The diagnosis of young-onset dementia

Abstract

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.

Figure 1. Epidemiology of young-onset dementia

Data from the community study of Harvey and colleagues.

Figure 2. Neuropsychological signatures of young-onset dementia

The target diagrams (based on McFie69) show neuropsychological profiles in a healthy individual (centre) and in patients with typical profiles from the range of young-onset dementias. Each sector of the target shows a particular cognitive domain. The distance along the radial dimension indicates the level of functioning, and the concentric lines indicate the percentile scores relative to a healthy age-matched population. Normal function in a cognitive domain is shown by colour extending to the perimeter of the target; loss of function is indicated by reduction of the coloured sector that corresponds to that cognitive domain. The neuropsychological profile of a particular disease is evident in the pattern of decline of cognitive functions: the differential loss of function across cognitive domains. These profiles define clinical syndromes but the correspondence with tissue pathology is variable between diseases; for example, whereas semantic dementia is closely associated with TARDBP-positive cellular inclusions, other tissue pathologies such as cerebrovascular disease or dementia with Lewy bodies have more variable clinical syndromes that overlap with those shown here. TARDBP=TAR-DNA binding protein (also known as TDP-43).

Figure 3. Flow chart for assessment and investigation of young-onset dementia

This algorithm provides an overview of the diagnostic approach to patients with young-onset dementia. Given the many causes, this can only act as a general guide.*In amnestic young-onset dementia, first-line genetic testing is for APP, PSEN1, PSEN2, and prion. In behavioural cases, first-line testing is for MAPT (particularly if symmetrical atrophy on MRI) and GRN (particularly if asymmetric pattern of atrophy). EEG=electroencephalogram. FDG=fluorodeoxyglucose. SPECT=single photon emission computed tomography. Aβ=amyloid β. VGKC=voltage-gated potassium channel. FTLD=frontotemporal lobar degeneration. CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CJD=Creutzfeldt-Jakob disease.

Figure 4. The value of MRI in investigation of young-onset dementia

(A) Mild Alzheimer's disease in a 60-year-old individual with sporadic Alzheimer's disease (T1-weighted MRI): atrophy of hippocampi (arrows) is the earliest feature in amnestic Alzheimer's disease but hippocampi might appear normal, particularly in younger patients with Alzheimer's disease. (B, C) Posterior cortical atrophy in a 58-year-old individual (T1-weighted MRI). The sagittal view (B) shows a relatively well preserved hippocampus (arrow head); parieto-occipital atrophy (arrows) is seen on sagittal (B) and coronal (C) views. (D) T1-weighted MRI of a 58-year-old individual with progressive non-fluent aphasia who had pathologically proven Pick's disease. (E) T1-weighted MRI of a 63-year-old woman with semantic dementia who had tau-negative, TARDBP-positive inclusions at autopsy. (F) A 21-year-old individual with increased signal bilaterally in the pulvinar (arrows) on axial FLAIR MRI. The pulvinar sign is indicative of variant Creutzfeldt-Jakob disease and is best seen on axial FLAIR (or T2-weighted) MRI where the postero-medial thalami are brighter than the basal ganglia. Variant Creutzfeldt-Jakob disease was subsequently confirmed on tonsillar biopsy. (G) By use of FLAIR MRI, bilateral hippocampal high signal and atrophy is shown in a 57-year-old man with voltage-gated potassium channel antibody limbic encephalitis (arrows). FLAIR=fluid attenuated inversion recovery. TARDBP=TAR-DNA binding protein (also known as TDP-43).