Showing papers in "JAMA Neurology in 2010"
TL;DR: Dopamine agonist treatment in PD is associated with 2- to 3.5-fold increased odds of having an ICD, which represents a drug class relationship across ICDs.
Abstract: Context An association between dopamine-replacement therapies and impulse control disorders (ICDs) in Parkinson disease (PD) has been suggested in preliminary studies. Objectives To ascertain point prevalence estimates of 4 ICDs in PD and examine their associations with dopamine-replacement therapies and other clinical characteristics. Design Cross-sectional study using an a priori established sampling procedure for subject recruitment and raters blinded to PD medication status. Patients Three thousand ninety patients with treated idiopathic PD receiving routine clinical care at 46 movement disorder centers in the United States and Canada. Main Outcome Measures The Massachusetts Gambling Screen score for current problem/pathological gambling, the Minnesota Impulsive Disorders Interview score for compulsive sexual behavior and buying, and Diagnostic and Statistical Manual of Mental Disorders research criteria for binge-eating disorder. Results An ICD was identified in 13.6% of patients (gambling in 5.0%, compulsive sexual behavior in 3.5%, compulsive buying in 5.7%, and binge-eating disorder in 4.3%), and 3.9% had 2 or more ICDs. Impulse control disorders were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08-3.54; P P = .14). Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems. Conclusions Dopamine agonist treatment in PD is associated with 2- to 3.5-fold increased odds of having an ICD. This association represents a drug class relationship across ICDs. The association of other demographic and clinical variables with ICDs suggests a complex relationship that requires additional investigation to optimize prevention and treatment strategies. Trial Registration clinicaltrials.gov Identifier:NCT00617019
1,220 citations
TL;DR: Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction.
Abstract: Objectives To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design Six-month, randomized, controlled, clinical trial. Setting Veterans Affairs Puget Sound Health Care System clinical research unit. Participants Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.
1,036 citations
TL;DR: Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects.
Abstract: Objective To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells ) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Design A phase 1/2 open-safety clinical trial. Patients Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention After culture, a mean (SD) of 63.2 × 10 6 (2.5 × 10 6 ) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex). Main Outcome Measures The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation. Results Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4 + CD25 + regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40 + , CD83 + , CD86 + , and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation. Conclusion Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration clinicaltrials.gov Identifier:NCT00781872
864 citations
TL;DR: It is demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of α-synuclein, suggesting that this pathway may be a suitable therapeutic target in PD.
Abstract: 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 alpha-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 alpha-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.
465 citations
TL;DR: 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.
Abstract: 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 e4 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.
437 citations
TL;DR: Motor decline as indexed by gait speed accelerates up to 12 years before MCI, and 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.
Abstract: 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 P = .003) and nondominant hand ( P P 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.
424 citations
Boston University1, University of Miami2, University of Pennsylvania3, Columbia University4, Mayo Clinic5, Johns Hopkins University6, University of Louisville7, Tel Aviv University8, Oregon Health & Science University9, University of Toronto10, University of Cambridge11, Indiana University – Purdue University Indianapolis12, University of Arizona13, Rush University Medical Center14, Washington University in St. Louis15, University of Washington16, Harvard University17, Vanderbilt University18
TL;DR: It is confirmed in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations.
Abstract: 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 e4 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 e4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE e4, and an interaction term showed significant interaction between presence or absence of APOE e4 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 e4-positive subjects. Thus, APOE and PICALM synergistically interact.
411 citations
TL;DR: Simultaneous consideration of previous knowledge regarding potentially AD-related nutrients and multiple food groups can aid in identifying food combinations that are associated with AD risk.
Abstract: Results: Two hundred fifty-three subjects developed AD during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43-0.89) after multivariable adjustment (P for trend=.01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of highfat dairy products, red meat, organ meat, and butter. Conclusion: Simultaneous consideration of previous knowledge regarding potentially AD-related nutrients and multiple food groups can aid in identifying food combinations that are associated with AD risk.
404 citations
TL;DR: In this paper, a cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution-and anchor-based approaches based on the following external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey).
