and Rochester, Minnesota.

Participants  Community-based patients of European descent with late-onset Alzheimer disease (LOAD) and controls without dementia who were seen at the Mayo clinics, and autopsy-confirmed cases and controls whose pathology was evaluated at the Mayo Clinic in Jacksonville. Additional samples were obtained from the National Cell Repository for Alzheimer Disease (NCRAD). A total of 1829 LOAD cases and 2576 controls were analyzed.

Interventions  The most significant single-nucleotide polymorphisms in CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179) were tested for allelic association with LOAD.

Main Outcome Measure  Clinical or pathology-confirmed diagnosis of LOAD.

Results  Odds ratios for CLU, CR1, and PICALM were 0.82, 1.15, and 0.80, respectively, comparable in direction and magnitude with those originally reported. P values were 8.6 x 10^–5, .014, and 1.3 x 10^–5, respectively; they remain significant even after Bonferroni correction for the 3 single-nucleotide polymorphisms tested.

Conclusion  These results show near-perfect replication and provide the first additional evidence that CLU, CR1, and PICALM are associated with the risk of LOAD.

Background  Symptomatic intracerebral hemorrhage (sICH) is the most devastating complication of thrombolytic therapy for acute stroke. It is not clear whether patients with sICH continue to bleed after diagnosis, nor has the most appropriate treatment been determined.

Methods  We performed a retrospective analysis of our prospectively collected Get With the Guidelines–Stroke database between April 1, 2003, and December 31, 2007. Radiologic images and all procoagulant agents used were reviewed. Multivariable logistic regression was performed to identify factors associated with in-hospital mortality.

Results  Of 2362 patients with acute ischemic stroke during the study period, sICH occurred in 19 of the 311 patients (6.1%) who received intravenous tissue plasminogen activator and 2 of the 72 (2.8%) who received intra-arterial thrombolysis. In-hospital mortality was significantly higher in patients with sICH than in those without (15 of 20 [75.0]% vs 56 of 332 [16.9%], P < .001). Eleven of 20 patients (55.0%) received therapy for coagulopathy: 7 received fresh frozen plasma; 5, cryoprecipitate; 4, phytonadione (vitamin K₁); 3, platelets; and 1, aminocaproic acid. Independent predictors of in-hospital mortality included sICH (odds ratio, 32.6; 95% confidence interval, 8.8-120.2), increasing National Institutes of Health Stroke Scale score (1.2; 1.1-1.2), older age (1.3; 1.0-1.7), and intra-arterial thrombolysis (2.9; 1.4-6.0). Treatment for coagulopathy was not associated with outcome. Continued bleeding (>33% increase in intracerebral hemorrhage volume) occurred in 4 of 10 patients with follow-up scans available (40.0%).

Conclusions  In many patients with sICH after thrombolysis, coagulopathy goes untreated. Our finding of continued bleeding after diagnosis in 40.0% of patients suggests a powerful opportunity for intervention. A multicenter registry to analyze management of thrombolysis-associated intracerebral hemorrhage and outcomes is warranted.

Objective  To determine the association of the genes that encode -, β-, and -synuclein (SNCA, SNCB, and SNCG, respectively) with diffuse Lewy body disease (DLBD).

Design  Case-control study.

Subjects  A total of 172 patients with DLBD consistent with a clinical diagnosis of Parkinson disease dementia/dementia with Lewy bodies and 350 clinically and 97 pathologically normal controls.

Interventions  Sequencing of SNCA, SNCB, and SNCG and genotyping of single-nucleotide polymorphisms performed on an Applied Biosystems capillary sequencer and a Sequenom MassArray pLEX platform, respectively. Associations were determined using ² or Fisher exact tests.

Results  Initial sequencing studies of the coding regions of each gene in 89 patients with DLBD did not detect any pathogenic substitutions. Nevertheless, genotyping of known polymorphic variability in sequence-conserved regions detected several single-nucleotide polymorphisms in the SNCA and SNCG genes that were significantly associated with disease (P = .05 to <.001). Significant association was also observed for 3 single-nucleotide polymorphisms located in SNCB when comparing DLBD cases and pathologically confirmed normal controls (P = .03-.01); however, this association was not significant for the clinical controls alone or the combined clinical and pathological controls (P > .05). After correction for multiple testing, only 1 single-nucleotide polymorphism in SNCG (rs3750823) remained significant in all of the analyses (P = .05-.009).

Conclusion  These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.

Background  The m.3243A>G mutation can cause multisystem medical problems and can affect the autonomic nervous system.

Objective  To study the frequency and spectrum of autonomic symptoms associated with the m.3243A>G mitochondrial DNA point mutation.

