Early affective changes and increased connectivity in preclinical Alzheimer's disease.
Alzheimer's & dementia (Amsterdam, Netherlands)
Fredericks, C. A., Sturm, V. E., Brown, J. A., Hua, A. Y., Bilgel, M., Wong, D. F., Resnick, S. M., Seeley, W. W.
2018; 10: 471–79
Abstract
Introduction: Affective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a "salience network" attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown.Methods: One hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid-PET. We hypothesized amyloid-positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes.Results: In participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth.Conclusions: Affective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social-emotional processing.
View details for DOI 10.1016/j.dadm.2018.06.002
View details for PubMedID 30302368
Abstract
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.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 other's ratings, rated the quality of all residents at the end of the residency. The data were then anonymized for all analyses.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 applicant's undergraduate college, but not the ranking of their medical school.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.
View details for DOI 10.1016/j.clineuro.2015.05.007
View details for Web of Science ID 000357226800014
View details for PubMedID 26038279
Abstract
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 patient's 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.
View details for DOI 10.1177/0961203314524292
View details for Web of Science ID 000339103900015
View details for PubMedID 24531080
Abstract
In past decades, neuroimaging research in bipolar disorder has demonstrated a convergence of findings in an amygdala-anterior paralimbic cortex neural system. This paper reviews behavioral neurology literature that first suggested a central role for this neural system in the disorder and the neuroimaging evidence that supports it.Relevant articles are reviewed to provide an amygdala-anterior paralimbic cortex neural system model of bipolar disorder, including articles from the fields of behavioral neurology and neuroanatomy, and neuroimaging.The literature is highly supportive of key roles for the amygdala, anterior paralimbic cortices, and connections among these structures in the emotional dysregulation of bipolar disorder. The functions subserved by their more widely distributed connection sites suggest that broader system dysfunction could account for the range of functions-from neurovegetative to cognitive-disrupted in the disorder. Abnormalities in some components of this neural system are apparent by adolescence, while others, such as those in rostral prefrontal regions, appear to progress over adolescence and young adulthood, suggesting a neurodevelopmental model of the disorder. However, some findings conflict, which may reflect the small sample sizes of some studies, and clinical heterogeneity and methodological differences across studies.Consistent with models derived from early behavioral neurology studies, neuroimaging studies support a central role for an amygdala-anterior paralimbic neural system in bipolar disorder, and implicate abnormalities in the development of this system in the disorder. This system will be an important focus of future studies on the developmental pathophysiology, detection, treatment, and prevention of the disorder.
View details for DOI 10.1111/j.1399-5618.2012.01015.x
View details for Web of Science ID 000304441200003
View details for PubMedID 22631619
Abstract
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.
View details for DOI 10.1016/j.bbi.2009.10.014
View details for Web of Science ID 000275217300004
View details for PubMedID 19883751
Abstract
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.
View details for DOI 10.1038/npp.2008.107
View details for Web of Science ID 000263259500013
View details for PubMedID 18704093
Abstract
Abnormalities in volumes of the amygdala have been reported previously in adolescents and adults with bipolar disorder (BD). Several studies have reported reduced volumes in adolescents with BD; however, both decreases and increases in volumes have been reported in adults with BD. Understanding of potential developmental contributions to these disturbances in morphology of the amygdala has been limited by the absence of longitudinal data in persons with BD. Here we use a within-subject longitudinal design to investigate whether amygdala volume abnormalities persist in adolescents and young adults with BD over a time interval of approximately 2 years.Participants included 18 adolescents and young adults: 10 participants with BD I and 8 healthy comparison participants. Amygdala volumes were measured on high-resolution magnetic resonance imaging scans acquired twice for each subject over intervals of approximately 2 years. Amygdala volumes were the dependent measures in a mixed-model statistical analysis to compare amygdala volumes between groups over time while covarying for total brain volume.Amygdala volumes were significantly smaller in adolescents and young adults with BD compared with healthy participants (p = 0.018). The effect of time was not significant.Although the sample size is modest, this study provides preliminary evidence to support the presence of decreased amygdala volumes in adolescents and young adults with BD that persist during this developmental epoch.
View details for Web of Science ID 000233818300010
View details for PubMedID 16403182
Abstract
Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder.Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change.Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005).Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.
View details for Web of Science ID 000183424900007
View details for PubMedID 12796223
