Louisa Norrie

The neurobiology of depression in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features

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.

Enhancing Memory in Late-Life Depression: The Effects of a Combined Psychoeducation and Cognitive Training Program

OBJECTIVE To evaluate the efficacy of a multifactorial cognitive training (CT) program for older people with a lifetime history of depressive disorder. METHODS This was a single-blinded waitlist control design. The study was conducted in the Healthy Brain Ageing Clinic, a specialist outpatient clinic at the Brain & Mind Research Institute, Sydney, Australia. Forty-one participants (mean age = 64.8 years, sd = 8.5) with a lifetime history of major depression were included. They were stabilized on medication and had depressive symptoms in the normal to mild range. The intervention encompassed both psychoeducation and CT. Each component was 1-hour in duration and was delivered in a group format over a 10-week period. Psychoeducation was multifactorial, was delivered by health professionals and targeted cognitive strategies, as well depression, anxiety, sleep, vascular risk factors, diet and exercise. CT was computer-based and was conducted by Clinical Neuropsychologists. Baseline and follow-up neuropsychological assessments were conducted by Psychologists who were blinded to group allocation. The primary outcome was memory whilst secondary outcomes included other aspects of cognition and disability. RESULTS CT was associated with significant improvements in visual and verbal memory corresponding to medium to large effect sizes. CONCLUSION CT may be a viable secondary prevention technique for late-life depression, a group who are at risk of further cognitive decline and progression to dementia.

Does sleep disturbance mediate neuropsychological functioning in older people with depression

BACKGROUND Depression in older adults is associated with neuropsychological dysfunction, fronto-subcortical brain changes and sleep disturbance. Research suggests that adequate sleep is critical for many aspects of cognition including processing speed, verbal skills and memory. However, the association between sleep disturbance and neuropsychological functioning in depression has not been well evaluated. The current study therefore aimed to investigate these relationships. METHODS Forty-eight people (mean age=59.6, sd=8.2) meeting DSM-IV criteria for unipolar major depression were included for analysis. Neuropsychological assessment included assessment of processing speed, learning and memory, verbal fluency and executive functions. Early and late insomnia were defined by scores on the Hamilton Depression Rating Scale. RESULTS While early insomnia was related to depression severity and poorer global cognition, late insomnia was associated with later age of depression onset, depression severity, and poorer scores on tests of verbal fluency and memory. The associations between cognition and late insomnia were not accounted for by depression severity or age of onset of disorder. LIMITATIONS This study was retrospective in nature, and did not include objective measures of sleep. CONCLUSIONS This is the first known study to indicate that late insomnia in older people with major depression may be independently and aetiologically linked to neuropsychological performance, particularly verbal fluency and memory. It may also indicate underlying structural and neurochemical changes. Sleep and circadian disturbance may serve as a biomarker for ongoing cognitive decline and may be a potentially modifiable risk factor.

Sleep disturbance relates to neuropsychological functioning in late-life depression

BACKGROUND Sleep-wake disturbance in older people is a risk factor for depression onset and recurrence. The aim of this study was to determine if objective sleep-wake disturbance in late-life depression relates to neuropsychological functioning. METHODS Forty-four older patients with a lifetime history of major depression and 22 control participants underwent psychiatric, medical and neuropsychological assessments. Participants completed self-report sleep measures, sleep diaries and wore wrist actigraphy for two weeks. Outcome measures included sleep latency, the number and duration of nocturnal awakenings and the overall sleep efficiency. RESULTS Patients with depression had a greater duration of nocturnal awakenings and poorer sleep efficiency, in comparison to control participants. Sleep disturbance in patients was associated with greater depression severity and later ages of depression onset. It also related to poorer psychomotor speed, poorer verbal and visual learning, poorer semantic fluency as well as poorer performance on tests of executive functioning. These relationships largely remained significant after controlling for depression and estimated apnoea severity. LIMITATIONS This sample had only mild levels of depression severity and results require replication in patients with moderate to severe depression. The inclusion of polysomnography and circadian markers would be useful to delineate the specific features of sleep-wake disturbance that are critical to cognitive performance. CONCLUSIONS Sleep-wake disturbance in older patients with depression is related to neuropsychological functioning and to later ages of illness onset. This study suggests that common neurobiological changes may underpin these disease features, which may, in turn, warrant early identification and management.