Abstract: Objective To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinson's Disease Rating Scale (UPDRS). Design Cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution- and anchor-based approaches based on the following 3 external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey). Setting University of Maryland Parkinson Disease and Movement Disorders Center, Patients Six hundred fifty-three patients with PD. Results A minimal CID was 2.3 to 2.7 points on the UPDRS motor score and 4.1 to 4.5 on the UPDRS total score. A moderate CID was 4.5 to 6.7 points on the UPDRS motor score and 8.5 to 10.3 on the UPDRS total score. A large CID was 10.7 to 10.8 points on the UPDRS motor score and 16.4 to 17.8 on the UPDRS total score. Conclusions Concordance among multiple approaches of analysis based on subjective and objective data show that reasonable estimates for the CID on the UPDRS motor score are 2.5 points for minimal, 5.2 for moderate, and 10.8 for large CIDs. Estimates for the UPDRS total score are 4.3 points for minimal, 9.1 for moderate, and 17.1 for large CIDs. These estimates will assist in determining clinically meaningful changes in PD progression and response to therapeutic interventions.
403 citations
TL;DR: Any frequency of moderate exercise performed in midlife or late life was associated with a reduced odds of having mild cognitive impairment (MCI), and the findings were consistent among men and women.
Abstract: Background Physical exercise is associated with decreased risk of dementia and Alzheimer disease. Objective To investigate whether physical exercise is associated with decreased risk of mild cognitive impairment (MCI). Design Population-based case-control study. Setting The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota. Participants A total of 1324 subjects without dementia who completed a Physical Exercise Questionnaire. Main Outcome Measures An expert consensus panel classified each subject as having normal cognition or MCI based on published criteria. Results We compared the frequency of physical exercise among 198 subjects with MCI with that among 1126 subjects with normal cognition and adjusted the analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratios for any frequency of moderate exercise were 0.61 (95% confidence interval, 0.43-0.88; P = .008) for midlife (age range, 50-65 years) and 0.68 (95% confidence interval, 0.49-0.93; P = .02) for late life. The findings were consistent among men and women. Light exercise and vigorous exercise were not significantly associated with decreased risk of MCI. Conclusion In this population-based case-control study, any frequency of moderate exercise performed in midlife or late life was associated with a reduced odds of having MCI.
363 citations
TL;DR: Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy and less than 5% of patients with ACS now stand to benefit from revascularization.
Abstract: Objective To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS). Design A prospective study. Setting A teaching hospital. Patients Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity. Main Outcome Measures We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003. Results Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 ( P P 2 (SD, 96 mm 2 ) to 23 mm 2 (SD, 86 mm 2 ) ( P Conclusions Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy.Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.
TL;DR: 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, place PDP within a symptom complex signaling a malignant disease course.
Abstract: 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.
TL;DR: Dopamine agonists have a stereotyped withdrawal syndrome that can lead to profound disability in a subset of patients and Physicians should monitor patients closely when tapering these medications.
Abstract: Objectives:Toreportandcharacterizeadopamineagonist (DA) withdrawal syndrome (DAWS) in Parkinson disease. Design: Retrospective cohort study. Setting:Outpatient tertiary movement disorders clinic. Patients:Acohortof93nondementedpatientswithParkinson disease enrolled in a prospective study of nonmotor and motor disease manifestations. Main Outcome Measure: The presence of DAWS, defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other Parkinson disease medications, and cannot be accounted for by other clinical factors. Results: Of 40 subjects treated with a DA, 26 underwent subsequent DA taper. Of these 26 subjects, 5 (19%) developedDAWSand21(81%)didnot.Allsubjectswith DAWS had baseline DA-related impulse control disorders. Symptoms of DAWS resembled those of other drug withdrawal syndromes and included anxiety, panic attacks,agoraphobia,depression,dysphoria,diaphoresis,fatigue, pain, orthostatic hypotension, and drug cravings. Subjects with DAWS as compared with those without DAWShadhigherbaselineDAuse(mean[SD],420[170] vs 230 [180] DA levodopa equivalent daily doses [DALEDD], respectively; P=.04) and higher cumulative DA exposure (mean [SD], 1800 [1200] vs 700 [900] DALEDD-years, respectively; P=.03). Subjects with DAWS also had considerably lower Unified Parkinson’s Disease RatingScalemotorscoresthanthosewithoutDAWS(mean [SD],21[5]vs31[10],respectively;P=.007),despitecomparable disease duration (mean [SD], 7.3 [7] vs 6.3 [4] years, respectively; P=.77) and similar total dopaminergic medication use (mean [SD], 830 [450] vs 640 [610] total LEDD, respectively; P=.52) in the 2 groups. Conclusions:Dopamineagonistshaveastereotypedwithdrawal syndrome that can lead to profound disability in a subset of patients. Physicians should monitor patients closely when tapering these medications.
