Shantel L. Duffy

Glutathione relates to neuropsychological functioning in mild cognitive impairment

Mild cognitive impairment (MCI) represents an at‐risk state for Alzheimers disease in which underlying pathophysiological mechanisms could be delineated. Oxidative stress has been implicated in Alzheimers disease and can be measured by levels of the antioxidant glutathione. This study aims to assess in vivo levels of glutathione via proton magnetic resonance spectroscopy in patients with MCI and to determine how glutathione relates to cognitive decline.

In vivo glutathione levels in young persons with bipolar disorder: A magnetic resonance spectroscopy study

Oxidative stress has recently been reported to assume a significant role in the pathophysiology of bipolar disorder. Several studies have demonstrated the replenishment of glutathione (GSH) diminishes oxidative cellular damage and ameliorates depressive symptoms in this disorder. Whilst the mechanism by which GSH exerts any clinical effect is unknown it has been proposed that it involves the bolstering of antioxidant defences by increasing the bioavailability of GSH, which in turn reverses clinical symptoms of depression. Such a proposal is predicated on the implicit assumption that GSH is diminished in these patients prior to GSH supplementation. However hitherto no study has reported in vivo measures of GSH in patients with bipolar disorder. Using magnetic resonance spectroscopy we obtained in vivo measures of GSH in young people with bipolar disorder and contrasted these with matched healthy controls. Young people with bipolar disorder were found to have no diminution in baseline GSH concentration and, furthermore, no significant correlations were found between GSH and clinical scores of depression or mania. The results do not support the hypothesis that oxidative stress is involved in the primary pathophysiology of bipolar disorder.

Deficits in episodic memory retrieval reveal impaired default mode network connectivity in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is believed to represent a transitional stage between normal healthy ageing and the development of dementia. In particular, aMCI patients have been shown to have higher annual transition rates to Alzheimers Disease (AD) than individuals without cognitive impairment. Despite intensifying interest investigating the neuroanatomical basis of this transition, there remain a number of questions regarding the pathophysiological process underlying aMCI itself. A number of recent studies in aMCI have shown specific impairments in connectivity within the default mode network (DMN), which is a group of regions strongly related to episodic memory capacities. However to date, no study has investigated the integrity of the DMN between patients with aMCI and those with a non-amnestic pattern of MCI (naMCI), who have cognitive impairment, but intact memory storage systems. In this study, we contrasted the DMN connectivity in 24 aMCI and 33 naMCI patients using seed-based resting state fMRI. The two groups showed no statistical difference in their DMN intra-connectivity. However when connectivity was analysed according to performance on measures of episodic memory retrieval, the two groups were separable, with aMCI patients demonstrating impaired functional connectivity between the hippocampal formation and the posterior cingulate cortex. We provide evidence that this lack of connectivity is driven by impaired communication from the posterior cingulate hub and does not simply represent hippocampal atrophy, suggesting that posterior cingulate degeneration is the driving force behind impaired DMN connectivity in aMCI.

Anterior cingulate integrity: Executive and neuropsychiatric features in Parkinson's disease†‡

Patients with advanced Parkinsons disease (PD) commonly suffer with significant executive dysfunction and concomitant visual hallucinations. Although the underlying pathophysiology remains poorly understood, numerous studies have highlighted the strong association between these neuropsychiatric features, suggesting common neural pathways. Although previous neuroimaging studies have identified widespread volume loss across a number of cortical regions, to date, no studies have utilized proton magnetic resonance spectroscopy to provide insights into how neurometabolic changes may relate to such symptoms. Twenty patients with PD and 20 healthy controls underwent spectroscopy to determine the N‐acetyl aspartate/creatine (NAA/Cr) ratio, which reflects the degree of neuronal integrity in neurodegenerative diseases. Voxels were obtained from the anterior cingulate cortex (ACC), an area critical for a wide range of executive mechanisms as well as from a control volume in the posterior cingulate cortex (PCC). Compared to controls, patients with PD had lower NAA/Cr ratios in the ACC. In turn, lower NAA/Cr ratios significantly correlated with poorer executive function on tasks of attentional set‐shifting and response inhibition, as well as more‐severe psychotic symptoms and poorer performance on the Bistable Percept Paradigm, a neuropsychological probe of visual hallucinations. NAA/Cr ratios were significantly lower in hallucinators, compared to nonhallucinators, within the ACC, but did not differ in the PCC. These results suggest that loss of neuronal integrity within the ACC plays an important role in the pathophysiology underlying executive functioning and visual hallucinations in PD.

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.

