A clinicopathological approach to the diagnosis of dementia

Abstract

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes - Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases - with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.

Figure 1. Clinicopathological spectrum of neurodegenerative proteinopathies

Schematic representation of the molecular underpinnings of neurodegenerative diseases and their main clinical manifestations. The figure lists genes with full penetrance that are considered causative and risk genes (in parentheses) that influence molecular processes culminating in the misfolding and/or aggregation of six fundamental proteins: cellular prion protein (PrP^C), Aβ₄₂ (and, to a lesser extent, Aβ₄₀), tau, TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), and α-synuclein. These normal proteins misfold and/or accumulate in intracellular or extracellular compartments in specific areas of the CNS. Four major pathological disease categories are recognized: prion disease, Alzheimer disease (AD), frontotemporal lobar degeneration (FTLD) and Lewy body diseases (LBD). The pathologies can involve multiple molecules; for example, AD is a dual proteinopathy with Aβ and tau aggregates. Also, in some cases of prion disease, Aβ in seen in addition to the principal aggregates of misfolded scrapie prion protein (PrP^Sc). The majority of FTLD cases are associated with three different proteinopathies: tau, TDP-43 and FUS. Each pathological entity can in turn manifest as a variety of clinical syndromes, sometimes featuring symptoms that bridge syndromes. Asterisks indicate frontotemporal dementia (FTD) syndromes that, in addition to FTLD, can be associated with AD neuropathology. Genetic pleiotropy is also at play: mutations in certain genes — for example, GRN — have full penetrance for one pathology (FTLD-TDP) and associated FTD syndromes, while representing a risk factor for another pathology (AD). In addition, certain fully penetrant genetic mutations (for example, VCP mutations), are associated with additional systemic disease manifestations. The rich and diverse clinical expression of neurodegenerative processes is best illustrated in FTLD, a pathological category with six distinct clinical syndromes. Of note, FUS pathology causing FTLD is typically not associated with FUS mutations, which more often cause amyotrophic lateral sclerosis. Aβ, amyloid-β; CJD, Creutzfeldt–Jakob disease; FTD–MND, FTD with motor neuron disease; PPA, primary progressive aphasia.

Figure 2. Patterns of brain atrophy in Alzheimer disease

The images show patterns of atrophy on structural neuroimaging observed in various clinical syndromes associated with Alzheimer disease (AD) pathology. In typical amnestic late-onset Alzheimer disease (LOAD), atrophy is first noted in the medial temporal lobes, and gradually spreads to involve the broader temporoparietal and posterior cingulate cortices. Logopenic variant primary progressive aphasia (lvPPA) is characterized by atrophy in the posterior perisylvian region or parietal lobe. For lvPPA, the left (dominant) hemisphere is represented here to indicate that the left-hemispheric cortical areas are predominantly affected. In posterior cortical atrophy (PCA), degeneration of the occipitoparietal and sometimes the posterior temporal lobes is observed. In the behavioural dysexecutive variant of AD, voxel-based morphometric studies reveal temporoparietal atrophy with relative preservation of frontal grey matter.

Figure 3. Possible clinicopathological correlations for frontotemporal dementia syndromes

The figure shows the pathologies associated with each frontotemporal dementia (FTD) syndrome. The three main frontotemporal lobar degeneration (FTLD) molecular pathologies — FTLD-tau, FTLD-TDP and FTLD-FUS — are represented in different shades of blue, and Alzheimer disease (AD) pathology is in yellow. The areas of crossover between syndromes and pathologies are qualitative rather than quantitative. The centre of the rhombus indicates the most frequent pathology for each syndrome. bvFTD, behavioural variant FTD; CBS, corticobasal syndrome; FTD–MND, FTD with motor neuron disease; FUS, fused in sarcoma; nfvPPA, nonfluent/agrammatic variant PPA; PPA, primary progressive aphasia; PSP-S, progressive supranuclear palsy syndrome; svPPA, semantic variant PPA; TDP-43, TAR DNA-binding protein 43.

Figure 4. Patterns of brain atrophy in frontotemporal dementia syndromes

The images show the patterns of atrophy observed on structural imaging in various frontotemporal dementia (FTD) syndromes, which arise from frontotemporal lobar degeneration. The core neuropsychiatric symptoms of behavioural variant FTD (bvFTD), such as apathy, disinhibition, eating disorders and aberrant motor behaviour, localize to right frontal structures. Patients with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) present with fluency impairment and/or agrammatism. These deficits localize to the frontoinsular language network, with atrophy noted most frequently in the left inferior frontal and insular cortices (the entire network is not depicted on this figure). In semantic variant PPA (svPPA), degeneration of the anterior temporal lobes disrupts access to semantic memory.