TL;DR: The study results confirm that PNS influences oncologic patient survival, and elucidate the clinical evolution of paraneoplastic cerebellar syndrome according to the onconeural antibodies present.
Abstract: Background Paraneoplastic neurologic syndrome (PNS) represents the remote effects of cancer on the nervous system. Diagnostic criteria for the syndrome were published by the PNS Euronetwork and form the basis of a database to collect standardized clinical data from patients with PNS. Objectives To analyze various types of PNS, frequent tumor and antibody associations, clinical characteristics of individual syndromes, and possible therapeutic and prognostic strategies. Design Prospective case series and database study. Setting Twenty European centers. Patients Patients were recruited from January 1, 2000, to December 31, 2008. Main Outcome Measures Based on diagnostic criteria published by the PNS Euronetwork consortium, clinical characteristics of classic PNS and several other less well-characterized syndromes associated with cancer were assessed. Results Data from 979 patients were analyzed, representing the largest PNS investigation to date. The findings elucidate the clinical evolution of paraneoplastic cerebellar syndrome according to the onconeural antibodies present, the heterogeneity and prognosis of dysautonomic disorders, and the clinical variability of paraneoplastic limbic encephalitis. Conclusion The study results confirm that PNS influences oncologic patient survival. Tumors are the main cause of death, but some types of PNS (such as dysautonomia) have a poorer prognosis than malignant neoplasms.
TL;DR: A patient with neuromyelitis optica whose aquaporin 4 (AQP4) antibody levels increased following treatment with interferon beta is described, the first to illustrate an increase in AQP4 antibodies associated with such treatment.
Abstract: 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.
TL;DR: Loss of lean mass is accelerated in AD and is associated with brain atrophy and cognitive performance, perhaps as a direct or indirect consequence of AD pathophysiology or through shared mechanisms common to both AD and sarcopenia.
Abstract: Objective To examine body composition in individuals with early AD and without dementia and its relation to cognition and brain volume. Design Cross-sectional case-control study. Participants Individuals without dementia (Clinical Dementia Rating, 0; n = 70) and with early-stage AD (Clinical Dementia Rating, 0.5 or 1; n = 70) in the Alzheimer and Memory Program at the University of Kansas School of Medicine. Main Outcome Measures Participants were evaluated with brain magnetic resonance imaging (MRI), neuropsychological testing, and dual-energy x-ray absorptiometry to determine whole-body fat and lean masses. Body mass index was calculated as weight in kilograms divided by height in meters squared. Results Lean mass was reduced in persons with early AD compared with controls without dementia ( F = 7.73; P = .006) after controlling for sex. Whole-brain volume (β = .20; P P P = .007) were associated with lean mass (dependent variable) when controlling for age and sex. The total body fat and percentage of body fat values were not different across groups or related to cognition and brain volume. Conclusion Loss of lean mass is accelerated in AD and is associated with brain atrophy and cognitive performance, perhaps as a direct or indirect consequence of AD pathophysiology or through shared mechanisms common to both AD and sarcopenia.
TL;DR: Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART, and argue for redoubled efforts to determine HIV- SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
Abstract: Objective To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era. Design Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models. Setting Six US academic medical centers. Patients One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study. Main Outcome Measures The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey. Results We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95% confidence interval, 1.8-2.5] per 10 years), lower CD4 nadir (1.2 [1.1-1.2] per 100-cell decrease), current CART use (1.6 [1.3-2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3-2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir. Conclusions Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
TL;DR: The results are consistent with the suggestion that high vitamin D status provides protection against Parkinson disease, and individuals with higher vitamin D concentrations showed a reduced risk of Parkinson disease.
