Cytokine/chemokine dysregulation in progressive MS patient is apparent and can be modulated by calpain inhibition.

This study examines the cytokine/chemokine profile of a 62-year-old African American male with progressive multiple sclerosis (MS). MRI images of the MS patient demonstrated generalized white matter involvement with multiple lesions in the periventricular area. A 42-plex Discovery Assay® (Eve Technologies) of the patient's plasma and peripheral blood mononuclear cells (PBMCs) supernatant or PBMC-derived T cell supernatant samples from two separate clinic visits revealed vastly differing cytokine/chemokine levels. In addition, certain cytokine/chemokine profiles had notable differences when compared to the larger patient group or patients' PBMCs treated with a calpain inhibitor in vitro. Interestingly, large numbers of cytokines/chemokines and growth factors in MS PBMCs are modulated by calpain inhibition, suggesting the clinical significance of these findings in designing better therapeutics against progressive MS.

Efficacy and Safety of Alemtuzumab in Patients of African Descent with Relapsing-Remitting Multiple Sclerosis: 8-Year Follow-up of CARE-MS I and II (TOPAZ Study).

INTRODUCTION: Multiple sclerosis (MS) patients of African descent have increased risk for disease progression and may be less responsive to disease-modifying therapy. METHODS: Patients in the CARE-MS studies received alemtuzumab 12 mg/day [initial alemtuzumab treatment (IAT); baseline: 5 days; 12 months later: 3 days] or subcutaneous interferon beta-1a (SC IFNB-1a) 3 ×/week. Core study outcomes were compared between treatment groups. In the extension study CAMMS03409, SC IFNB-1a-treated patients switched to alemtuzumab [delayed alemtuzumab treatment (DAT)]. Data from IAT and DAT arms were pooled to assess outcomes through 6 years post alemtuzumab initiation; IAT patients had an additional 2 years of follow-up in TOPAZ. RESULTS: Of 1200 CARE-MS patients, 43 (4%) were of African descent (35 IAT; 8 DAT) and received alemtuzumab in the 2-year core and/or 6-year extension; 29 (67%) remained on study at the time of analysis (24 IAT patients completed year 8 post alemtuzumab; 5 DAT patients completed year 6 post alemtuzumab). In year 2, annualized relapse rate (ARR; 0.09 versus 0.42), percentage of patients with improved Expanded Disability Status Scale (EDSS; 18% versus 11%), 6-month confirmed disability improvement (CDI; 28% versus 13%), no evidence of disease activity (55% versus 13%), and cumulative brain volume loss (BVL; - 0.55% versus - 1.32%) favored alemtuzumab versus SC IFNB-1a. Alemtuzumab remained efficacious at year 6 (pooled IAT/DAT) and at year 8 (IAT only) post alemtuzumab (ARR: 0.15 and 0.30; improved EDSS: 17% and 25%; CDI: 47% and 55%; BVL: - 1.14% and - 0.70%, respectively). No safety signals were unique to this population. CONCLUSIONS: Alemtuzumab was efficacious in a small cohort of relapsing-remitting MS patients of African descent over 8 years. Safety was consistent with the overall CARE-MS population, although the small sample size may have prevented the detection of known low-frequency adverse events. CLINICALTRIALS. GOV REGISTRATION NUMBERS: CARE-MS I, II, extension, TOPAZ: NCT00530348, NCT00548405, NCT00930553, NCT02255656. FUNDING: Sanofi (Cambridge, MA, USA) and Bayer HealthCare Pharmaceuticals (Leverkusen, Germany).

Posterior cortical atrophy of a suspected non-Alzheimer type: a case report.

OBJECTIVE: A case of Posterior Cortical Atrophy syndrome of a suspected non-Alzheimer disease pathology type is presented to illustrate prospective diagnosis and course. METHOD: A 54-year-old woman with vague memory complaints underwent serial neuropsychological assessment, MRI, PET, and CSF screening; data are reviewed. RESULTS: While early diagnosis was confounded by multiple factors, classic visuospatial symptoms were later demonstrated using routine neuropsychological methods. Serial MRI, PET, and CSF screening argued strongly for an alternative underlying pathology to AD. At age 59, her condition had progressed to dementia. CONCLUSIONS: Findings underscore the need for further research on suspected non-amyloid-based pathologies.

APOE genotype in the diagnosis of Alzheimer's disease in patients with cognitive impairment.

BACKGROUND: Although an association between the apolipoprotein E (APOE) ε4 allele and increased risk of Alzheimer's disease (AD) is established, the utility of APOE genotyping in the clinical diagnosis of AD is still under investigation. METHODS: Medical records of 89 patients with cognitive impairment and APOE genotype data underwent a retrospective review. RESULTS: Comparison of age, age at onset, education, Mini-Mental State Examination, months of follow-up, and family history of dementia did not reveal statistical difference among the patients with different APOE genotypes. The APOE ε4 carriers had a higher percentage of AD diagnoses after a median 16 months follow-up than non-APOE ε4 carriers. The APOE ε4 designation had a high sensitivity and high positive predictive value for the diagnosis of AD but a low negative predictive value and specificity. CONCLUSIONS: The APOE genotyping may be helpful in diagnosing AD especially in patients presenting with atypical features or early age of onset of dementia.

