Showing papers in "JAMA Neurology in 2012"

Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment

Abstract: Objective To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Design Randomized, double-blind, placebo-controlled trial. Setting Clinical research unit of a Veterans Affairs medical center. Participants The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Main Outcome Measures Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale–cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study–activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Results Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P Conclusions These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568

Accuracy of a Panel of 5 Cerebrospinal Fluid Biomarkers in the Differential Diagnosis of Patients With Dementia and/or Parkinsonian Disorders

Abstract: els of -amyloid 1-42 were decreased in DLB and even further decreased in AD. Cerebrospinal fluid levels of total tau and hyperphosphorylated tau were increased in AD. Multivariate analysis revealed that these biomarkers could differentiate AD from DLB and PDD with an area under the curve of 0.90, with -synuclein and total tau contributing most to the model. Cerebrospinal fluid levels of neurofilament light chain were substantially increased in atypical parkinsonian disorders (ie, PSP, MSA, and CBD), and multivariate analysis revealed that the level of neurofilament light chain alone could differentiate PD from atypical parkinsonian disorders, with an area under the curve of 0.93. Conclusions: Ascertainment of the -synuclein level in CSF somewhat improves the differential diagnosis of AD vs DLB and PDD when combined with established AD biomarkers. The level of neurofilament light chain alone may differentiate PD from atypical parkinsonian disorders.

Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab

Abstract: Background Gantenerumab is a fully human anti-Aβ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). Objectives To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to elucidate the mechanism of amyloid reduction. Design A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed. Setting Three university medical centers. Patients Patients with mild-to-moderate AD. Intervention Two consecutive cohorts of patients received 2 to 7 infusions of intravenous gantenerumab (60 or 200 mg) or placebo every 4 weeks. Brain slices from patients who had AD were coincubated with gantenerumab at increasing concentrations and with human microglial cells. Main Outcome Measures Percent change in the ratio of regional carbon 11–labeled Pittsburgh Compound B retention in vivo and semiquantitative assessment of gantenerumab-induced phagocytosis ex vivo. Results Sixteen patients with end-of-treatment positron emission tomographic scans were included in the analysis. The mean (95% CI) percent change from baseline difference relative to placebo (n = 4) in cortical brain amyloid level was −15.6% (95% CI, −42.7 to 11.6) for the 60-mg group (n = 6) and −35.7% (95% CI, −63.5 to −7.9) for the 200-mg group (n = 6). Two patients in the 200-mg group showed transient and focal areas of inflammation or vasogenic edema on magnetic resonance imaging scans at sites with the highest level of amyloid reduction. Gantenerumab induced phagocytosis of human amyloid in a dose-dependent manner ex vivo. Conclusion Gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell–mediated mechanism of action.

Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease

Abstract: 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.

Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease

Abstract: Objective To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the γ-secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). Design Randomized, double-blind, placebo-controlled, 24-week phase 2 study. Setting Global, multicenter trial. Patients A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years, 58.9% were APOE ϵ4 carriers, and baseline measures of disease severity were similar among groups. Intervention Avagacestat, 25, 50, 100, or 125 mg daily, or placebo administered orally daily. Main Outcome Measures Safety and tolerability of avagacestat. Results Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups. Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and 125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal and dermatologic. Other adverse events occurring more frequently in patients undergoing treatment included reversible glycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomatic magnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. Conclusions Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for γ-secretase target engagement, but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses. This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. Trial Registration clinicaltrials.gov Identifier: NCT00810147

Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures

Abstract: Objective To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Design Double-blind, placebo-controlled clinical trial. Setting Academic medical centers. Participants Subjects with mild to moderate Alzheimer disease. Intervention Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Main Outcome Measures Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale). Results Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau 181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Conclusions Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. Trial Registration clinicaltrials.gov Identifier: NCT00117403

Autoimmune Epilepsy: Clinical Characteristics and Response to Immunotherapy

Abstract: Objective To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. Design Observational, retrospective case series. Setting Mayo Clinic Health System. Patients Thirty-two patients with an exclusive (n = 11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N -methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. Intervention Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. Main Outcome Measure Seizure frequency. Results After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P Conclusion When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.

Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.

Abstract: Objective To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. Design Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. Setting Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. Patients Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Main Outcome Measure Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). Results In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. Conclusions Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.

Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition

Abstract: The recent development of the radiopharmaceutical carbon 11–labeled Pittsburgh Compound B ([11C]PiB)1 has made it possible to image fibrillar forms of the β-amyloid (Aβ) protein, which is the major constituent of the amyloid plaque in Alzheimer disease (AD) Studies applying this technique have demonstrated [11C]PiB accumulation throughout cortex in most patients with AD More important, 20% to 30% of healthy, cognitively normal older individuals2,3 also display significant PiB uptake, which is consistent with evidence that some older individuals who were cognitively intact during life show substantial numbers of Aβ plaques post mortem4 Greater understanding of the factors associated with Aβ variability in the healthy older population could have important consequences for disease prevention Recent evidence indicates that lifestyle practices, such as increased physical exercise, are associated with reduced Aβ deposition based on [11C]PiB positron emission tomography (PET) and cerebrospinal fluid Aβ42 measurements5 Participation in cognitively stimulating activities has also been linked to reduced risk of late-life cognitive decline and AD6–8 An individual’s tendency to engage in physically and cognitively stimulating activities is likely related to a broad set of lifestyle factors that are difficult to quantify but include occupational, social, community, and recreational practices We assessed engagement in cognitive and physical activities and hypothesized that greater levels of engagement may be associated with less Aβ later in life We investigated this hypothesis by performing [11C]PiB PET and neuropsychological testing in a sample of cognitively normal older participants Aβ deposition, characterized as mean cortical [11C]PiB PET uptake, was examined in healthy older participants and comparison samples of young participants and patients with AD A variety of neuropsychological and lifestyle measurements were also obtained and assessed in relation to Aβ deposition for healthy older participants only, including frequency of engagement in cognitively demanding activities, frequency of engagement in physical and leisure activities, and current episodic memory function

Autoantibodies to Lipoprotein-Related Protein 4 in Patients With Double-Seronegative Myasthenia Gravis

Abstract: Objectives To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipoprotein-related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti-LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.

Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals.

Abstract: Objective To study the relationship between subjective cognition and the neuropathological hallmark of Alzheimer disease (AD), amyloid-β (Aβ) deposition, using carbon 11–labeled Pittsburgh Compound B (PiB) positron emission tomography in normal elderly individuals. Design Cross-sectional analysis. Subjects Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations, magnetic resonance imaging, and positron emission tomography. Setting Berkeley Aging Cohort Study. Main Outcome Measure Relationship between PiB uptake and subjective cognition measures. Results Subjects with high PiB uptake showed significantly lower performance than those with low PiB uptake on an episodic memory measure and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB uptake groups did not differ on the accuracy of their cognitive self-reports compared with objective cognitive performance. General memory self-reports from the whole group were significantly correlated with regional PiB uptake in the right medial prefrontal cortex and anterior cingulate cortex and in the right precuneus and posterior cingulate cortex. Reduced confidence about memory abilities was associated with greater PiB uptake in these brain regions. All results were independent of demographic variables and depressive affects. Conclusions A decrease of self-confidence about memory abilities in cognitively normal elderly subjects may be related to the neuropathological hallmark of AD measured with PiB–positron emission tomography. Subjective cognitive impairment may represent a very early clinical manifestation of AD.

Diabetes, Glucose Control, and 9-Year Cognitive Decline Among Older Adults Without Dementia

Abstract: 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 incidentDMduring follow-up. Participants with prevalent DM had lower baseline test scores than participants withoutDM(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. ©2012 American Medical Association. All rights reserved.

Epidemiology of neuromyelitis optica in the United States: A multicenter analysis