Napping in older people ‘at risk’ of dementia: relationships with depression, cognition, medical burden and sleep quality

Sleep disturbance is prevalent in older adults, particularly so in those at a greater risk of dementia. However, so far the clinical, medical and neuropsychological correlates of daytime sleep have not been examined. The aims of this study were to investigate the characteristics and effects of napping using actigraphy in older people, particularly in those ‘at risk’ of dementia. The study used actigraphy and sleep diaries to measure napping habits in 133 older adults ‘at risk’ of dementia (mean age = 65.5 years, SD = 8.4 years), who also underwent comprehensive medical, psychiatric and neuropsychological assessment. When defined by actigraphy, napping was present in 83.5% (111/133) of participants; however, duration and timing varied significantly among subjects. Nappers had significantly greater medical burden and body mass index, and higher rates of mild cognitive impairment. Longer and more frequent naps were associated with poorer cognitive functioning, as well as higher levels of depressive symptoms, while the timing of naps was associated with poorer nocturnal sleep quality (i.e. sleep latency and wake after sleep onset). This study highlights that in older adults ‘at risk’ of dementia, napping is associated with underlying neurobiological changes such as depression and cognition. Napping characteristics should be more routinely monitored in older individuals to elucidate their relationship with psychological and cognitive outcomes.

Sleep quality in healthy older people: relationship with ¹H magnetic resonance spectroscopy markers of glial and neuronal integrity.

The hippocampus and thalamus assume a significant role in the overnight consolidation of memories, a process that is negatively impacted by sleep disruption. Emerging evidence suggests that disturbances of sleep in older people may co-occur with underlying neurobiological changes. This study sought to assess glial and neuronal integrity in these regions in relation to subjective sleep disturbance in a healthy older sample. Forty-three healthy older people (mean age = 70, SD = 5.0) were assessed clinically and medically and screened for cognitive and depressive symptoms, as well as sleep disturbance. Single voxel hippocampal and thalamus metabolite ratios of N-acetyl aspartate (NAA) and myo-inositol (mI) with total creatine (Cr + PCr) were measured using magnetic resonance spectroscopy at 3-Tesla. Higher hippocampal mI/Cr + PCr ratios were significantly correlated with poorer self-reported sleep quality (r = .42, p < .01) and less sleep efficiency (r = -0.42, p < .01) as recorded by the Pittsburgh Sleep Quality Index (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). No other significant correlations were observed within the hippocampus or within the thalamus. These results indicate that in healthy older people, subjective sleep disturbance may be associated with glial alterations in the hippocampus. Future research is now needed to examine these associations with respect to objective sleep measures and overnight memory consolidation.

The effect of 12-wk ω-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients "at risk" for major depression

OBJECTIVES As life expectancy increases, the need to prevent major health disorders is clear. Depressive symptoms are common in older adults and are associated with cognitive decline and greater risk for transitioning to major depression. Oxidative stress may be implicated in the pathophysiology of major depression and can be measured in vivo using proton magnetic resonance spectroscopy via the neurometabolite glutathione (GSH). Evidence suggests ω-3 fatty acid (FA) supplementation may prevent depression and directly affect GSH concentration. The aim of this study was to examine the effect of ω-3 FA supplementation on in vivo GSH concentration in older adults at risk for depression. METHODS Fifty-one older adults at risk for depression were randomized to receive either four 1000-mg ω-3 FA supplements daily (containing eicosapentaenoic acid 1200 mg plus docosahexaenoic acid 800 mg) or placebo (four 1000-mg paraffin oil placebo capsules daily) for 12 wk. Participants underwent magnetic resonance spectroscopy, as well as medical, neuropsychological, and self-report assessments at baseline and after 12 wk of supplementation. GSH was measured in the thalamus and calculated as a ratio to creatine. Depressive symptoms were measured using the Patient Health Questionnaire. RESULTS Compared with the group given the ω-3 FA supplements, the placebo group had greater change in the GSH-to-creatine ratio in the thalamus (t = 2.00; P = 0.049) after the 12 wk intervention. This increase was in turn associated with a worsening of depressive symptoms (r = 0.43; P = 0.043). CONCLUSIONS Depressive symptom severity in older adults appears to be associated with increased brain levels of GSH, a key marker of oxidative stress. Importantly, ω-3 FA supplementation may attenuate oxidative stress mechanisms, thereby offering benefits for depression prevention.

Mild Cognitive Impairment Subtypes in Older People With Depressive Symptoms Relationship With Clinical Variables and Hippocampal Change

Aims: To examine the rates and clinical characteristics of mild cognitive impairment (MCI) in older people with depressive symptoms and to determine the relative contribution of hippocampal volume and MCI to memory change. Method: One hundred and fifty-two participants with lifetime Major Depression and remitted or mild symptoms and 28 healthy controls underwent psychiatric and neuropsychological assessments. Magnetic resonance imaging was also conducted in a subset of the patients (n = 81) and healthy controls (n = 18). Results: MCI was diagnosed in 75.7% of the patients and was associated with increasing age, medical burden, vascular risk factors, later age of depression onset and smaller hippocampi. Multiple regression showed that both hippocampal volume and MCI diagnosis mediate memory performance in depression. Conclusions: MCI occurs in older adults with a history of depression and is not simply due to symptom severity. Memory change is linked to underlying hippocampal atrophy in this patient group.

Cluster analysis reveals abnormal hippocampal neurometabolic profiles in young people with mood disorders

While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data-driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self-reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies.