Biomedical Informatics Applications for Precision Management of Neurodegenerative Diseases

Modern medicine is in the midst of a revolution driven by “big data,” rapidly advancing computing power, and broader integration of technology into healthcare. Highly detailed and individualized profiles of both health and disease states are now possible, including biomarkers, genomic profiles, cognitive and behavioral phenotypes, high-frequency assessments, and medical imaging. Although these data are incredibly complex, they can potentially be used to understand multi-determinant causal relationships, elucidate modifiable factors, and ultimately customize treatments based on individual parameters. Especially for neurodegenerative diseases, where an effective therapeutic agent has yet to be discovered, there remains a critical need for an interdisciplinary perspective on data and information management due to the number of unanswered questions. Biomedical informatics is a multidisciplinary field that falls at the intersection of information technology, computer and data science, engineering, and healthcare that will be instrumental for uncovering novel insights into neurodegenerative disease research, including both causal relationships and therapeutic targets and maximizing the utility of both clinical and research data. The present study aims to provide a brief overview of biomedical informatics and how clinical data applications such as clinical decision support tools can be developed to derive new knowledge from the wealth of available data to advance clinical care and scientific research of neurodegenerative diseases in the era of precision medicine

Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

IntroductionDisruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).MethodsWe examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).ResultsWe measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected q< 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.DiscussionOur results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD

Antiretroviral Non-Adherence is Associated With a Retrieval Profile of Deficits in Verbal Episodic Memory.

HIV-associated deficits in verbal episodic memory are commonly associated with antiretroviral non-adherence; however, the specific aspects of memory functioning (e.g., encoding, consolidation, or retrieval) that underlie this established relationship are not well understood. This study evaluated verbal memory profiles of 202 HIV+ participants who underwent a 30-day electronic monitoring of antiretroviral adherence. At the group level, non-adherence was significantly associated with lower scores on immediate and delayed passage recall and word list learning. Retention and recognition of passages and word lists were not related to adherence. Participants were then classified as having either a normal verbal memory profile, a "subcortical" retrieval profile (i.e., impaired free recall with relatively spared recognition), or a "cortical" encoding profile (e.g., cued recall intrusions) based on the Massman et al. ( 1990 ) algorithm for the California Verbal Learning Test. HIV+ participants with a classic retrieval deficit had significantly greater odds of being non-adherent than participants with a normal or encoding profile. These findings suggest that adherence to prescribed antiretroviral regimens may be particularly vulnerable to disruption in HIV+ individuals due to deficits in the complex process of efficiently accessing verbal episodic information with minimal cues. A stronger relationship between non-adherence and passage (vs. word list) recall was also found and may reflect the importance of contextual features in remembering to take medications. Targeted interventions for enhancing and supporting episodic memory retrieval processes may improve antiretroviral adherence and overall health outcomes among persons living with HIV

Bilingualism Is Associated with a Delayed Onset of Dementia but Not with a Lower Risk of Developing it: a Systematic Review with Meta-Analyses.

Some studies have linked bilingualism with a later onset of dementia, Alzheimer's disease (AD), and mild cognitive impairment (MCI). Not all studies have observed such relationships, however. Differences in study outcomes may be due to methodological limitations and the presence of confounding factors within studies such as immigration status and level of education. We conducted the first systematic review with meta-analysis combining cross-sectional studies to explore if bilingualism might delay symptom onset and diagnosis of dementia, AD, and MCI. Primary outcomes included the age of symptom onset, the age at diagnosis of MCI or dementia, and the risk of developing MCI or dementia. A secondary outcome included the degree of disease severity at dementia diagnosis. There was no difference in the age of MCI diagnosis between monolinguals and bilinguals [mean difference: 3.2; 95% confidence intervals (CI): -3.4, 9.7]. Bilinguals vs. monolinguals reported experiencing AD symptoms 4.7 years (95% CI: 3.3, 6.1) later. Bilinguals vs. monolinguals were diagnosed with dementia 3.3 years (95% CI: 1.7, 4.9) later. Here, 95% prediction intervals showed a large dispersion of effect sizes (-1.9 to 8.5). We investigated this dispersion with a subgroup meta-analysis comparing studies that had recruited participants with dementia to studies that had recruited participants with AD on the age of dementia and AD diagnosis between mono- and bilinguals. Results showed that bilinguals vs. monolinguals were 1.9 years (95% CI: -0.9, 4.7) and 4.2 (95% CI: 2.0, 6.4) older than monolinguals at the time of dementia and AD diagnosis, respectively. The mean difference between the two subgroups was not significant. There was no significant risk reduction (odds ratio: 0.89; 95% CI: 0.68-1.16) in developing dementia among bilinguals vs. monolinguals. Also, there was no significant difference (Hedges' g = 0.05; 95% CI: -0.13, 0.24) in disease severity at dementia diagnosis between bilinguals and monolinguals, despite bilinguals being significantly older. The majority of studies had adjusted for level of education suggesting that education might not have played a role in the observed delay in dementia among bilinguals vs. monolinguals. Although findings indicated that bilingualism was on average related to a delayed onset of dementia, the magnitude of this relationship varied across different settings. This variation may be due to unexplained heterogeneity and different sources of bias in the included studies. Registration: PROSPERO CRD42015019100

Analysis of electroencephalograms in Alzheimer's disease patients with multiscale entropy

The aim of this study was to analyse the electroencephalogram (EEG) background activity of Alzheimer’s disease (AD) patients using the Multiscale Entropy (MSE). The MSE is a recently developed method that quantifies the regularity of a signal on different time scales. These time scales are inspected by means of several coarse-grained sequences formed from the analysed signals. We recorded the EEGs from 19 scalp electrodes in 11 AD patients and 11 age-matched controls and estimated the MSE profile for each epoch of the EEG recordings. The shape of the MSE profiles reveals the EEG complexity, and it suggests that the EEG contains information in deeper scales than the smallest one. Moreover, the results showed that the EEG background activity is less complex in AD patients than control subjects. We found significant difference

Establishing diagnostic criteria: the role of clinical pragmatics

The study of pragmatic disorders is of interest to speech-language pathologists who have a professional responsibility to assess and treat communication impairments. However, these disorders, it will be argued in this paper, have a significance beyond the clinical management of clients with communication impairments. Specifically, pragmatic disorders can now make a contribution to the diagnosis of a range of clinical conditions in which communication is adversely affected. These conditions include attention deficit hyperactivity disorder (ADHD), the autistic spectrum disorders, schizophrenia and the dementias. Pragmatic disorders are already among the criteria used to diagnose some of these conditions (e.g. ADHD), although they are not described in these terms. In other conditions (e.g. the dementias), pragmatic disorders have potential diagnostic value in the absence of reliable biomarkers markers of these conditions and similar initial presenting symptoms. Using clinical data, and the findings of empirical studies, the case is made for the inclusion and/or greater integration of pragmatic disorders in the formal classificatory systems that are used to diagnose a range of disorders. A previously unrecognised role for pragmatic impairments in the nosology and diagnosis of clinical disorders is thereby established