Design, Setting, and Patients  We studied a cohort of 88 matrilineal relatives from 40 families, including 35 fully symptomatic patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), 53 carrier relatives, and 16 controls using a questionnaire based on existing standard instruments for the evaluation of autonomic dysfunction. We compared the questionnaire with an expert evaluation. We compared data among the 3 groups using the Mantel-Haenszel ² test to determine the statistical significance of differences between groups.

Results  Mutation carriers frequently had symptoms of autonomic dysfunction, specifically gastrointestinal and orthostatic intolerance.

Conclusions  Carriers of the m.3243A>G mutation have frequent autonomic symptoms. The m.3243A>G mutation should be considered as an etiological factor in patients with autonomic dysfunction and a medical or family history suggestive of mitochondrial disease. Because some autonomic symptoms are treatable, early detection and proactive management may mitigate the burden of morbidity.

Objectives  To compare the trajectory of motor decline, as measured by gait speed and finger-tapping speed, between elderly people who developed mild cognitive impairment (MCI) and those who remained cognitively intact. We also sought to determine the approximate time at which the decline in motor function accelerated in persons who developed MCI.

Design  Longitudinal cohort study.

Participants  Participants were 204 healthy seniors (57.8% women) from the Oregon Brain Aging Study evaluated for up to 20 years using annual neurologic, neuropsychological, and motor examinations.

Main Outcome Measures  The pattern of motor decline with aging was compared using a mixed-effects model with an interaction term for age and a clinical diagnosis of MCI. The time before diagnosis of MCI, when the change in gait or finger-tapping speed accelerates, was assessed using a mixed-effects model with a change point for men and women, separately and combined, who developed MCI.

Results  The rates of change, with aging, in gait speed (P < .001) and finger-tapping speed in the dominant hand (P = .003) and nondominant hand (P < .001) were significantly different between participants who developed MCI (converters) and those who did not (nonconverters). Using a change point analysis for MCI converters, the decrease in gait speed accelerated by 0.023 m/s/y (P < .001), occurring 12.1 years before the onset of MCI. An acceleration in gait speed decline occurred earlier in men than women. For tapping speed, the change point occurred after the onset of MCI for both dominant and nondominant hands when men and women were combined.

Conclusions  Motor decline as indexed by gait speed accelerates up to 12 years before MCI. Longitudinal changes in motor function may be useful in the early detection of dementia during preclinical stages, when the utility of disease-modifying therapies would be greatest.

Objective  To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation.

Design  Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects.

Setting  Southern Lombardy, Italy.

Patients  Individuals with and without amyloidosis in 4 unrelated Italian families (N = 37).

Main Outcome Measure  Genotype-phenotype relationship.

Results  The affected individuals presented with recurrent headache and multiple strokes, followed by epilepsy and cognitive decline in most of them. The disease was inherited with an autosomal dominant trait and segregated with the APP E693K mutation. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and leukoaraiosis. Amyloid-β immunoreactivity was detected in the wall of leptomeningeal and parenchymal vessels and in the neuropil, whereas phosphorylated tau, neurofibrillary changes, and neuritic plaques were absent.

Conclusions  These findings expand the number of APP mutations linked to hereditary cerebral hemorrhage with amyloidosis, reinforcing the link between this phenotype and codon 693 of APP.

Objective  To investigate the prevalence, incidence, risk factors, and concomitants of Parkinson disease (PD)–associated psychosis (PDP) in a population-based prevalent cohort.

Design  Prospective longitudinal cohort study.

Setting  Community-based study in southwestern Norway.

Participants  Two hundred thirty community-based PD patients were followed up prospectively for 12 years. Reassessments were conducted at 4 and 8 years and then annually.

Main Outcome Measures  Severity of PDP was measured by the Unified Parkinson Disease Rating Scale thought disorder (UPDRS-TD) item. Patients with a UPDRS-TD score of 2 or more or those taking antipsychotic drugs owing to psychotic symptoms were categorized at each visit as having PDP. Generalized estimating equations were applied to investigate baseline risk factors for incident PDP and clinical and demographic concomitants of PDP during 12 years.

Results  By study's end, 137 patients (60%) had developed hallucinations or delusions. The incidence rate of PDP was 79.7 per 1000 person-years. Higher age at onset, higher baseline levodopa-equivalent doses, probable rapid eye movement (REM) sleep behavior disorder at baseline, and follow-up time were independent risk factors of incident PDP. Significant concomitant features of patients with PDP during the 12-year study period were low activities of daily living function (UPDRS II), dementia, high levodopa-equivalent dose, and probable REM sleep behavior disorder.