Abstract: Setting: The study was based on the Mini-Finland Health Survey, which was conducted from 1978 to 1980, with Parkinson disease occurrence follow-up through the end of 2007. During the 29-year follow-up period, 50 incident Parkinson disease cases occurred. Serum 25-hydroxyvitamin D level was determined from frozen samples stored at baseline. Estimates of the relationship between serum vitamin D concentration and Parkinson disease incidence were calculated using the Cox model. Participants: Three thousand one hundred seventythree men and women, aged 50 to 79 years and free of Parkinson disease at baseline. Main Outcome Measure: Parkinson disease incidence. Results: Individuals with higher serum vitamin D concentrations showed a reduced risk of Parkinson disease. The relative risk between the highest and lowest quartiles was 0.33 (95% confidence interval, 0.14-0.80) after adjustment for sex, age, marital status, education, alcohol consumption, leisure-time physical activity, smoking, body mass index, and month of blood draw. Conclusions: The results are consistent with the suggestion that high vitamin D status provides protection against Parkinson disease. It cannot, however, be excluded that the finding is due to residual confounding and further studies are thus needed.
TL;DR: Recognition of a nonmotor preclinical phase spanning 20 or more years should guide the search for predictive biomarkers and the identification of risk or protective factors for Parkinson disease.
Abstract: There is convincing evidence that the Parkinson disease neurodegenerative process begins many years before the onset of motor manifestations. Initial estimates based on nigral neuropathological findings or striatal dopamine imaging suggested a 5- to 6-year preclinical period. However, more recent evidence of Lewy body pathology in other neuronal populations preceding nigral involvement suggests that the preclinical phase may be much longer. Epidemiologic studies of nonmotor manifestations, such as constipation, anxiety disorders, rapid eye movement sleep behavior disorder (RBD), and anemia, suggest that the preclinical period extends at least 20 years before the motor manifestations. Olfactory impairment and depression may also precede the onset of motor manifestations; however, the lag time may be shorter. Recognition of a nonmotor preclinical phase spanning 20 or more years should guide the search for predictive biomarkers and the identification of risk or protective factors for Parkinson disease.
TL;DR: Recent advances in therapy for glioblastoma are reviewed, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of gliOBlastoma is discussed.
Abstract: Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. Despite that, recurrence is quite common, and so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review recent advances in therapy for glioblastoma, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of glioblastoma is discussed in a separate article in this issue of the Archives.
TL;DR: The objective is to critically review the biological basis and translational potential of this action of minocycline on the nervous system.
Abstract: 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.
TL;DR: Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD.
Abstract: Background The Rotterdam Study previously found that higher dietary intakes of vitamins E and C related to lower risk of dementia and Alzheimer disease (AD) over 6 years of follow-up. Objective To study consumption of major dietary antioxidants relative to long-term risk of dementia. Design Population-based prospective cohort study. Setting The Rotterdam Study in the Netherlands. Participants A total of 5395 participants, 55 years and older, who were free of dementia and provided dietary information at study baseline. Main Outcome Measures Incidence of dementia and AD, based on internationally accepted criteria, relative to dietary intake of vitamin E, vitamin C, beta carotene, and flavonoids. Results During a mean follow-up period of 9.6 years, dementia developed in 465 participants, of whom 365 were diagnosed as having AD. In multivariate models adjusted for age, education, apolipoprotein E e4 genotype, total energy intake, alcohol intake, smoking habits, body mass index, and supplement use, higher intake of vitamin E at study baseline was associated with lower long-term risk of dementia ( P = .02 for trend). Compared with participants in the lowest tertile of vitamin E intake, those in the highest tertile were 25% less likely to develop dementia (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95 with adjustment for potential confounders). Dietary intake levels of vitamin C, beta carotene, and flavonoids were not associated with dementia risk after multivariate adjustment ( P > .99 for trend for vitamin C and beta carotene and P = .60 for trend for flavonoids). Results were similar when risk for AD was specifically assessed. Conclusion Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD.
TL;DR: These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD, and suggest the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.
Abstract: Objective To develop an algorithm that separates patients with Alzheimer disease (AD) from controls. Design Longitudinal case-control study. Setting The Texas Alzheimer's Research Consortium project. Patients We analyzed serum protein–based multiplex biomarker data from 197 patients diagnosed with AD and 203 controls. Main Outcome Measure The total sample was randomized equally into training and test sets and random forest methods were applied to the training set to create a biomarker risk score. Results The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively, and an area under the curve of 0.91 in detecting AD. When age, sex, education, and APOE status were added to the algorithm, the sensitivity, specificity, and area under the curve were 0.94, 0.84, and 0.95, respectively. Conclusions These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. A disproportionate number of inflammatory and vascular markers were weighted most heavily in the analyses. Additionally, these markers consistently distinguished cases from controls in significant analysis of microarray, logistic regression, and Wilcoxon analyses, suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.
