Carolyn A. Fredericks

Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder.

Histological and behavioral research in bipolar disorder (BD) implicates structural abnormalities in the hippocampus. Brain-derived neurotrophic growth factor (BDNF) protein is associated with hippocampal development and plasticity, and in mood disorder pathophysiology. We tested the hypotheses that both the BDNF val66met polymorphism and BD diagnosis are associated with decreased hippocampus volume, and that individuals with BD who carry the met allele have the smallest hippocampus volumes compared to individuals without BD and val/val homozygotes. We further explored localization of morphological differences within hippocampus in BD associated with the met allele. Twenty individuals with BD and 18 healthy comparison (HC) subjects participated in high-resolution magnetic resonance imaging scans from which hippocampus volumes were defined and measured. We used linear mixed model analysis to study effects of diagnosis and BDNF genotype on hippocampus volumes. We then employed three-dimensional mapping to localize areas of change within the hippocampus associated with the BDNF met allele in BD. We found that hippocampus volumes were significantly smaller in BD compared to HC subjects, and presence of the BDNF met allele was associated with smaller hippocampus volume in both diagnostic groups. The BD subgroup who carried the BDNF met allele had the smallest hippocampus volumes, and three-dimensional mapping identified these decreases as most prominent in left anterior hippocampus. These results support effects of BD diagnosis and BDNF genotype on hippocampus structure and suggest a genetic subgroup within BD who may be most vulnerable to deficits in hippocampus and may most benefit from interventions that influence BDNF-mediated signaling.

Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala–anterior paralimbic neural system

Blond BN, Fredericks CA, Blumberg HP. Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala–anterior paralimbic neural system. 
Bipolar Disord 2012: 14: 340–355.

Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions

The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab

Belimumab is a monoclonal antibody against soluble B-lymphocyte stimulator, an essential growth factor for B-cell maturation and activation, which was approved by the US FDA in 2011 for patients with active autoantibody-positive systemic lupus erythematosus (SLE) who have failed standard treatment. Here we present the case of a 40-year-old woman with SLE diagnosed with progressive multifocal leukoencephalopathy (PML) on belimumab. After a total of 10 infusions of belimumab, from August 2012 through April 2013, in April 2013 she developed progressive neurologic decline with episodic dystonia and autonomic symptoms. Her imaging showed multifocal, confluent regions of T2 hyperintensity in the white matter bilaterally, and CSF JCV PCR returned positive. Based on the patients clinically mild SLE and the timing of symptom onset, belimumab likely played a key role in the development of PML. Trials of belimumab for other autoimmune diseases are ongoing; as applications for this novel drug broaden, careful monitoring for this potentially fatal adverse effect is warranted.

Predicting success: What medical student measures predict resident performance in neurology?

OBJECTIVE Many medical school metrics are used by residency programs to differentiate residency applicants. The importance of each metric in the field of neurology is unclear. MATERIALS AND METHODS This is a single-site retrospective evaluation of characteristics that predict resident quality. Several measures from all 57 adult neurology residents over 8 years were obtained including Step I scores, college and medical school rankings, in-service training examination scores, advanced degrees, and number of publications during residency. Two program directors, blinded to these data and each others ratings, rated the quality of all residents at the end of the residency. The data were then anonymized for all analyses. RESULTS There was no significant relationship between Step I scores and resident quality, though Step I scores correlated significantly with in-service training examination scores. Medical students with PhDs did not perform differently in terms of resident quality, number of publications in residency, or in-service training examination scores. Resident quality was correlated with the ranking of each applicants undergraduate college, but not the ranking of their medical school. CONCLUSIONS While Step I is used by many residency programs in ranking potential residents, it does not correlate with overall resident quality, although Step I scores may predict success on future standardized medical examinations. Students with PhDs do not differ from other residents across several metrics. Applicants from highly selective colleges, though not highly selective medical schools, had significantly higher quality ratings. Further research is needed to determine characteristics of medical students that predict performance during neurology residency.

Primary chronic traumatic encephalopathy in an older patient with late-onset AD phenotype.

First described as dementia pugilistica in boxers, chronic traumatic encephalopathy (CTE) is associated with repeated head injury and has received much attention after several high-profile National Football League cases.1 Recent work suggests that both the nature of potential predisposing trauma and the clinical spectrum of CTE may be broader than previously recognized.1–3 We report a case of CTE presenting as Alzheimer-like dementia in a war reporter with a history of prolonged proximity to shelling but no acute head trauma.

THE CONTRIBUTION OF EARLY ALZHEIMER’S DISEASE MARKERS TO INDIVIDUAL DIFFERENCES IN EPISODIC MEMORY IN COGNITIVELY NORMAL OLDER ADULTS

P4-322 THE CONTRIBUTION OF EARLY ALZHEIMER’S DISEASE MARKERS TO INDIVIDUAL DIFFERENCES IN EPISODIC MEMORY IN COGNITIVELY NORMAL OLDER ADULTS Alexandra N. Trelle, Jeffrey Bernstein, Valerie A. Carr, Gayle Deutsch, Carolyn A. Fredericks, Scott A. Guerin, Wanjia Guo, Marc Harrison, Manasi Jayakumar, Jiefeng Jiang, Geoffrey A. Kerchner, Anna Khazhenzon, Celia Litovsky, Beth C. Mormino, Ayesha Nadiadwala, Sharon Sha, Natalie Tanner, Monica Thieu, Anthony D. Wagner, Stanford University, Stanford, CA, USA; University of California San Diego, San Diego, CA, USA; San Jose State University, San Jose, CA, USA; Stanford Hospital and Clinics, Palo Alto, CA, USA; Genentech, Inc, South San Francisco, CA, USA; Johns Hopkins University, Baltimore, MD, USA; Massachusetts General Hospital, Boston, MA, USA; University of California at Irvine, Irvine, CA, USA; Stanford University, Palo Alto, CA, USA; Columbia University, New York, NY, USA. Contact e-mail: atrelle@stanford.edu

Early affective changes and increased connectivity in preclinical Alzheimer's disease

Affective changes precede cognitive decline in mild Alzheimers disease and may relate to increased connectivity in a “salience network” attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimers disease, and its relationship to this network, is unknown.