The diagnosis of young-onset dementia. Lancet Neurol 9:793-806

Dementia Research Centre, Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, UK.
The Lancet Neurology (Impact Factor: 21.9). 08/2010; 9(8):793-806. DOI: 10.1016/S1474-4422(10)70159-9
Source: PubMed


A diagnosis of dementia is devastating at any age but diagnosis in younger patients presents a particular challenge. The differential diagnosis is broad as late presentation of metabolic disease is common and the burden of inherited dementia is higher in these patients than in patients with late-onset dementia. The presentation of the common degenerative diseases of late life, such as Alzheimer's disease, can be different when presenting in the fifth or sixth decade. Moreover, many of the young-onset dementias are treatable. The identification of causative genes for many of the inherited degenerative dementias has led to an understanding of the molecular pathology, which is also applicable to later-onset sporadic disease. This understanding offers the potential for future treatments to be tailored to a specific diagnosis of both young-onset and late-onset dementia.

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Available from: Cath Mummery, Dec 12, 2014
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    • "All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. type is clinically challenging because of difficulty in the assessment of memory and cognitive impairment (especially in the early stages) and incomplete knowledge of clinical phenotypes [2]. Even within the set of PSEN1 variants that cause early-onset Alzheimer's disease (EOAD), there is substantial clinical heterogeneity [3] [4] [5] [6]. "
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    ABSTRACT: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. Among the 720 nonsynonymous SNPs shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the PS1 protein. The presence of this same mutation in a French early-onset Alzheimer's disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer's disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-150051 · 4.15 Impact Factor
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    • "The most common causes of dementia are Alzheimer's disease (AD), vascular disease (in several forms), dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD), but there are many others.10 11 Accurate and early diagnosis has considerable implications for the patient in terms of prognosis and management and will be increasingly important if and when disease modifying treatments become available. Currently, postmortem examination of brain tissue remains the only definitive means of establishing diagnosis in most cases. "
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    ABSTRACT: Accurate and timely diagnosis of dementia is important to guide management and provide appropriate information and support to patients and families. Currently, with the exception of individuals with genetic mutations, postmortem examination of brain tissue remains the only definitive means of establishing diagnosis in most cases, however, structural neuroimaging, in combination with clinical assessment, has value in improving diagnostic accuracy during life. Beyond the exclusion of surgical pathology, signal change and cerebral atrophy visible on structural MRI can be used to identify diagnostically relevant imaging features, which provide support for clinical diagnosis of neurodegenerative dementias. While no structural imaging feature has perfect sensitivity and specificity for a given diagnosis, there are a number of imaging characteristics which provide positive predictive value and help to narrow the differential diagnosis. While neuroradiological expertise is invaluable in accurate scan interpretation, there is much that a non-radiologist can gain from a focused and structured approach to scan analysis. In this article we describe the characteristic MRI findings of the various dementias and provide a structured algorithm with the aim of providing clinicians with a practical guide to assessing scans.
    Journal of neurology, neurosurgery, and psychiatry 10/2013; 85(6). DOI:10.1136/jnnp-2013-306285 · 6.81 Impact Factor
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    • "Although causes of EOD are diverse, the four most common causes are Alzheimer's disease (AD), vascular dementia (VAD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB); responsible for 34, 18, 12, and 7 % of cases, respectively (Harvey et al. 2003). Dementia secondary to genetic or metabolic disease is more common in patients with early-onset disease (Rossor et al. 2010). Alzheimer's disease presents as a progressive amnestic disorder which evolves to affect other cognitive domains. "
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    ABSTRACT: Early-onset dementia (EOD) is characterized by functionally impairing deterioration in memory, language, personality or visuospatial skills emerging under the age of 65. Cerebral functioning can be assessed by visual electroencephalography (EEG) interpretation. The aim of this systematic review is to evaluate the diagnostic utility of visual EEG in EOD focusing on Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Medline, Embase, Scopus, Web of Knowledge, and Google Scholar were systematically searched for studies where EEGs were included in the diagnostic evaluation of patients with dementia under the age of 65. Each paper was quality assessed and the results grouped according to dementia cause with a narrative summary. 4,157 papers were screened, 12 studies met the eligibility criteria with a total of 965 patients. An abnormal EEG was common to all causes of EOD. EEG abnormalities are more severe in early-onset AD patients. EEG severity grade is independent of disease duration. Slow wave activity is common to all dementias, but is most prominent in DLB. Frontal intermittent rhythmic delta activity could be considered as supportive for the diagnosis of DLB as can a Grand Total EEG score of over 9.5. EEG is usually normal in FTD. Focal changes can be seen in advanced VAD. Studies employed small patient groups, varying diagnostic criteria, and only a minority of patient diagnoses was pathologically confirmed. EEG may be useful as an adjunct in the diagnosis of DLB and AD. Further prospective well-powered studies are required to investigate diagnostic utility more robustly.
    Journal of Neural Transmission 07/2013; 121(1). DOI:10.1007/s00702-013-1070-5 · 2.40 Impact Factor
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