TL;DR: Loci associated with AD also influence neuroim imaging correlates of this disease, and neuroimaging analysis identified 2 additional loci of high interest for further study.
Abstract: Patients: A total of 168 individuals with probable AD, 357 with mild cognitive impairment, and 215 cognitively normal control individuals recruited from more than 50 Alzheimer’s Disease Neuroimaging Initiative centers in the United States and Canada. All study participants had APOE and genome-wide genetic data available. Main Outcome Measures: We investigated the influence of GWAS-validated and GWAS-promising novel AD loci on hippocampal volume, amygdala volume, white matter lesion volume, entorhinal cortex thickness, parahippocampal gyrus thickness, and temporal pole cortex thickness. Results: Markers at theAPOE locus were associated with all phenotypes except white matter lesion volume (all false discovery rate–correctedP values.001). Novel and established AD loci identified by prior GWASs showed a significant cumulative score–based effect (false discovery rate P=.04) on all analyzed neuroimaging measures. The GWAS-validated variants at the CR1 and PICALM loci and markers at 2 novel loci (BIN1 and CNTN5) showed association with multiple magnetic resonance imaging characteristics (false discovery rate P.05). Conclusions: Loci associated with AD also influence neuroimaging correlates of this disease. Furthermore, neuroimaging analysis identified 2 additional loci of high interest for further study.
TL;DR: White matter hyperintensity volume predicts 1-year cognitive decline in a relatively healthy convenience sample that was similar to clinical trial samples, and therefore should be considered as a covariate of interest at baseline and longitudinally in future AD treatment trials.
Abstract: Objective To evaluate relationships between magnetic resonance imaging (MRI)–based measures of white matter hyperintensities (WMHs), measured at baseline and longitudinally, and 1-year cognitive decline using a large convenience sample in a clinical trial design with a relatively mild profile of cardiovascular risk factors Design Convenience sample in a clinical trial design Subjects A total of 804 participants in the Alzheimer Disease Neuroimaging Initiative who received MRI scans, cognitive testing, and clinical evaluations at baseline, 6-month follow-up, and 12-month follow-up visits For each scan, WMHs were detected automatically on coregistered sets of T1, proton density, and T2 MRI images using a validated method Mixed-effects regression models evaluated relationships between risk factors for WMHs, WMH volume, and change in outcome measures including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating Scale sum of boxes scores Covariates in these models included race, sex, years of education, age, apolipoprotein E genotype, baseline clinical diagnosis (cognitively normal, mild cognitive impairment, or Alzheimer disease), cardiovascular risk score, and MRI-based hippocampal and brain volumes Results Higher baseline WMH volume was associated with greater subsequent 1-year increase in ADAS-Cog and decrease in MMSE scores Greater WMH volume at follow-up was associated with greater ADAS-Cog and lower MMSE scores at follow-up Higher baseline age and cardiovascular risk score and more impaired baseline clinical diagnosis were associated with higher baseline WMH volume Conclusions White matter hyperintensity volume predicts 1-year cognitive decline in a relatively healthy convenience sample that was similar to clinical trial samples, and therefore should be considered as a covariate of interest at baseline and longitudinally in future AD treatment trials
TL;DR: This pilot study provides the first in vivo evidence suggesting a role for serotonin 2A receptors in mediating VHs via the ventral visual pathway in PD, and treatment studies should be performed using selective serotonin2A receptor antagonists.
Abstract: Background Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the serotonin 2 receptor. Objective To examine for the first time in vivo changes in serotonin 2A receptor neurotransmission among patients having Parkinson disease (PD) with VHs. Design Case-control study. Setting Academic research. Patients Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited. Main Outcome Measures We used the selective serotonin 2A receptor ligand setoperone F 18 during positron emission tomography among nondemented patients having PD with VHs. Results Patients having PD with VHs demonstrate increased serotonin 2A receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula. Conclusions This pilot study provides the first in vivo evidence suggesting a role for serotonin 2A receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective serotonin 2A receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD.
TL;DR: In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nerve system.