Hippocampal Volume in Older Adults at Risk of Cognitive Decline: The Role of Sleep, Vascular Risk, and Depression

BACKGROUND AND OBJECTIVES Decreased hippocampal volume in older adults is associated with neurodegenerative and psychiatric diseases. Several modifiable risk factors have been associated with the size of this structure, however the relative contribution of these factors to hippocampal atrophy is unclear. This study aimed to examine the relationship between modifiable risk factors and hippocampal volume in older adults at risk of cognitive decline. METHODS Two hundred and eighteen participants (mean age = 67.3 years, MMSE = 28.6) with mood and/or memory complaints underwent clinical and neuropsychological assessment, and magnetic resonance imaging. Measures of depression, global cognitive functioning, exercise, vascular health, cognitive reserve, sleep, and memory were collected. Hippocampal volumes were derived using image segmentation as implemented by FMRIB Software Library. RESULTS Smaller hippocampal volumes were strongly associated with poorer verbal learning and memory as well as diagnoses of either multiple or amnestic mild cognitive impairment. Based on univariate correlations, multivariable regressions were performed (controlling for age and total intracranial volume) to determine which modifiable risk factors were associated with hippocampal volume. For the left hippocampus, poor sleep efficiency and greater than five years untreated depressive illness remained significant predictors. For the right hippocampus, diabetes and low diastolic blood pressure significant predictors. CONCLUSIONS Although their contribution is small, lower sleep efficiency, low blood pressure, diabetes, and untreated depression are associated with reduced hippocampal volumes. Studies exploring the impact of early intervention for these risk factors on hippocampal integrity are warranted.

Managing depression across the life cycle: new strategies for clinicians and their patients

Depression is the leading cause of non‐fatal disease burden in Australia. Recently, increasing public recognition, together with the development of more integrated medical and psychological healthcare services has resulted in significant improvements. New pathophysiological models incorporate structural brain changes with established changes in neurotransmitter function. Further, recognition of predisposing factors and the salience of differential ages of onset have led to more pragmatic diagnostic systems. There is an ongoing need to promote early recognition, better information to inform treatment choices and more comprehensive treatment programmes that incorporate behavioural and lifestyle factors in addition to the wide range of pharmacological therapies that are now available.

Spectroscopic markers of memory impairment, symptom severity and age of onset in older people with lifetime depression: Discrete roles of N-acetyl aspartate and glutamate.

BACKGROUND Glutamate (Glu) and N-acetyl aspartate (NAA) are markers of excitatory processes and neuronal compromise respectively. Increased Glu and decreased NAA concentrations have been implicated in the pathophysiology of depression and cognitive impairment respectively. OBJECTIVE To determine the relationship between NAA, Glu, memory and key clinical features in older people with lifetime depression compared to comparison subjects. METHOD Thirty-five health-seeking older adults (mean age=63.57 years), with a lifetime depression diagnosis, and 21 age-matched healthy comparison subjects (mean age=65.48 years) underwent neuropsychological testing, psychiatric assessment and proton magnetic resonance spectroscopy from which Glu and NAA were measured (reported as a ratio to creatine). RESULTS Compared to comparison subjects, the depressed subjects showed poorer verbal learning and memory retention. Hippocampal NAA and Glu did not differ significantly between groups. However, in comparison subjects, lower levels of hippocampal Glu were associated with poorer memory retention (r=0.55, p=0.018). In the depressed subjects, lower levels of hippocampal NAA were related to poorer verbal learning (r=0.44, p=0.008) and memory retention (r=0.41, p=0.018). Greater hippocampal Glu was associated with more severe depressive symptoms (r=0.35, p=0.039) and an earlier age of illness onset (r=-0.37, p=0.031). LIMITATIONS This is a cross sectional study with a heterogeneous group of depressed subjects. CONCLUSION Our findings highlight that hippocampal neurometabolites are entwined with both clinical and cognitive features associated with depression in older adults and further suggest that differential mechanisms may underpin these features.

Episodic memory in depression: the unique contribution of the anterior caudate and hippocampus.