Conclusions  Psychotic symptoms affect most patients with PD, with increased risk in those with higher age at onset, need for high doses of dopaminergic drugs, and probable REM sleep behavior disorder. This risk factor pattern and the observed associations with increased disability and dementia place PDP within a symptom complex signaling a malignant disease course.

Background  TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.

Objective  To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.

Design, Setting, and Participants  Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.

Main Outcome Measure  We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.

Results  The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.

Conclusions  Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD cosegregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.

Objective  To report the clinical benefits of bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in a patient with X-linked dystonia parkinsonism (XDP).

Design  Case report.

Setting  Tertiary referral center.

Patient  A 40-year-old Filipino man with genetically confirmed XDP and severely disabling generalized dystonia.

Intervention  Bilateral GPi DBS.

Main Outcome Measures  The primary outcome measures were the Burke-Fahn-Marsden Dystonia Scale (BFMDS) severity and disability scores, and the secondary outcome measure was the Unified Parkinson Disease Rating Scores.

Results  At the 1-year postoperative follow-up, there was 80.4% improvement in the BFMDS severity score and 66.7% improvement in the BFMDS disability score.

Conclusion  Bilateral GPi DBS seems to be very effective in improving dystonia in XDP.

Objective  To describe a patient with neuromyelitis optica (NMO) whose aquaporin 4 (AQP4) antibody levels increased following treatment with interferon beta.

Design  Prospective clinical and laboratory case report.

Setting  Institutional referral center for multiple sclerosis (MS).

Patient  One patient with an initial diagnosis of MS that was later revised to NMO.

Interventions  A course of interferon beta-1a followed by conventional immunosuppression. Blood samples were collected from the onset of treatment, and clinical and laboratory assessment was performed.

Main Outcome Measures  Serum levels of AQP4 antibody and number and characteristics of neurological relapses.

Results  After 3 relapses during a 10-month period despite interferon beta-1a treatment, the diagnosis of AQP4 antibody–positive NMO was made and treatment was switched to prednisolone and methotrexate. The AQP4 antibody titers rose dramatically during treatment with interferon beta, and then fell when conventional immunosuppressive therapy was substituted; the patient has remained relapse-free for the subsequent years.

Conclusions  Although previous articles have suggested that interferon beta may increase relapses in NMO, this is the first to illustrate an increase in AQP4 antibodies associated with such treatment.

Background  Transverse myelitis has been reported in association with vaccination, including influenza vaccination.

Objective  To describe a case of longitudinally extensive transverse myelitis associated with vaccination with a nasal attenuated novel influenza A(H1N1) vaccine.

Design  Case report.

Setting  Sanford University of South Dakota Hospital.

Patient  A 27-year-old woman with longitudinally extensive transverse myelitis.

Results  Four days following novel influenza A(H1N1) vaccination, the patient developed longitudinally extensive transverse myelitis. Extensive diagnostic evaluation effectively ruled out causes other than vaccination-associated transverse myelitis. Following treatment with corticosteroids and plasmapheresis, the patient made a significant recovery.

Conclusions  Transverse myelitis may be associated with vaccination against novel influenza A(H1N1). Additionally, we believe this to be the first report of longitudinally extensive transverse myelitis associated with any vaccine.

Background  Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt-Jakob disease (vCJD) are homozygous for methionine at a common polymorphism at codon 129. A further genetic polymorphism at codon 219, a common variant in several Asian populations, is considered protective against sporadic CJD.

Objective  To report a finding of heterozygosity at codon 219 in 2 patients with vCJD.

Design  Case reports.

Setting  MRC (Medical Research Council) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery.

Patients  Two patients with clinical and investigation findings consistent with the diagnoses of probable vCJD.

Main Outcome Measures  Clinical and genetic findings.

Results  A 34-year-old man had a 15-month history of behavioral change progressing to ataxia, dysarthria, involuntary choreiform movements, and severe cognitive impairment. Cerebrospinal fluid analysis was positive for 14-3-3 protein, electroencephalography showed generalized slowing, and magnetic resonance imaging revealed thalamic high signal bilaterally, typical of vCJD. A 31-year-old woman had a 16-month history of cognitive decline, ataxia, involuntary choreiform movements, and myoclonic jerks. Magnetic resonance imaging showed bilateral pulvinar high signal. The diagnosis was confirmed by a tonsillar biopsy demonstrating abnormal prion protein deposition in a typical pattern for vCJD. PRNP sequencing showed a methionine homozygous codon 129 genotype and an E219K polymorphism in both patients.

Conclusions  The E219K polymorphism is neutral or may even confer susceptibility to vCJD. The observations are interpretable in the context of the conformational selection model of prion replication. A barrier to prion disease transmission depends on the degree to which permitted pathologic conformations of the prion protein overlap between the inoculum and the host.