Abstract: Background Rare diseases require integrated multicenter clinical networks to facilitate clinical research. Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) are uncommon neuroinflammatory syndromes that are distinct from multiple sclerosis and associated with NMO-IgG, a serologic antibody against aquaporin 4. Objective To develop a national multicenter NMO clinical consortium and report initial demographic, clinical, and radiographic features of a cohort of patients with NMO/NMOSD in the United States. Design Review of medical records from patients undergoing evaluation during a 5-year period. We used uniform diagnostic criteria and clinical, laboratory, and neuroimaging definitions to describe the cohort. Setting Three academic medical centers. Patients One hundred eighty-seven patients with NMO/NMOSD. Results Of the 187 patients included in the analysis, 86 had NMO-IgG–seropositive NMO; 40, NMO-IgG–seronegative NMO; and 61, NMO-IgG–seropositive NMOSD. Altogether, 29.4% of our patients were initially misdiagnosed with multiple sclerosis. The average age at onset of NMO/NMOSD was 41.1 years with a strong female predilection, similar to other autoimmune disorders. Nonwhite patients constituted 52.4% of the cohort. The hallmark of NMO and NMOSD is recurrent longitudinally extensive transverse myelitis, but patients with NMO tend to initially present with optic neuritis. Conclusions A national multicenter consortium to study NMO/NMOSD is feasible and facilitates accurate clinical diagnosis. This network establishes a foundation for determining disease prevalence, translational research, and clinical trials.

Failure of natalizumab to prevent relapses in neuromyelitis optica.

Abstract: Objective To describe first experiences with the integrin inhibitor natalizumab, given to patients with suspected relapsing-remitting multiple sclerosis (MS) who were later diagnosed with aquaporin 4–positive neuromyelitis optica (NMO). Design Retrospective case series. Setting Neurology departments at tertiary referral centers in Germany. Patients Patients with NMO who tested positive for antibodies to aquaporin 4. Intervention Treatment with natalizumab. Main Outcome Measures Relapses and accumulation of disability. Results We identified 5 patients (4 female; median age, 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established. Natalizumab was given as escalation therapy after failure of first- or second-line immunomodulatory therapies for MS. During natalizumab therapy (median duration, 8 infusions; range, 2-11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range, 45-230 days) after the start of treatment. Four patients had an accumulation of disability and 1 patient died 2 months after cessation of natalizumab treatment. Conclusions Our results suggest that natalizumab fails to control disease activity in patients with NMO. Neuromyelitis optica should be considered as a differential diagnosis in patients with suspected MS who are unresponsive to natalizumab therapy.

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition.

Abstract: Objective APOE ϵ4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. Design APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11–labeled Pittsburgh Compound B ([ 11 C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. Setting Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. Participants A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer’s Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. Results APOE ϵ4 carriers evidenced higher [ 11 C]PiB binding (P 11 C]PiB binding (P = .005) and lower CSF Aβ42 levels (P = .009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [ 11 C]PiB binding (P = .008) such that a more sedentary lifestyle was significantly associated with higher [ 11 C]PiB binding for ϵ4 carriers (P = .013) but not for noncarriers (P = .20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. Conclusion Collectively, these results suggest that cognitively normal sedentary APOE ϵ4–positive individuals may be at augmented risk for cerebral amyloid deposition.

Dementia Resulting From Traumatic Brain Injury: What Is the Pathology?

Abstract: Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life The best data indicate that moderate and severe TBIs increase risk of dementia between 2- and 4-fold It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed

Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease

Abstract: Background Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti–β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms. Objective To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. Design Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration. Setting Academic centers in the United States (Study 201) and England and Finland (Study 202). Patients Forty-six patients with mild to moderate Alzheimer disease. Interventions Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups. Main Outcome Measures Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau). Results Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (−72.3 pg/mL) and P-tau (−9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ. Conclusions To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. Trial Registrations clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.

Predictors of outcome in refractory status epilepticus.