BACKGROUND Learning and memory impairments in older adults with depression are linked to hippocampal atrophy. However, other subcortical regions may also be contributing to these deficits. We aimed to examine whether anterior caudate nucleus volume is significantly reduced in older adults with depression compared to controls; whether anterior caudate volume is associated with performance on tasks of episodic learning and memory, and if so, whether this association is independent of the effects of the hippocampus. METHOD Eighty-four health-seeking participants meeting criteria for lifetime major depressive disorder (mean age = 64.2, s.d. = 9.1 years) and 27 never-depressed control participants (mean age = 63.9, s.d. = 8.0 years) underwent neuropsychological assessment including verbal episodic memory tests [Rey Auditory Verbal Learning Test and Logical Memory (WMS-III)]. Magnetic resonance imaging was conducted, from which subregions of the caudate nucleus were manually demarcated bilaterally and hippocampal volume was calculated using semi-automated methods. RESULTS Depressed subjects had smaller right anterior caudate (RAC) (t = 2.3, p = 0.026) and poorer memory compared to controls (t = 2.5, p < 0.001). For depressed subjects only, smaller RAC was associated with poorer verbal memory (r = 0.3, p = 0.003) and older age (r = -0.46, p < 0.001). Multivariable regression showed that the RAC and hippocampus volume uniquely accounted for 5% and 3% of the variance in memory, respectively (β = 0.25, t = 2.16, p = 0.033; β = 0.19, t = 1.71, p = 0.091). CONCLUSIONS In older people with depression, the anterior caudate nucleus and the hippocampus play independent roles in mediating memory. While future studies examining this structure should include larger sample sizes and adjust for multiple comparisons, these findings support the critical role of the striatum in depression.

Screening for Sleep Apnoea in Mild Cognitive Impairment: The Utility of the Multivariable Apnoea Prediction Index

Purpose. Mild cognitive impairment (MCI) is considered an “at risk” state for dementia and efforts are needed to target modifiable risk factors, of which Obstructive sleep apnoea (OSA) is one. This study aims to evaluate the predictive utility of the multivariate apnoea prediction index (MAPI), a patient self-report survey, to assess OSA in MCI. Methods. Thirty-seven participants with MCI and 37 age-matched controls completed the MAPI and underwent polysomnography (PSG). Correlations were used to compare the MAPI and PSG measures including oxygen desaturation index and apnoea-hypopnoea index (AHI). Receiver-operating characteristics (ROC) curve analyses were performed using various cut-off scores for apnoea severity. Results. In controls, there was a significant moderate correlation between higher MAPI scores and more severe apnoea (AHI: r = 0.47, P = 0.017). However, this relationship was not significant in the MCI sample. ROC curve analysis indicated much lower area under the curve (AUC) in the MCI sample compared to the controls across all AHI severity cut-off scores. Conclusions. In older people, the MAPI moderately correlates with AHI severity but only in those who are cognitively intact. Development of further screening tools is required in order to accurately screen for OSA in MCI.

Current sleep disturbance in older people with a lifetime history of depression is associated with increased connectivity in the Default Mode Network

BACKGROUND The present study investigated Default Mode Network (DMN) functional connectivity in subjects with a lifetime history of major depression, comparing those with and without current sleep disturbance. Controls were included to assess DMN abnormalities specific to depression. METHODS A total of 93 adults aged 50 years and over were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. The sample comprised two groups, including 22 controls and 71 participants with a lifetime history of DSM-IV major depression (with depressive episode current or remitted). 52 of those with a lifetime history of depression also met criteria for Mild Cognitive Impairment (MCI). Participants underwent resting-state fMRI along with comprehensive psychiatric, neuropsychological, and medical assessment. Subjective sleep quality was assessed via the Pittsburgh Sleep Quality Index (PSQI). Sleep disturbance was defined as a PSQI score > 5. A total of 68% (n = 48) of cases with a lifetime history of depression met criteria for sleep-disturbance. DMN functional connectivity was assessed via ROI-to-ROI analyses. RESULTS Relative to controls, those with lifetime major depression demonstrated significantly increased functional connectivity between the ventromedial prefrontal cortex and the temporal pole. Within the depression group (n = 48), those with current sleep disturbance had significantly increased connectivity between the anterior medial prefrontal cortex and both the parahippocampal cortex and the hippocampal formation, relative to those without sleep disturbance (n = 23). These results were present after controlling for MCI diagnosis. CONCLUSIONS Current sleep disturbance together with depression is associated with distinct abnormalities in DMN functioning incorporating regions responsible for self-reflection and declarative memory processes. Impaired sleep is associated with increased connectivity between these regions. Future studies may augment these findings with complementary imaging techniques including cortical thickness and diffusion tensor imaging, as well as high density electroencephalogram recording.