Research Investigation
Mild Cognitive Impairment Subtypes in Older People With Depressive Symptoms: Relationship With Clinical Variables and Hippocampal Change
Journal of Geriatric Psychiatry and Neurology 1-10 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0891988715573535 jgpn.sagepub.com
Hirosha K. Jayaweera, BSc (Hons)1,2, Ian B. Hickie, MD, FRANZCP1,2, Shantel L. Duffy, PhD1,2, Daniel F. Hermens, PhD2, Loren Mowszowski, DPsych (Clin. Neuro)1,2, Keri Diamond, DCN/MSc1,2, Zoe Terpening, DCN/MSc1,2, Matthew Paradise, MBChB, FRANZCP1,2, Simon J. G. Lewis, MD1,2, Jim Lagopoulos, PhD2, and Sharon L. Naismith, DPsych (Clin. Neuro)1,2
Abstract 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 ¼ 81) and healthy controls (n ¼ 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. Keywords Mild Cognitive Impairment, Depression, Memory, Neuroimaging, MRI
Introduction Cognitive deficits in depression are common and typically include impairments in processing speed, executive functions (i.e, ‘‘frontal’’ or higher-order functions), learning and memory.1 More pronounced cognitive changes may occur in those with later ages of depression onset, greater vascular risk factors and white matter brain lesions.2-5 The presence of cognitive impairment in this group is of prognostic significance and is a risk factor for mild cognitive impairment (MCI).6 This syndrome is characterized by cognitive impairments greater than expected for age and level of education, in the absence of significant functional decline.7 Approximately 50% of those with predominantly ‘‘amnestic’’ MCI (aMCI) profiles (where there are impairments in the domain of memory) may convert to Alzheimer’s disease (AD) within 5 years.7 Less prognostic data are known about those who present with impairments in non-memory domains (‘‘non-amnestic’’ MCI, naMCI), as these presentations are likely to be underpinned by more diverse pathophysiologies and consequently, the disease trajectory may be more variable.8
In addition to being a risk factor for MCI, depression and MCI often coexist.6 Of significance, when a person has both MCI and depression, there is an increased risk of conversion to dementia9,10 and cognitive deficits do not simply resolve with resolution of depressive symptoms.11 Regardless of underlying etiological mechanisms, it is now widely recognized that depression is a risk factor for AD and in particular vascular dementia.2,12 However, only a few studies have examined the rates and clinical characteristics of MCI in older adults with depressive disorders. Lee et al.13 specifically focused on
1
Healthy Brain Ageing Program, Brain & Mind Research Institute, University of Sydney, Sydney, Australia 2 Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Sydney, Australia Corresponding Author: Sharon Naismith, Brain & Mind Research Institute, Level 5, 94 Mallett Street, Camperdown, New South Wales, 2050, Australia. Email: [email protected]
Downloaded from jgp.sagepub.com at GEORGIAN COURT UNIV on March 21, 2015
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Journal of Geriatric Psychiatry and Neurology
the amnestic subtype in patients with mild to moderate depressive symptoms and showed that 55% of these patients met aMCI criteria.13 A study by Bhalla and colleagues14 examined the rates and characteristics of MCI in a remitted sample and found that 48% had either a dementia or MCI diagnosis compared to 28% of age-matched controls. Here, almost two-thirds of the MCI sample (63%) had an amnestic profile, with the large majority (85%) showing deficits across multiple domains. Accordingly, 37% of the MCI sample had the non-amnestic subtype, with approximately equivalent numbers having single (53%) and multiple (47%) cognitive domains affected.14 Yeh et al. also reported that MCI was evident in around half of those with remitted symptoms but found that amnestic and nonamnestic subtypes were roughly equal in prevalence (28.5% aMCI compared to 23.8% naMCI).15 Although a dearth of studies have examined the neurobiological underpinnings of such MCI profiles, Yeh et al.15 visually rated ventricular enlargement on magnetic resonance imaging (MRI) scans. They found that the amnestic subtype tended to have more ventricular enlargement and later ages of depression onset. By contrast, naMCI was associated with greater vascular risk factors. There were no differences in white matter lesions between those with aMCI, naMCI, no MCI, or control participants in their sample.15 Examining patients in remission as performed in the above-mentioned studies13-15 is important to help eliminate the possibility that the ‘‘state’’ effects of depressive symptoms are primarily accounting for changes in cognitive performance. However, it is noted that some degree of cognitive impairment in such samples tends to persist despite resolution of depressive symptoms,11 and indeed this is of key interest in this study. To our knowledge, no studies have examined MCI in older adults with mild/ remitted depression with regard to quantitative measurement of the hippocampus. This research is warranted since reduced hippocampal volume is not only associated with AD but is also associated with later onset of depression, memory impairment,16 years of cumulative depression,17 poor clinical outcome,18 cognitive decline,19 and progression to dementia20 longitudinally. In a sample of older adults with remitted (or very mild residual) symptoms, we therefore aimed to (1) ascertain the rates of MCI and its associated subtypes; (2) examine the clinical correlates of MCI; (3) determine whether the MCI subtypes differ in terms of hippocampal size; and (4) determine whether any relationship between MCI diagnosis and memory is influenced by hippocampal volume. We hypothesized that (1) the majority of the sample would meet criteria for MCI; (2) MCI would be associated with smaller hippocampal volumes, vascular risk and later ages of depression onset; (3) smaller hippocampal volumes would be particularly pronounced in the amnestic subtype; and (4) hippocampal volume would mediate the relationship between MCI diagnosis and memory.