Response to disease modifying therapies in African Americans with multiple sclerosis.

BACKGROUND: The African American (AA) population has a lower risk for developing multiple sclerosis (MS) than Caucasian (CA) population; however, the disease tends to be more severe with early disability in AA. The reason underlying the discrepancy in disease severity is not yet understood, and it could be caused by different response to disease modifying therapies (DMTs). OBJECTIVE: To evaluate whether there are significant differences in profile of response to disease modifying therapies related to ethnicity, while controlling for disease characteristics. DESIGN: We performed a retrospective chart analysis of MS patients undergoing treatment with DMTs. Rating of disease progression was based on expanded disability status score (EDSS) difference at the time of first and last visit. PATIENTS: AA and CA patients with MS. RESULTS: Sex and age at the time of diagnosis did not differ significantly between AA and CA. There was statistically significant difference in disease duration, which was longer among CA patients (P < .001). Median of EDSS difference was higher in AA population than in CA population (P < .001). Increased EDSS difference suggests poorer response to DMTs among AA patients in our study. CONCLUSIONS: AA patients showed poorer response to DMTs when compared with CA patients. This suggests a trend, however, further prospective studies on the response of AA patients to DMTs are warranted.

Establishment of a predominantly African-American cohort for the study of Alzheimer's disease: the South Carolina Alzheimer's disease clinical core.

BACKGROUND/AIMS: The recruitment of culturally diverse subject populations into research studies, particularly African-Americans (AA), has been the focus of intense interest by many groups. METHODS: In this paper, we present the methodology utilized to create a predominantly AA cohort for the longitudinal study of risk factors in Alzheimer's disease (AD). The underlying strategy was that of identifying geographically diverse clinical venues within South Carolina (SC) where large numbers of AA patients already come to seek medical care. RESULTS: This strategy was successful, although recruitment rates for AA subjects (43.4%) still fell below those for white subjects (70.3%; p = 0.0025). Subject characteristics of AA subjects that chose to enroll were not substantially different from those that declined to participate. The demographic characteristics of this cohort were largely similar to those of the SC Alzheimer Disease Registry, a population-based database. The problems of standardization of subject recruitment and assessment across diverse clinical venues are also addressed. CONCLUSION: The utilization of geographically diverse sites for research recruitment where minorities already receive medical care is one practical solution to the problem of minority participation in research. Multi-site recruitment to improve minority recruitment can be accomplished with acceptable standardization and inter-rater reliability.

Preliminary examination of progression of Alzheimer's disease in a rural Southern African American cohort.

African Americans are at significantly increased risk for the development of Alzheimer's disease (AD), yet are seriously underrepresented in research trials. Preliminary experiences on a large scale, multi-site, 5-year longitudinal trial investigating the psychometric expression and progression of AD targeting an aging Southern rural cohort of African Americans are reported. Sixty-five participants, ranging from asymptomatic to severely demented, underwent extensive individual diagnostic and psychometric evaluation. Results indicated that cultural factors strongly influenced the data. Recruitment with asymptomatic volunteers were found to have greater educational attainment than other participant groups. Psychomotor measures showed greater impairment in African Americans compared to Caucasians suggesting increased cerebrovascular burden. African Americans' performance on the Boston Naming Test and the Wechsler Test of Adult Reading tests were significantly different than performance of Caucasian groups. The findings demonstrated that a better understanding of sociocultural factors associated with AD in the African American population may facilitate the development of primary and secondary preventions, especially when considering the role of cerebrovascular comorbidity which is a modifiable risk factor.

Therapeutic options in neurosarcoidosis.

Neurosarcoidosis is an uncommon disorder that requires careful clinical evaluation to reach the diagnosis. It may involve the CNS and peripheral nervous system and in the majority of cases it is associated with systemic disease. The demonstration of the activity of the immune system, as suggested by routine and immunopathological studies, forms a theoretical basis for the common forms of immunosuppressive therapies that are employed in sarcoidosis. Classic treatment consists of steroids either intravenously or orally. In refractory cases or in order to reduce or eliminate steroids, methotrexate, cyclophosphamide, azathioprine, cyclosporin, chlorambucil, chloroquine and hydroxychloroquine use may be an option.

Neurosarcoidosis.

Neurosarcoidosis is an uncommon disorder and requires a careful clinical evaluation to reach a diagnosis. Generally, patients with peripheral symptoms, which include paresthesias, painful patches over extremities, and stocking glove deficits, have a better outcome when compared with those with central nervous system (CNS) involvement. Patients with mass lesions or hydrocephalus tend to have more relapses and are often more resistant to routine therapy. Neurosarcoidosis often responds to glucocorticoids, usually within days or weeks of initiating therapy. Patients are usually maintained on 40 to 80 mg per day for 4 to 6 weeks, then tapered slowly. The use of alternative treatments for refractory neurosarcoidosis, or to reduce or eliminate steroids, includes methotrexate, cyclophosphamide, azathioprine, cyclosporine, chlorambucil, chloroquine, and hydroxychloroquine.