The neurobiology of depression in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features Sharon L. Naismith *, Louisa M. Norrie, Loren Mowszowski, Ian B. Hickie Ageing Brain Centre, Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Sydney, NSW, Australia Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2. Neural circuitry relevant to depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3. Phenotypic features of late-life depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.1. ‘Vascular’ depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.2. Risk factors for ‘vascular’ and late-onset depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.3. Depression as a cardiovascular risk factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 3.4. Depression and illness burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 4. Neuropsychological features of late-life depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4.1. Predictors of cognitive decline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 4.2. The relationship between late-life depression, mild cognitive impairment and dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Progress in Neurobiology 98 (2012) 99–143 A R T I C L E I N F O Article history: Received 19 December 2011 Received in revised form 3 May 2012 Accepted 9 May 2012 Available online 17 May 2012 Keywords: Depression Late-life depression Late-onset Cognitive Neuroimaging Genetic A B S T R A C T As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality. Considerable heterogeneity in the clinical presentation of major depression across the life cycle may reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late- onset depression). The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated. New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations. This review highlights the major features of late-life depression, with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological, inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non- pharmacological and novel treatments for depression are discussed. Ultimately, future research must aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced health outcomes via the implementation of early intervention paradigms. ß 2012 Elsevier Ltd. All rights reserved. Abbreviations: 5HTTLPR, serotonin transporter gene; 5-HT, serotonin; ACC, anterior cingulate cortex; AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; BOLD, blood oxygen level dependent; Cho, choline; CM, cerebral metabolism; CNS, central nervous system; Cr, creatine; CVD, cardiovascular disease; DLPFC, dorsolateral prefrontal cortex; DTI, diffusion tensor imaging; ECT, electroconvulsive therapy; EoD, early-onset depression; FA, fractional anisotropy; FDG, fluorodeoxyglucose; fMRI, functional magnetic resonance imaging; HDL, high density lipoprotein; HMPAO, hexamethyl-propylene amine oxime; HPA, hypothalamic pituitary axis; LLD, late-life depression; LoD, late-onset depression; MCI, mild cognitive impairment; MD, major depression; MEG, magnetoencephalography; mI, myoinositol; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MTHFR, methylenetetrahydrofolate reductase; MTR, magnetization transfer ratio; NAA, N-acetyl aspartate; OFC, orbitofrontal cortex; PET, positron emission tomography; PFC, prefrontal cortex; PiB, Pittsburgh B; rCBF, regional cerebral blood flow; RCT, randomised controlled trial; SPECT, single photon emission computed tomography; SSRI, selective serotonin reuptake inhibitor; VRFs, vascular risk factors; WMLs, white matter lesions. * Corresponding author at: Clinical Research Unit, Brain & Mind Research Institute, 94 Mallett Street, Camperdown NSW, Australia. Tel.: +61 2 9351 0781; fax: +61 2 9351 0855. E-mail address: sharon.naismith@sydney.edu.au (S.L. Naismith). Contents lists available at SciVerse ScienceDirect Progress in Neurobiology jo u rn al ho m epag e: ww w.els evier .c om /lo cat e/pn eu ro b io 0301-0082/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pneurobio.2012.05.009