Can primary care electronic health records facilitate the prediction of early cognitive decline associated with dementia: a systematic literature review

Introduction Identifying the early stages of dementia is key in care management, clinical trial recruitment and mitigating the impact of cognitive impairment. At present, cognitive tests are most commonly used to investigate early stages of dementia and are often only conducted after initial symptoms of cognitive decline have been identified. There is potential to harness routinely collected data from electronic health records (EHR) to discover markers of early-stage dementia, both in its cognitive and non-cognitive manifestations. However, the extent to which primary care EHR can facilitate earlier diagnosis of dementia has not systematically been examined. We aim to determine the extent to which EHR can be utilized to identify prodromal dementia in primary care settings through a systematic review of the literature. Method We searched electronic medical databases (including Scopus, Web of Science, OvidSP, MEDLINE and PsychINFO) for potentially relevant studies up to and including September 2016 and written in English. We used the following MeSH search terms: “dementia” (including its subtypes), “electronic health records” (variations thereof) and “primary care”. Additionally, grey literature was searched including reports released by the government, councils and relevant major UK charities. Results We identified and reviewed 31 studies. In total 35 risk factors and 147 potential markers of early cognitive decline were identified. There was considerable variability across studies as to whether markers were classed as confounders, risk factors, early markers or co-morbidities. Markers predominantly fell within cognitive, affective, motor and autonomic symptoms, prescription patterns of both dementia and non-dementia medication and health system utilization, including type of consultation, frequency of contact and duration. Three studies investigated variation in the markers’ predictive strengths at different time points during the prodromal period of dementia. In the 24 months prior to diagnosis of dementia, gait disturbances, changes in weight, number of consultations, specialty referrals and hospital admissions showed the strongest strength of association with dementia diagnosis. Number of consultations, unpredictability in consulting patterns, such as “Did not attend”, carer and social care involvement showed the strongest strength of association with dementia diagnosis during a longer prodromal period (up to 54 months). Discussion Tests which specifically investigate cognitive health, such as the Mini Mental State Exam (MMSE) exam, are often only conducted in the period of Mild Cognitive Impairment (MCI) preceding dementia diagnosis, once irremediable damage has occurred. In many cases, these symptoms are conflated with normal ageing, affective disorders, or attenuated by multimorbidities, and are therefore not directly linked to dementia. These results show that there is a broad range of potential markers which could be used to better define prodromal dementia, however very little literature has been published in this area. Conclusion There is significant potential to use routinely collected data from EHR to investigate and define prodromal dementia. The use of EHR allows us to obtain a more complete understanding of early-stage dementia according to its more commonly investigated cognitive signs, as well as non-cognitive presentations. Understanding the breadth and trajectories in prodromal dementia period will be key in facilitating earlier diagnosis

Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges

Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway

Neurological update: hereditary neuropathies

In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of hereditary motor neuropathy and CMT2. We also report on recent therapeutic advances in hereditary neuropathy including the use of lipid nanoparticle sequestered antisense oligonucleotides in CMT1A and lipid nanoparticle delivered CRISPR-Cas9 gene editing in ATTR amyloidosis

Antisense oligonucleotides and other genetic therapies made simple

Many genetic neurological diseases result from the dysfunction of single proteins. Genetic therapies aim to modify these disease-associated proteins by targeting the RNA and DNA precursors. This review provides a brief overview of the main types of genetic therapies, with a focus on antisense oligonucleotides (ASOs) and RNA interference (RNAi). We use examples of new genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy and familial amyloid polyneuropathy to highlight the different mechanisms of action of ASOs and RNAi