Abstract: Objective To further characterize the demographics, outcomes, and prognostic factors for refractory status epilepticus (RSE). Design Retrospective analysis of all the episodes of RSE treated between January 1, 1999, and August 30, 2011. Setting Neurointensive care unit within a tertiary referral center, Mayo Clinic, Rochester, Minnesota. Patients Refractory status epilepticus was defined as generalized convulsive or nonconvulsive status epilepticus (SE) that continued despite initial first- and second-line therapies. Exclusion criteria were aged younger than 18 years, anoxic/myoclonic SE, psychogenic SE, simple partial SE, and absence SE. Main Outcome Measures Functional outcome was defined by modified Rankin scale (mRS) dichotomized into good (mRS, 0-3) and poor (mRS, 4-6). Functional decline was defined as a change in mRS greater than 1 from hospital admission to discharge. Results We identified 63 consecutive episodes of non–anoxic RSE in 54 patients. Anesthetic agents were used in 55 episodes (87.30%), and duration of drug-induced coma was (mean [SD]) 11.0 (17.9) days. In-hospital mortality was 31.75% (20 of 63 episodes). Poor functional outcome at discharge occurred in 48 of 63 episodes (76.19%). Hospital length of stay was (mean [SD]) 27.7 (37.3) days. Duration of drug-induced coma (P = .03), arrhythmias requiring intervention (P = .01), and pneumonia (P = .01) were associated with poor functional outcome. Prolonged mechanical ventilation was associated with mortality (P = .04). Seizure control without suppression-burst or isoelectric electroencephalogram predicted good functional recovery (P = .01). Age, history of epilepsy, previous SE, type of SE, and anesthetic drug used were not associated with functional outcome. Conclusions Three-quarters of patients with RSE have a poor outcome. Achieving control of the SE without requiring prolonged drug-induced coma or severe electroencephalographic suppression portends better prognosis.

Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System

Abstract: Background The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). Objective To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. Design Repeated-measures case-control study. Setting Washington University School of Medicine in St Louis, Missouri. Participants Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. Main Outcome Measures In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. Results Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. Conclusions A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community.

Abstract: Background New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. Objective To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting The Washington Heights/Inwood Columbia Aging Project. Participants Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. Main Outcome Measure Incident AD. Results White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). Conclusions The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology.

Stiff-man syndrome and variants: clinical course, treatments, and outcomes.

Abstract: Background Little information is available about the incidence of stiff-man syndrome (SMS) (the classic form or its variants) or about long-term treatment responses and outcomes. Objective To comprehensively describe the characteristics of a cohort of patients with SMS. Design Observational study. Setting Mayo Clinic, Rochester, Minnesota. Patients Ninety-nine patients with classic SMS vs variants of the disorder, both glutamic acid decarboxylase 65 kD isoform (GAD65) antibody seropositive and seronegative. Main Outcome Measures Neurological, autoimmune, serological, and oncological findings; treatments; and outcomes between January 1984 and December 2008. Results The median follow-up duration was 5 years (range, 0-23 years). Seventy-nine patients (59 having classic SMS, 19 having partial SMS, and 1 having progressive encephalomyelitis with rigidity and myoclonus [PERM]) were GAD65 antibody seropositive. Sixty-seven percent (53 of 79) of them had at least 1 coexisting autoimmune disease, and 4% (3 of 79) had cancer. GAD65 antibody values at initial evaluation were significantly higher among patients with classic SMS (median value, 623 nmol/L) than among patients with partial SMS (median value, 163 nmol/L) (P Conclusions Recognition of classic SMS vs variants is important because appropriate therapy improves symptoms in most patients. Classification by anatomical extent and by GAD65 antibody serostatus gives important diagnostic and prognostic information.

Awaji criteria for the diagnosis of amyotrophic lateral sclerosis:a systematic review.

Abstract: Objective To estimate the potential diagnostic added value of the Awaji criteria for diagnosis of a myotrophiclateral sclerosis (ALS), which have been compared with the previously accepted gold standard the revised El Escorial criteria in several studies. Data sources MEDLINE and Web of Science (until October2011). Study selection We searched for studies testing the diagnostic accuracy of the Awaji criteria vs the revised El Escorial criteria in patients referred with suspected ALS. Data extraction Evaluation and data extraction of identified studies were done independently. The Quality Assessment of Diagnostic Accuracy Studies list was used to assess study quality. We determined the proportion of patients classified as having probable/definite ALS and derived indices of diagnostic performance(sensitivity, specificity, and diagnostic odds ratio). Quantitative data synthesis was accomplished through random-effects meta-analysis, and heterogeneity was assessed with the I2 test. Data synthesis Eight studies were included (3 prospective and 5 retrospective) enrolling 1187 patients. Application of Awaji criteria led to a 23% (95% CI, 12% to 33%; I2=84%) increase in the proportion of patients classified as having probable/definite ALS. Diagnostic performance of the Awaji criteria was higher than the revised El Escorial criteria (pooled sensitivity: 81.1% [95%CI, 72.2% to 90.0%; I2=91%] vs 62.2% [95% CI, 49.4%to 75.1%; I2=93%]; pooled diagnostic odds ratio, 35.8[95% CI, 15.2 to 84.7; I2=3%] vs 8.7 [95% CI, 2.2 to 35.6;I2=50%]). Diagnostic accuracy of Awaji criteria was higher in bulbar- than in limb-onset cases. Conclusion The Awaji criteria have a significant clinical impact allowing earlier diagnosis and clinical trial entry in ALS.

