Predictors of progression from mild cognitive impairment to Alzheimer disease
Abstract
Objective: To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI).
Method: We followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria.
Results: Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk [RR] = 1.8 [1.2 to 2.7] per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 [1.0 to 3.6] per symptom).
Conclusions: The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.
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Published online: May 7, 2007
Published in issue: May 8, 2007
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We analyzed 93 patients with Mild Cognitive Impairment (MCI) who were consecutively recruited (January 2004 - January 2006) from the Center of Neurodegenerative and Aging related Disease of the Neurological Department, University of Brescia. All subjects fulfilled the criteria proposed by Petersen et al. [2] At one- and two-year evaluations, a complete neuropsychological battery was administered. The aim of the study was to analyze the relation between depressive symptoms, loneliness and the conversion to dementia in MCI outpatients.
All subjects had a caregiver and nobody lived alone. Emotional loneliness was assessed utilizing two items: Do you feel that your life is empty?; and Do you often feel helpless? That are included in the Geriatric Depression Scale (GDS, short version). [3] Patients were defined as emotionally isolated (loneliness) if they answered positively to at least one of the two items. Depressive symptoms were assessed with the remaining thirteen GDS items.
At two years from baseline, 42 MCI patients (45.2%) converted to dementia; 28 to Alzheimer disease (AD); 4 to AD with cerebrovascular disease; 5 to Lewy Body dementia; and 5 to frontotemporal dementia. In a logistic regression analysis, ADAS-Cog basal score and loneliness, but not depressive symptoms, were independently associated with the conversion of MCI to dementia (Table). Data confirm a previous report demonstrating that loneliness is associated with an increased risk of dementia. [4]
We also found that depressive symptoms are unrelated to cognitive deterioration, confirming previous data where we demonstrated that depressed patients remained more stable on cognitive performances than MCI patients who did not have depression. [5] We should also consider that fourteen MCI patients converted to non Alzheimer dementias, supporting the hypothesis that loneliness is not directly related to Alzheimer pathological mechanisms but may compromise neural system broadly underlying cognition and memory, thereby making lonely individuals more vulnerable to the effect of age-related neuropathology.
This data could be important for a deeper understanding of the influence of psychological conditions in the progression of cognitive impairment. Table
References
1. Palmer K, Berger AK, Monastero et al. Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology 2007;68:1596-1602.
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3. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clinical Gerontol: A Guide to Assessment and Intervention. 1986;165-173, NY: The Haworth Press.
4. Wilson RS, Krueger KR, Arnold SE et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry 2007;64:234-240.
5. Rozzini L, Vicini Chilovi B, Trabucchi M, Padovani A. Depression is unrelated to conversion to dementia in patients with mild cognitive impairment. Arch Neurol 2005;62:505.
Disclosure: The authors report no conflicts of interest.
We thank Rozzini et al for their comments. We agree that depressive symptoms are not related to progression from MCI to dementia. Their important findings are derived from a specialized clinical sample and likely included much younger persons. Our population-based cohort included very old elderly. Despite these sample differences, our studies reported similar results which reinforce the main findings that depressive symptoms in MCI are not associated with neurodegeneration.
The lack of association between depressive symptoms and progression from MCI to dementia, although not confirmed in another study [6], could be due to the high frequency of symptoms in MCI persons who remain stable or improve.
We found that depressive symptoms did not predict progression from MCI to AD because symptoms were frequent in MCI persons who remained dementia-free and those who developed AD. In some cases, the cognitive impairment might be related to an underlying psychiatric disorder, while in others may be related to neurodegeneration. [7] Furthermore, mood-related depressive symptoms predicted AD development in persons without cognitive impairment supporting Wilson's findings that depression is a risk factor for AD. [8]
Rozzini reported that loneliness was associated with progression from MCI to dementia, citing similar findings by Wilson [4], who examined the association between loneliness and AD development in a non-demented cohort. However, it is likely that the population included also MCI persons. Rozzini separated the loneliness items from the GDS [3], but the remaining items were grouped together to assess a general depression category. It is important to consider whether any of the individual symptoms or clusters were independently related to dementia development. Findings from the Kungsholmen Project have highlighted the importance of separating mood-related and motivation-related depressive symptoms, especially for distinguishing between preclinical AD and late-life depression. [9-10]
From these studies we conclude that: depression is related to dementia development but not to progression from MCI to dementia; loneliness is related to dementia development and progression from MCI to dementia; and depression is related to a nondegenerative MCI etiology. The results of Rozzini's and our study highlight that many persons with both MCI and depressive symptoms do not develop dementia, suggesting that depressive symptoms in some MCI cases may be related to another etiology separate from a neurodegenerative mechanism.
Major research goals are to determine the role of depressive symptoms in MCI, establish whether depression may contribute to cognitive deficits in the elderly, and determine whether successful treatment of depressive mood may result in subsequent improvement in cognition.
References.
6. Modrego PJ, Ferrandez J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol 2004;61:1290–1293.
7. Monastero R, Palmer K, Qiu C, Winblad B, Fratiglioni L. Heterogeneity in risk factors for cognitive impairment, no dementia: population-based longitudinal study from the Kungsholmen Project. Am J Geriatr Psychiatry. 2007;15:60-69.
8. Wilson RS, Barnes LL, Mendes de Leon CF, et al. Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology. 2002 13;59:364-70.
9. Berger A-K, Fratiglioni L, Forsell Y, Winblad B, Bäckman L. The occurrence of depressive symptoms in the preclinical phase of Alzheimer's disease: A population-based study. Neurology, 1999;53:1998-2002.
10. Berger A-K, Small BJ, Forsell Y, Winblad B, Bäckman L. Preclinical symptoms of major depression in old age. A prospective longitudinal study. American Journal of Psychiatry, 1998;155:1039-1043.
Disclosure: The authors report no conflicts of interest.