Methods Sample One hundred and fifty-two health-seeking (i.e, seeking assessment and/or treatment for mood or memory concerns)
participants (56 male and 96 female) meeting criteria for lifetime Major Depressive Disorder were recruited from the Healthy Brain Ageing Clinic at the Brain & Mind Research Institute, Sydney, Australia. Twenty-eight never depressed and cognitively intact participants (8 male and 20 female) served as a healthy control group. Inclusion criteria: participants were required to speak English fluently and be older than 50 years. This age was chosen in line with our early intervention clinic and agenda for risk factor reduction and also by data demonstrating a long preclinical phase of dementia that even precedes MCI.7,21,22 Patients were also required to have a 17-item Hamilton Depression Rating Scale (HDRS) score of less than 20 (i.e, in remission or mild symptom severity)23; to have had a Major Depressive Episode in the last 5 years; and to be stabilized on medication. Exclusion criteria were significant neurological disorder (other than MCI), head injury with loss of consciousness > 30 minutes, medical condition known to affect cognition (e.g, cancer), psychiatric illness other than affective disorder, MiniMental State Examination (MMSE) score24
Mild Cognitive Impairment Subtypes in Older People With Depressive Symptoms: Relationship With Clinical Variables and Hippocampal Change
Journal of Geriatric Psychiatry and Neurology 1-10 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0891988715573535 jgpn.sagepub.com
Hirosha K. Jayaweera, BSc (Hons)1,2, Ian B. Hickie, MD, FRANZCP1,2, Shantel L. Duffy, PhD1,2, Daniel F. Hermens, PhD2, Loren Mowszowski, DPsych (Clin. Neuro)1,2, Keri Diamond, DCN/MSc1,2, Zoe Terpening, DCN/MSc1,2, Matthew Paradise, MBChB, FRANZCP1,2, Simon J. G. Lewis, MD1,2, Jim Lagopoulos, PhD2, and Sharon L. Naismith, DPsych (Clin. Neuro)1,2
Abstract 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 ¼ 81) and healthy controls (n ¼ 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. Keywords Mild Cognitive Impairment, Depression, Memory, Neuroimaging, MRI
Introduction Cognitive deficits in depression are common and typically include impairments in processing speed, executive functions (i.e, ‘‘frontal’’ or higher-order functions), learning and memory.1 More pronounced cognitive changes may occur in those with later ages of depression onset, greater vascular risk factors and white matter brain lesions.2-5 The presence of cognitive impairment in this group is of prognostic significance and is a risk factor for mild cognitive impairment (MCI).6 This syndrome is characterized by cognitive impairments greater than expected for age and level of education, in the absence of significant functional decline.7 Approximately 50% of those with predominantly ‘‘amnestic’’ MCI (aMCI) profiles (where there are impairments in the domain of memory) may convert to Alzheimer’s disease (AD) within 5 years.7 Less prognostic data are known about those who present with impairments in non-memory domains (‘‘non-amnestic’’ MCI, naMCI), as these presentations are likely to be underpinned by more diverse pathophysiologies and consequently, the disease trajectory may be more variable.8
In addition to being a risk factor for MCI, depression and MCI often coexist.6 Of significance, when a person has both MCI and depression, there is an increased risk of conversion to dementia9,10 and cognitive deficits do not simply resolve with resolution of depressive symptoms.11 Regardless of underlying etiological mechanisms, it is now widely recognized that depression is a risk factor for AD and in particular vascular dementia.2,12 However, only a few studies have examined the rates and clinical characteristics of MCI in older adults with depressive disorders. Lee et al.13 specifically focused on
1
Healthy Brain Ageing Program, Brain & Mind Research Institute, University of Sydney, Sydney, Australia 2 Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Sydney, Australia Corresponding Author: Sharon Naismith, Brain & Mind Research Institute, Level 5, 94 Mallett Street, Camperdown, New South Wales, 2050, Australia. Email: [email protected]
Downloaded from jgp.sagepub.com at GEORGIAN COURT UNIV on March 21, 2015
2
Journal of Geriatric Psychiatry and Neurology