Plasma amyloid-β as a predictor of dementia and cognitive decline: a systematic review and meta-analysis.

Abstract: Background Preclinical prediction of Alzheimer disease (AD) is important and critical to effective intervention. Plasma levels of amyloid-β (Aβ) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data. Objective To conduct a systematic review and meta-analysis of relevant prospective studies to determine whether plasma amyloid-β levels may predict development of dementia, AD, and cognitive decline. Design We searched prospective studies published between 1995 and 2011 indexed in the MEDLINE, EMBASE, and PsycINFO databases. Selected studies included those measuring at least 1 relevant plasma amyloid-β species (Aβ(40), Aβ(42), or Aβ(42):Aβ(40) ratio) and reporting an effect estimate for dementia, AD, or cognitive change. Main outcome measures Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were used to generate summary risk ratios and 95% confidence intervals comparing the bottom vs top quantiles for each plasma measure. Results Thirteen studies with a total of 10 303 subjects met inclusion criteria for meta-analysis. Lower Aβ(42):Aβ(40) ratios were significantly associated with development of AD (summary risk ratio, 1.60; 95% CI, 1.04-2.46; P = .03) and dementia (risk ratio, 1.67; 95% CI, 1.02-2.75; P = .04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants' age, sex distribution, the study's follow-up time, or year of publication. Plasma levels of Aβ(40) and Aβ(42) alone were not significantly associated with either outcome. Conclusions Overall, the literature indicates that plasma Aβ(42):Aβ(40) ratios predict development of AD and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid-β levels as a preclinical biomarker.

Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis

Abstract: Objective To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS). Design Cross-sectional study. Setting Johns Hopkins University, Baltimore, Maryland. Participants A total of 84 patients with MS and 24 healthy control subjects. Main Outcome Measures High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes. Results Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer + inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P = .01 and P = .04, respectively) and caudate (P = .04 and P = .03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P = .007) and inversely associated with normal-appearing white matter volume (P = .005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT–brain substructure relationships were adjusted for intracranial volume. Conclusions Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

Plasma Biomarkers Associated With the Apolipoprotein E Genotype and Alzheimer Disease

Abstract: 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 Apoϵ3/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.

Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study

Abstract: Objective To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A 2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Design Prospective cohort study. Setting Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Participants Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. Main Outcome Measures We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ϵ4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Results Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median. Conclusion In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Heterogeneity of coenzyme Q10 deficiency: patient study and literature review.

Abstract: Coenzyme Q(10) (CoQ(10)) deficiency has been associated with 5 major clinical phenotypes: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cerebellar ataxia, and isolated myopathy. Primary CoQ(10) deficiency is due to defects in CoQ(10) biosynthesis, while secondary forms are due to other causes. A review of 149 cases, including our cohort of 76 patients, confirms that CoQ(10) deficiency is a clinically and genetically heterogeneous syndrome that mainly begins in childhood and predominantly manifests as cerebellar ataxia. Coenzyme Q(10) measurement in muscle is the gold standard for diagnosis. Identification of CoQ(10) deficiency is important because the condition frequently responds to treatment. Causative mutations have been identified in a small proportion of patients.

Brain Excitability in Stroke: The Yin and Yang of Stroke Progression

Abstract: There is no current medical therapy for stroke recovery. Principles of physiological plasticity have been identified during recovery in both animal models and human stroke. Stroke produces a loss of physiological brain maps in adjacent peri-infarct cortex and then a remapping of motor and sensory functions in this region. This remapping of function in peri-infarct cortex correlates closely with recovery. Recent studies have shown that the stroke produces abnormal conditions of excitability in neuronal circuits adjacent to the infarct that may be the substrate for this process of brain remapping and recovery. Stroke causes a hypoexcitability in peri-infarct motor cortex that stems from increased tonic γ-aminobutyric acid activity onto neurons. Drugs that reverse this γ-aminobutyric acid signaling promote recovery after stroke. Stroke also increases the sensitivity of glutamate receptor signaling in peri-infarct cortex well after the stroke event, and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors in peri-infarct cortex promotes recovery after stroke. Both blocking tonic γ-aminobutyric acid currents and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors promote recovery after stroke when initiated at quite a delay, more than 3 to 5 days after the infarct. These changes in the excitability of neuronal circuits in peri-infarct cortex after stroke may underlie the process of remapping motor and sensory function after stroke and may identify new therapeutic targets to promote stroke recovery.

