The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder

Abstract

Depression is frequent in older individuals and is often associated with cognitive impairment and increasing risk of subsequent dementia. Late-life depression (LLD) has a negative impact on quality of life, yet the underlying pathobiology is still poorly understood. It is characterized by considerable heterogeneity in clinical manifestation, genetics, brain morphology, and function. Although its diagnosis is based on standard criteria, due to overlap with other age-related pathologies, the relationship between depression and dementia and the relevant structural and functional cerebral lesions are still controversial. LLD has been related to a variety of pathogenic mechanisms associated with the underlying age-related neurodegenerative and cerebrovascular processes. In addition to biochemical abnormalities, involving serotonergic and GABAergic systems, widespread disturbances of cortico-limbic, cortico-subcortical, and other essential brain networks, with disruption in the topological organization of mood- and cognition-related or other global connections are involved. Most recent lesion mapping has identified an altered network architecture with "depressive circuits" and "resilience tracts", thus confirming that depression is a brain network dysfunction disorder. Further pathogenic mechanisms including neuroinflammation, neuroimmune dysregulation, oxidative stress, neurotrophic and other pathogenic factors, such as β-amyloid (and tau) deposition are in discussion. Antidepressant therapies induce various changes in brain structure and function. Better insights into the complex pathobiology of LLD and new biomarkers will allow earlier and better diagnosis of this frequent and disabling psychopathological disorder, and further elucidation of its complex pathobiological basis is warranted in order to provide better prevention and treatment of depression in older individuals.

What do we know about pseudodementia?

“…Despite the heterogeneity, there are some distinctive neurocognitive and behavioural changes that appear to be attributable to geriatric depression and that are characteristic of a large group of patients who do not have neurological disease. 27 …”

“…The incidence of depression may be 30% in vascular dementia and in AD, and over 40% in Parkinson’s disease dementia and Huntington’s disease dementia. 27 A study published in 2023 shows that depression is a comorbidity often associated with dementia and also that depression increases the risk of dementia. 13 People with any type of dementia have a high incidence of major depression, particularly if they have vascular dementia or Parkinson’s disease dementia—these patients often have more insight and awareness of their condition than people with AD.…”

“…Despite the heterogeneity, there are some distinctive neurocognitive and behavioural changes that appear to be attributable to geriatric depression and that are characteristic of a large group of patients who do not have neurological disease. 27 Pseudodementia typically encompasses memory issues, impairments in executive functioning and speech deficits. Notable cognitive symptoms may include difficulties in remembering words or remembering things in general, reduced attention and concentration, challenges in task completion or decision-making, decreased speech fluency and speed and impaired processing speed.…”

Challenges in Identifying Individualized Brain Biomarkers of Late Life Depression

“…Another reason for inconsistent results is heterogeneity in LLD [ 22 , 23 , 71 ]. Here, we define heterogeneity as variability due to ‘true’ etiological differences between patients, as opposed to construct or analytical variability leading to experimentally introduced differences between LLD samples.…”

Research status and global trends of late-life depression from 2004 to 2023: bibliometric analysis

“…The former refers to depressive disorders with the first onset before age 60 and recurrence after age 60, whereas the latter refers to depressive disorders with the first episode after age 60 ( Ly et al, 2021 ). With global population aging, the prevalence of LLD is increasing every year ( Jellinger, 2023 ). A recent report showed that the prevalence of depressive symptoms in older adults is 20% and is highly heterogeneous ( Tang et al, 2022 ).…”