the amnestic subtype in patients with mild to moderate depressive symptoms and showed that 55% of these patients met aMCI criteria.13 A study by Bhalla and colleagues14 examined the rates and characteristics of MCI in a remitted sample and found that 48% had either a dementia or MCI diagnosis compared to 28% of age-matched controls. Here, almost two-thirds of the MCI sample (63%) had an amnestic profile, with the large majority (85%) showing deficits across multiple domains. Accordingly, 37% of the MCI sample had the non-amnestic subtype, with approximately equivalent numbers having single (53%) and multiple (47%) cognitive domains affected.14 Yeh et al. also reported that MCI was evident in around half of those with remitted symptoms but found that amnestic and nonamnestic subtypes were roughly equal in prevalence (28.5% aMCI compared to 23.8% naMCI).15 Although a dearth of studies have examined the neurobiological underpinnings of such MCI profiles, Yeh et al.15 visually rated ventricular enlargement on magnetic resonance imaging (MRI) scans. They found that the amnestic subtype tended to have more ventricular enlargement and later ages of depression onset. By contrast, naMCI was associated with greater vascular risk factors. There were no differences in white matter lesions between those with aMCI, naMCI, no MCI, or control participants in their sample.15 Examining patients in remission as performed in the above-mentioned studies13-15 is important to help eliminate the possibility that the ‘‘state’’ effects of depressive symptoms are primarily accounting for changes in cognitive performance. However, it is noted that some degree of cognitive impairment in such samples tends to persist despite resolution of depressive symptoms,11 and indeed this is of key interest in this study. To our knowledge, no studies have examined MCI in older adults with mild/ remitted depression with regard to quantitative measurement of the hippocampus. This research is warranted since reduced hippocampal volume is not only associated with AD but is also associated with later onset of depression, memory impairment,16 years of cumulative depression,17 poor clinical outcome,18 cognitive decline,19 and progression to dementia20 longitudinally. In a sample of older adults with remitted (or very mild residual) symptoms, we therefore aimed to (1) ascertain the rates of MCI and its associated subtypes; (2) examine the clinical correlates of MCI; (3) determine whether the MCI subtypes differ in terms of hippocampal size; and (4) determine whether any relationship between MCI diagnosis and memory is influenced by hippocampal volume. We hypothesized that (1) the majority of the sample would meet criteria for MCI; (2) MCI would be associated with smaller hippocampal volumes, vascular risk and later ages of depression onset; (3) smaller hippocampal volumes would be particularly pronounced in the amnestic subtype; and (4) hippocampal volume would mediate the relationship between MCI diagnosis and memory.
Methods Sample One hundred and fifty-two health-seeking (i.e, seeking assessment and/or treatment for mood or memory concerns)
participants (56 male and 96 female) meeting criteria for lifetime Major Depressive Disorder were recruited from the Healthy Brain Ageing Clinic at the Brain & Mind Research Institute, Sydney, Australia. Twenty-eight never depressed and cognitively intact participants (8 male and 20 female) served as a healthy control group. Inclusion criteria: participants were required to speak English fluently and be older than 50 years. This age was chosen in line with our early intervention clinic and agenda for risk factor reduction and also by data demonstrating a long preclinical phase of dementia that even precedes MCI.7,21,22 Patients were also required to have a 17-item Hamilton Depression Rating Scale (HDRS) score of less than 20 (i.e, in remission or mild symptom severity)23; to have had a Major Depressive Episode in the last 5 years; and to be stabilized on medication. Exclusion criteria were significant neurological disorder (other than MCI), head injury with loss of consciousness > 30 minutes, medical condition known to affect cognition (e.g, cancer), psychiatric illness other than affective disorder, MiniMental State Examination (MMSE) score24