Charcot-Marie-Tooth disease and related disorders: an evolving landscape

PURPOSE OF REVIEW: Charcot-Marie-Tooth (CMT) disease and related disorders are the commonest group of inherited neuromuscular diseases and represent a heterogeneous group of disorders. This review will cover recent advances in genetic diagnosis and the evolving genetic and phenotype landscape of this disease group. We will review recent evidence of the increasingly recognized phenotypic overlap with other neurodegenerative conditions including hereditary spastic paraplegia, hereditary ataxias and mitochondrial diseases and highlight the importance of deep phenotyping to inform genetic diagnosis and prognosis. RECENT FINDINGS: Through whole exome sequencing and multicentre collaboration new genes are being identified as causal for CMT expanding the genetic heterogeneity of this condition. In addition, an increasing number of variants have been identified in genes known to cause complex inherited diseases in which the peripheral neuropathy is part of the disorder and may be the presenting feature. The recent discovery of a repeat expansion in the RFC1 gene in cerebellar ataxia, neuropathy, vestibular areflexia syndrome highlights the prevalence of late-onset recessive conditions which have historically been considered to cause early-onset disease. SUMMARY: CMT is an evolving field with considerable phenotypic and genetic heterogeneity and deep phenotyping remains a cornerstone in contemporary CMT diagnostics

Toward common mechanisms for risk factors in Alzheimer's syndrome

The global strategic goal of reducing health care cost, especially the prospects for massive increases due to expanding markets for health care services demanded by aging populations and/or people with a wide range of chronic disorders-disabilities, is a complex and formidable challenge with many facets. Current projection s predict marked increases in the demand for health driven by both the exponential climb in the prevalence of chronic disabilities and the increases in the absolute numbers of people in need of some form of health care. Thus, the looming predicament for the economics of health care systems worldwide mandates the formulation of a strategic goal to foster significant expansion of global R & D efforts to discover and develop wide-ranging interventions to delay and/or prevent the onset of chronic disabling conditions. The rationale for adopting such a tactical objective is based on the premise that the costs and prevalence of chronic disabling conditions will be reduced by half even if a modest delay of 5 years in the onset of disability is obtained by a highly focused multinational research initiative. Because of the recent history of many failures in drug trials, the central thesis of this paper is to argue for the exploration-adoption of novel mechanistic ideas, theories, and paradigms for developing wide range and/or types of interventions. Although the primary focus of our discussion has been on biological approaches to therapy, we recognize the importance of emerging knowledge on nonpharmacological interventions and their potential impact in reducing health care costs. Although we may not find a drug to cure or prevent dementia for a long time, research is starting to demonstrate the potential contributes of nonpharmacological interventions toward the economics of health care in terms of rehabilitation, promoting autonomy, and potential to delay institutionalization, thus promoting healthy aging and reductions in the cost of care

The cognitive footprint of medication: A review of cognitive assessments in clinical trials

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy is common, and many medications have cognitive side effects. Such effects can be transient and subside when the drug in question is discontinued or can be long-lasting with effects present for years afterwards. Although formal assessment of cognition is feasible and often undertaken in neuropsychiatric trials, these effects are usually neglected in the evaluation of any non-neuropsychiatric health intervention. Medication effects can be assessed within a cognitive footprint framework, to account for the magnitude and the duration of cognitive side effects, with some likely to have a greater and more lasting effect than others. COMMENT: Adverse event reporting suggests that many medications may be indirectly associated with cognitive effects, for example due to headaches, somnolence and 'dizziness'; however, inferring causation from adverse event reporting can be problematic. In order to better understand the impact of investigational drug and concomitant medications effect on cognition, it would be essential to ensure cognition is prioritized in drug development evaluation. It is suggested that simple instruments that can be easily incorporated into existing trial designs are used to assess the cognitive footprint of medication. WHAT IS NEW AND CONCLUSION: We present an overview of existing measures of cognition that can be integrated into drug trials in order to provide a cognitive footprint. Like quality of life testing, such tests should be administered as a standard throughout the key assessment stages of the design of the trial to ensure that any effects on this equally important outcome are also documented. Furthermore, employing routine cognition testing may also enable researchers to identify unanticipated beneficial and non-beneficial effects on cognition. Provision of such a cognitive footprint profile of drugs may provide the necessary evidence to enable decision-makers to make informed decisions on risk-benefit analysis that can subsequently make trade-offs between different drug regimens