A population-representative post-mortem study of 153 older people without dementia (UK Medical Research Council Cognitive Function and Ageing Study) found late-life depression associated with Lewy bodies in brainstem nuclei and with neuronal loss in the hippocampus, substantia nigra, raphe nucleus and nucleus basalis, but not with Alzheimer-type or gross cerebrovascular pathology, and left open whether the pathology precedes and predisposes to depression or whether long-standing depression contributes to the neurodegeneration. The direction of causality between late-life depression and subcortical Lewy body pathology with regional neuronal loss (prodromal Lewy body disease versus consequence of recurrent depression) remains the open question.

Background

Late-life depression (LLD) — depressive illness arising in, or persisting into, old age — is common in the community and is associated with increased risk of later dementia, yet which brain pathologies underlie it in the general older population was, until 2011, essentially unknown. Neuropathological studies before then, drawn mostly from clinical samples of severely ill patients, had found no consistent association between LLD and Alzheimer-type pathology (neuritic and diffuse plaques and neurofibrillary tangles) or with cerebral small-vessel disease, whereas magnetic resonance imaging reliably linked LLD to white matter hyperintensities (WMH — bright areas on T2-weighted scans reflecting white-matter damage, usually of ischaemic origin), motivating the 'vascular depression' hypothesis that cerebrovascular disease can precipitate depressive illness in old age. The UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), a population-representative cohort of people aged 65 and over interviewed repeatedly in life with the Geriatric Mental State (GMS) structured interview scored by the AGECAT computerised diagnostic algorithm (here at a threshold defining depression of clinical significance — broader than DSM major depression), includes a brain-donation programme with standardised post-mortem assessment performed masked to clinical data. Tsopelas and colleagues (2011) compared 153 donors without dementia — 36 with and 117 without depression ascertained during life — on semi-quantitative measures of Alzheimer, cerebrovascular and Lewy body pathology and of neuronal preservation across cortical areas, the hippocampus, and the four subcortical and brainstem nuclei assessed (the dopamine-rich substantia nigra, the serotonin-rich raphe nuclei, the noradrenergic locus coeruleus and the cholinergic nucleus basalis of Meynert; these nuclei supply the chemical transmitters that regulate mood, motivation and cognition). Depression was associated with neuronal loss in the hippocampus, nucleus basalis, substantia nigra and raphe nucleus, and with Lewy bodies (intraneuronal inclusions of aggregated α-synuclein, the defining lesion of Parkinson's disease and dementia with Lewy bodies) in brainstem nuclei; no association was found with Alzheimer-type or gross cerebrovascular pathology. Because subcortical pathology was rare, most depressed donors had no detectable subcortical lesion, so these associations account for only a fraction of LLD in the population. The authors left these questions open: the direction of cause and effect between depression and neuronal loss; whether more sensitive vascular and histological measures would reveal associations their crude protocols missed; the constraints of the broad AGECAT case definition and unknown lifetime course of depression; the need for replication in large population-representative cohorts; and the observation that the increase in Lewy bodies in brainstem nuclei had not been previously reported in depression and merits further investigation, since depression is increased in synucleinopathies such as dementia with Lewy bodies and Parkinson's disease, so that some cases of late-life depression may be related to this pathology. Subsequent studies have replicated the Lewy-body and neuronal-loss associations in independent cohorts using quantitative cell counting, and more sensitive vascular measures have revealed a cerebrovascular contribution to late-life depression.

Problem Statement

In older people without dementia, what is the direction of causality underlying the association between late-life depression and subcortical Lewy body pathology (in the substantia nigra and locus coeruleus) with neuronal loss (in the hippocampus, nucleus basalis, substantia nigra and raphe nucleus): does this pathology precede and predispose to depressive syndromes — such that late-life depression is, in a subset of cases, a prodromal manifestation of incipient Lewy body disease — or does long-standing or recurrent depression contribute to this neurodegeneration? Because post-mortem tissue findings are cross-sectional, the direction of causality remains unresolved. The other issues the authors raised are background to this question.

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