Primary objective: The purpose of this paper is to review the clinical and research utility and applications of blood, cerebrospinal fluid (CSF), and cerebral microdialysis biomarkers in traumatic brain injury (TBI). Research design: Not applicable. Methods and procedures: A selective review was performed on these biofluid biomarkers in TBI. Main outcome and results: Neurofilament heavy chain protein (NF-H), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCHL1), neuron-specific enolase (NSE), myelin basic protein (MBP), tau, and s100β blood biomarkers are elevated during the acute phase of severe head trauma but have key limitations in their research and clinical applications to mild TBI (mTBI). CSF biomarkers currently provide the best reflection of the central nervous system (CNS) pathobiological processes in TBI. Both animal and human studies of TBI have demonstrated the importance of serial sampling of biofluids and suggest that CSF biomarkers may be better equipped to characterize both TBI severity and temporal profiles. Conclusions: The identification of biofluid biomarkers could play a vital role in identifying, diagnosing, and treating the underlying individual pathobiological changes of TBI. CNS-derived exosomes analyzed by ultra-high sensitivity detection methods have the potential to identify blood biomarkers for the range of TBI severity and time course.

Dementia is underdiagnosed in both the general population and among Veterans. This underdiagnosis decreases quality of life, reduces opportunities for interventions, and increases health-care costs. New approaches are therefore necessary to facilitate the timely detection of dementia. This study seeks to identify cases of undiagnosed dementia by developing and validating a weakly supervised machine-learning approach that incorporates the analysis of both structured and unstructured electronic health record (EHR) data. A topic modeling approach that included latent Dirichlet allocation, stable topic extraction, and random sampling was applied to VHA EHRs. Topic features from unstructured data and features from structured data were compared between Veterans with (n = 1861) and without (n = 9305) ICD-9 dementia codes. A logistic regression model was used to develop dementia prediction scores, and manual reviews were conducted to validate the machine-learning results. A total of 853 features were identified (290 topics, 174 non-dementia ICD codes, 159 CPT codes, 59 medications, and 171 note types) for the development of logistic regression prediction scores. These scores were validated in a subset of Veterans without ICD-9 dementia codes (n = 120) by experts in dementia who performed manual record reviews and achieved a high level of inter-rater agreement. The manual reviews were used to develop a receiver of characteristic (ROC) curve with different thresholds for case detection, including a threshold of 0.061, which produced an optimal sensitivity (0.825) and specificity (0.832). Dementia is underdiagnosed, and thus, ICD codes alone cannot serve as a gold standard for diagnosis. However, this study suggests that imperfect data (e.g., ICD codes in combination with other EHR features) can serve as a silver standard to develop a risk model, apply that model to patients without dementia codes, and then select a case-detection threshold. The study is one of the first to utilize both structured and unstructured EHRs to develop risk scores for the diagnosis of dementia.

This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. CSF amyloid beta1–42 (Aβ42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aβ42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × ε4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3’-exon, and this CGI’s effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.

Background: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington’s disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic r

Unusual or unexpected effect of treatment Many patients with dementia with Lewy bodies (DLB) experience cholinesterase inhibitor- and antipsychotic-resistant psychosis. The new second-generation antipsychotic pimavanserin has been used with some success in the treatment of psychosis in other forms of dementia, including Alzheimer disease and Parkinson disease dementia. It is possible that pimavanserin may also be useful in the treatment of psychosis in DLB. We sought to describe the disease course and treatment of psychosis in 4 patients with DLB who were prescribed pimavanserin after other medications failed to reduce the frequency or severity of hallucinations and delusions. This is a case series of 4 male patients (ages 56 to 74 at the beginning of the reports) who developed DLB and psychosis (eg, visual illusions, visual and olfactory hallucinations, and paranoid delusions). All 4 patients were prescribed cholinesterase inhibitors (eg, donepezil or rivastigmine) prior to pimavanserin, and only 1 patient experienced improved psychosis while on cholinesterase inhibitors. All 3 patients who were prescribed first-generation antipsychotics (eg, haloperidol) or traditional second-generation antipsychotics (eg, olanzapine, risperidone, or quetiapine) experienced initial or lasting side effects with no improvement of psychosis. Conversely, all 4 patients tolerated pimavanserin well, and 3 of the 4 patients experienced significant improvement of psychosis (eg, fewer hallucinations, fewer delusions, reduced paranoia, and/or reduced distress or agitation related to hallucinations and delusions) when prescribed pimavanserin. This case series suggests that pimavanserin is tolerable in older males with DLB and that it may be useful for the reduction of distressful hallucinations, delusions, and paranoia in patients with DLB.