Abstract: Background B cells are implicated in the pathogenesis of multiple sclerosis. A beneficial effect of B-cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. Objective To determine the relationship between T and B cells and changes in cerebrospinal fluid (CSF) chemokine levels with rituximab, a monoclonal antibody that targets CD20. Design Phase 2 trial of rituximab as an add-on therapy. Setting The John L. Trotter Multiple Sclerosis Center, Washington University. Participants and Intervention Thirty subjects who had relapsing-remitting multiple sclerosis with clinical and magnetic resonance imaging activity despite treatment with an immunomodulatory drug received 4 weekly doses of rituximab (375 mg/m 2 ). Main Outcome Measures Lumbar puncture was performed before and after rituximab infusions in 26 subjects. Levels of B and T lymphocytes in the CSF were enumerated by flow cytometry, and chemoattractant levels were measured by enzyme-linked immunosorbent assay. Results After rituximab administration, CSF B-cell levels were decreased or undetectable in all subjects, and CSF T-cell levels were reduced in 21 subjects (81%). The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 levels decreased ( P = .002 and P = .03, respectively). The proportional decline in CSF T-cell levels correlated with the proportional decrease in CXCL13 levels ( r = 0.45; P = .03), suggesting a possible relationship. The CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. Conclusions In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nervous system.
TL;DR: High HDL-C levels in elderly individuals may be associated with a decreased risk of AD in analyses adjusting for age, sex, education, ethnic group, and APOE e4 genotype.
Abstract: Objective To reexamine the association of lipid levels with Alzheimer disease (AD) using Cox proportional hazards models. Design Prospective cohort study. Setting Northern Manhattan, New York. Participants One thousand one hundred thirty elderly individuals free of cognitive impairment at baseline. Main Outcome Measure High-density lipoprotein cholesterol (HDL-C) levels. Results Higher levels of HDL-C (>55 mg/dL) were associated with a decreased risk of both probable and possible AD and probable AD compared with lower HDL-C levels (hazard ratio, 0.4; 95% confidence interval, 0.2-0.9; P = .03 and hazard ratio, 0.4; 95% confidence interval, 0.2-0.9; P = .03). In addition, higher levels of total and non–HDL-C were associated with a decreased risk of AD in analyses adjusting for age, sex, education, ethnic group, and APOE e4 genotype. Conclusion High HDL-C levels in elderly individuals may be associated with a decreased risk of AD.
TL;DR: Results show near-perfect replication and provide the first additional evidence that CLU, CR1, and PICALM are associated with the risk of LOAD.
Abstract: 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 × 10 −5 , .014, and 1.3 × 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.
TL;DR: These findings cross-validate the previously published CDR-SB interpretative guidelines for staging dementia severity and extend those findings to a large heterogeneous sample of patients with dementia.
Abstract: Background It was recently demonstrated that the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score can be used to accurately stage severity of Alzheimer dementia and mild cognitive impairment (MCI). However, to our knowledge, the utility of those interpretive guidelines has not been cross-validated or applied to a heterogeneous sample of dementia cases. Objective To cross-validate the staging guidelines proposed in a previous study using the National Alzheimer's Coordinating Center (NACC) database. Design The previously published cut scores were applied to the NACC sample and diagnostic accuracy estimates obtained. Next, analyses were restricted to NACC participants with a CDR global score (CDR-GS) of 0.5 and receiver operating characteristic curves generated to determine optimal CDR-SB cut scores for distinguishing MCI from very early dementia. Setting The 2008 NACC uniform data set. Participants There were 12 462 participants (5115 controls; 2551 patients with MCI; 4796 patients with dementia, all etiologies) in the NACC data set used for the current analysis. Main Outcome Measure Accurate prediction of diagnoses (MCI or dementia) using the CDR-SB score. Results The previously proposed CDR-SB ranges successfully classified the vast majority of patients across all impairment ranges with a κ of 0.91 and 94% overall correct classification rate. Additionally, the CDR-SB score discriminated between patients diagnosed with MCI and dementia when CDR-GS was restricted to 0.5 (overall area under the curve = 0.83). Conclusions These findings cross-validate the previously published CDR-SB interpretative guidelines for staging dementia severity and extend those findings to a large heterogeneous sample of patients with dementia. Additionally, the CDR-SB scores distinguished MCI from dementia in patients with reasonable accuracy when CDR-GS was restricted to 0.5.