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A clinicopathological approach to the diagnosis of dementia

This article has been updated

Key Points

  • Definite classification of dementia is based on the underlying neuropathology

  • Accumulation of abnormally folded proteins lies at the heart of dementia neuropathology

  • Alzheimer disease pathology can give rise to subtypes with focal onset in functional networks outside the memory system, such as language, visuospatial and behavioural executive domains

  • Frontotemporal lobar degeneration, associated with aggregates of tau, TDP-43 or FUS, can give rise to three core frontotemporal dementia syndromes and three associated syndromes

  • Clinical classification of dementia syndromes is based on diagnostic criteria that rely heavily on the specificity of affected domains and the evolution of deficits in these domains

  • In vivo biomarkers of disease include imaging findings of morphological, molecular and functional changes, both upstream and downstream of the disease processes

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.

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Figure 1: Clinicopathological spectrum of neurodegenerative proteinopathies.
Figure 2: Patterns of brain atrophy in Alzheimer disease.
Figure 3: Possible clinicopathological correlations for frontotemporal dementia syndromes.
Figure 4: Patterns of brain atrophy in frontotemporal dementia syndromes.

Change history

  • 28 July 2017

    In the online biography for Fanny M. Elahi, 'American Academy of Neurology' was incorrectly written as 'American Association of Neurology'. This error has been corrected in the HTML version of the article.

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Authors and Affiliations

Authors

Contributions

F.M.E. researched data for the article and wrote the manuscript. Both authors made substantial contributions to discussions of the content, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Fanny M. Elahi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Diagnostic criteria for selected dementia syndromes. (DOC 72 kb)

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Glossary

Acalculia

Inability to perform calculations.

Phonemic paraphasias

Errors in speech resulting in substitution of parts of the intended word by other phonemes, leading to generation of a — sometimes non-existent — word sounding similar to the target word (for example, pipe for pile, loan for moan, or papple for apple).

Visual agnosia

Inability to recognize or interpret visual stimuli despite intact vision.

Alexia

Inability to read, which comprises inability to read out loud and/or comprehend.

Ideomotor apraxia

Deficit in the ability to voluntarily plan or complete a motor task, with preservation of involuntary (automatic) motor planning when the subject is cued. This preserved ability to perform automated motoric responses to cuing contrasts with 'ideational apraxia', in which the ability to select the appropriate motor programme or sequencial steps, even in the presence of cuing, is lost.

Prosopagnosia

Inability to recognize faces, also known as 'face blindness'.

Pseudobulbar affect

Also referred to as marked emotional lability or emotional incontinence. This symptom is characterized by uncontrollable episodes of crying or laughter, proportionately in excess of the valence of an emotional stimulus.

Virchow–Robin spaces

Perivascular spaces surrounding the penetrating vessels that arise from the subarachnoid space and perforate the brain parenchyma. Prominence — in terms of visibility and numbers — of enlarged Virchow–Robin spaces has been associated with cognitive ageing, small vessel disease, and neurodegeneration.

CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited small vessel disease, with notable dysregulation of inflammatory markers and pathognomonic T2/FLAIR white matter hyperintensities in anterior temporal lobes.

Anticipation

Genetic phenomenon relating to the gradual expansion of a mutation with each generation, usually resulting in earlier age of onset and more-severe symptoms when passed on to the next generation.

Surface dyslexia and dysgraphia

Impairment in the ability to read and write words that are considered 'irregular' with regard to their spelling-to-sound correspondence (for example, friend, island or yacht), as opposed to 'regular' words (for example, fire, lemon or computer). This impairment can result in regularization errors, that is, words are erroneously spelled according to the regular phonetic rules.

Associative agnosia

Impaired recognition of visually presented objects despite intact visual perception of these objects. Also known as 'visual object agnosia'.

Hypergraphia

Compulsive and overwhelming urge to write, with potential intraindividual variability in style and content during the disease course.

Astereognosis

Inability to recognize an object by active touch alone, in the absence of primary sensory deficit.

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Elahi, F., Miller, B. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13, 457–476 (2017). https://doi.org/10.1038/nrneurol.2017.96

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