Category: Neurology

Hot Topics: Stem Cell Transplants May Slow Progression of Multiple Sclerosis

Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis

Muraro PA, Pasquini M, Atkins HL,et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurology. 2017.

Importance  Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

Objective  To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

Design, Setting, and Participants  Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

Exposures  Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

Main Outcomes and Measures  The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

Results  Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

Conclusions and Relevance  In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

Posted in Hot Topics in Research, Neurology

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

Importance  The aging of the US population is expected to lead to a large increase in the number of adults with dementia, but some recent studies in the United States and other high-income countries suggest that the age-specific risk of dementia may have declined over the past 25 years. Clarifying current and future population trends in dementia prevalence and risk has important implications for patients, families, and government programs.

Objective  To compare the prevalence of dementia in the United States in 2000 and 2012.

Design, Setting, and Participants  We used data from the Health and Retirement Study (HRS), a nationally representative, population-based longitudinal survey of individuals in the United States 65 years or older from the 2000 (n = 10 546) and 2012 (n = 10 511) waves of the HRS.

Main Outcomes and Measures  Dementia was identified in each year using HRS cognitive measures and validated methods for classifying self-respondents, as well as those represented by a proxy. Logistic regression was used to identify socioeconomic and health variables associated with change in dementia prevalence between 2000 and 2012.

Results  The study cohorts had an average age of 75.0 years (95% CI, 74.8-75.2 years) in 2000 and 74.8 years (95% CI, 74.5-75.1 years) in 2012 (P = .24); 58.4% (95% CI, 57.3%-59.4%) of the 2000 cohort was female compared with 56.3% (95% CI, 55.5%-57.0%) of the 2012 cohort (P < .001). Dementia prevalence among those 65 years or older decreased from 11.6% (95% CI, 10.7%-12.7%) in 2000 to 8.8% (95% CI, 8.2%-9.4%) (8.6% with age- and sex-standardization) in 2012 (P < .001). More years of education was associated with a lower risk for dementia, and average years of education increased significantly (from 11.8 years [95% CI, 11.6-11.9 years] to 12.7 years [95% CI, 12.6-12.9 years]; P < .001) between 2000 and 2012. The decline in dementia prevalence occurred even though there was a significant age- and sex-adjusted increase between years in the cardiovascular risk profile (eg, prevalence of hypertension, diabetes, and obesity) among older US adults.

Conclusions and Relevance  The prevalence of dementia in the United States declined significantly between 2000 and 2012. An increase in educational attainment was associated with some of the decline in dementia prevalence, but the full set of social, behavioral, and medical factors contributing to the decline is still uncertain. Continued monitoring of trends in dementia incidence and prevalence will be important for better gauging the full future societal impact of dementia as the number of older adults increases in the decades ahead.


Kenneth M. Langa, MD, PhD1,2,3,4; Eric B. Larson, MD, MPH5; Eileen M. Crimmins, PhD6; et alJessica D. Faul, PhD3; Deborah A. Levine, MD, MPH; Mohammed U. Kabeto, MS; David R. Weir, PhD 
JAMA Intern Med. Published online November 21, 2016. doi:10.1001/jamainternmed.2016.6807
Posted in Alzheimer Disease, December, Dementia, Hot Topics in Research

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue


 The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits.


Saturation and competition binding studies of 3H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with 3H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo 18F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo 18F-FDG PET and in vitro 3H-THK5117 autoradiography was observed in two of the three AD cases.


This study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.

Acta Neuropathologica Communications20153:40, DOI: 10.1186/s40478-015-0220-4; Lemoine et al. 2015; Received: 14 June 2015; Accepted: 15 June 2015; Published: 2 July 2015
Posted in Alzheimer Disease, April, Hot Topics in Research

Schizophrenia risk from complex variation of complement component 4

Schizophrenia risk from complex variation of complement component 4


Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Corresponding Author: McCarroll, Steven A.

Nature (2016), doi:10.1038/nature16549, Published online 27 January 2016

Posted in Dementia, February, Hot Topics in Research, Memory Impairment

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.


Cho-Yi Chen, Proceedings of the National Academy of Sciences 2015 of the USA ; published ahead of print December 22, 2015, doi:10.1073/pnas.1508249112. 


Posted in Brain, Dementia, Hot Topics in Research, Memory Impairment, Neurology