Autosomal Recessive Causes Likely in Early-Onset Alzheimer Disease

Abstract: Objectives To determine the genetic contribution to non–autosomal dominant early-onset Alzheimer disease (EOAD) (onset age ≤60 years) cases and identify the likely mechanism of inheritance in those cases. Design A liability threshold model of disease was used to estimate heritability of EOAD and late-onset Alzheimer disease (AD) using concordance for AD among parent-offspring pairs. Setting The Uniform Data Set, whose participants were collected from 32 US Alzheimer's Disease Centers, maintained by the National Alzheimer's Coordinating Center. Participants Individuals with probable AD and detailed parental history (n = 5370). Main Outcome Measures The concordance among relatives and heritability of EOAD and late-onset AD. Results For late-onset AD (n = 4302), we found sex-specific parent-offspring concordance that ranged from approximately 10% to 30%, resulting in a heritability of 69.8% (95% confidence interval, 64.6%-75.0%), and equal heritability for both sexes regardless of parental sex. For EOAD (n = 702), we found that the parent-offspring concordance was 10% or less and concordance among siblings was 21.6%. Early-onset AD heritability was 92% to 100% for all likely values of EOAD prevalence. Conclusions We confirm late-onset AD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the patterns of observed concordance for parent-offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that approximately 90% of EOAD cases are due to autosomal recessive causes.

Symptoms and signs of posterior circulation ischemia in the new England medical center posterior circulation registry.

Abstract: Objective To evaluate the frequencies of symptoms and signs in patients with posterior circulation ischemia in a large case series of prospectively collected patients. Design Case series. Setting Outpatient and inpatient setting at the New England Medical Center, a tertiary care referral center in Boston, Massachusetts. Patients Consecutive sample of 407 adult patients who had stroke and/or transient ischemic attacks in the posterior circulation within 6 months of study inclusion. All patients were examined by senior stroke neurologists. All patients had either computed tomography or magnetic resonance imaging of the brain as well as vascular imaging of the head and neck. The study included 256 men (63%) and 151 women (37%). Main Outcome Measures Frequencies of posterior circulation ischemic symptoms and signs. These outcome measures were planned before data collection began. Correlations between symptoms and signs with separate vascular territories of the posterior circulation were then analyzed. Results The most frequent posterior circulation symptoms were dizziness (47%), unilateral limb weakness (41%), dysarthria (31%), headache (28%), and nausea or vomiting (27%). The most frequent signs were unilateral limb weakness (38%), gait ataxia (31%), unilateral limb ataxia (30%), dysarthria (28%), and nystagmus (24%). Logistic regression analysis reveals that the clinical features dysphagia (P = .004; 95% CI, 1.8-24.4), nausea or vomiting (P = .002; 95% CI, 1.6-8.2), dizziness (P = .047; 95% CI, 1.0-5.4), and Horner syndrome (P = .001; 95% CI, 2.4-26.6) were positively correlated with the proximal vascular territory. Unilateral limb weakness (P = .001; 95% CI, 1.7-8.7) and cranial nerve VII deficits (P = .02; 95% CI, 1.1-5.3) were positively correlated with the middle territory. Limb sensory deficit (P = .001; 95% CI, 1.8-7.8), lethargy (P = .001; 95% CI, 2.3-12.4), and visual field loss (P = .001; 95% CI, 5.3-23.9) were positively correlated with the distal territory. Conclusions We report the most frequent symptoms and signs in the largest published registry, the New England Medical Center Posterior Circulation Registry, of patients with posterior circulation ischemia who had complete neurological examinations and extensive cerebrovascular imaging. Knowledge of the vascular territory involved aids in the diagnosis of the causative vascular lesion and stroke mechanism.