536237 research-article2014

ANP0010.1177/0004867414536237Australian & New Zealand Journal of PsychiatryBrodaty et al.

Research

Progression from mild cognitive impairment to dementia: A 3-year longitudinal study

Australian & New Zealand Journal of Psychiatry 2014, Vol. 48(12) 1137­–1142 DOI: 10.1177/0004867414536237 © The Royal Australian and New Zealand College of Psychiatrists 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav anp.sagepub.com

Henry Brodaty1,2, Michael H Connors1,2, David Ames3,4 and Michael Woodward5 on behalf of the PRIME study group

Abstract Objective: To examine characteristics that predict the progression from mild cognitive impairment to dementia. Methods: Of 970 patients recruited from nine memory clinics around Australia, 185 had mild cognitive impairment diagnosed. Measures of cognitive ability, functional ability, and neuropsychiatric symptoms were completed at baseline and over 3 years of follow up. Results: Over 3 years, 52 (28%) patients with mild cognitive impairment developed dementia. Older age, lower cognitive ability at baseline, and faster decline in cognitive ability over the first 6 months of follow up, but not depression, predicted progression to dementia. Conclusions: The findings confirm that simple clinical data such as age, cognitive ability at baseline, and rate of cognitive decline are important predictors of progression from mild cognitive impairment to dementia over 3 years. Keywords Dementia, depression, longitudinal studies, mild cognitive impairment, risk factors

Introduction Mild cognitive impairment (MCI), often conceptualised as an intermediate state between normal ageing and dementia, is characterised by cognitive deficits that are noticeable to the patients or their families, yet do not interfere significantly with the patients’ ability to function in everyday life. While patients with MCI are at a higher risk of developing dementia then the general population (Petersen et al., 2009; Winblad et al., 2004), not all patients with MCI develop dementia (Xie et al., 2011). There is considerable controversy over the validity of MCI criteria and the prognostic significance of various proposed subtypes of MCI (Allegri et al., 2008; Visser and Brodaty, 2006). More accurate identification of which patients with MCI will develop dementia would be helpful to clinicians to advise their patients. Of particular importance is whether easily measured variables such as older age (Bruscoli and Lovestone, 2004), lower cognitive ability (Bruscoli and Lovestone, 2004), rates of cognitive and functional decline (Hensel et al., 2009), and neuropsychiatric symptoms (Teng et al., 2007), especially depression (Modrego and Ferrández, 2004; Palmer et al., 2007; Teng et al., 2007), increase the risk of progression.

Most research on predictors of progression from MCI has emanated from tertiary referral centres or population studies (Mitchell and Shiri-Feshki, 2009; Petersen et al., 2009), especially from the USA. This is significant given that rates of progression to dementia in patients with MCI vary depending on location and setting (Bruscoli and Lovestone, 2004; Brodaty et al., 2013). We examined predictors of dementia in patients with MCI who were 1Dementia

Collaborative Research Centre, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia. 2Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia. 3National Ageing Research Institute, Melbourne, Australia. 4University of Melbourne Academic Unit for Psychiatry of Old Age, Melbourne, Australia. 5Austin Hospital, Heidelberg, Australia. Corresponding author: Henry Brodaty, Dementia Collaborative Research Centre, Level 3, AGSM Bldg (G27), University of New South Wales, NSW 2052, Australia. Email: [email protected]

Australian & New Zealand Journal of Psychiatry, 48(12)

1138 attending memory clinics across Australia. Measures of cognitive ability, functional ability, and neuropsychiatric symptoms were completed at baseline and patients were followed for 3 years. Following previous research, we hypothesised that older age, lower cognitive ability at baseline, more neuropsychiatric symptoms (especially greater depression at baseline), and steeper trajectory of cognitive decline would predict progression to dementia.

Materials and methods Design The participants were drawn from the PRIME study in Australia (Brodaty et al., 2011). This study was a 3-year, nonprescriptive, observational study examining relationships between predictors and outcome variables in patients with dementia and MCI. All participants were receiving specialist assessment or treatment at one of nine memory clinics in Australia. The memory clinics were in four of the eight states and territories of Australia and included both regional and capital centres. Patients were followed up at 3, 6, 12, 24, and 36 months by a research nurse or their specialist clinician. Patients were also followed up after their regular clinical appointments if their specialist clinician indicated a change in diagnosis. Ethics approval was obtained from institutional ethics committees associated with individual referring centres (National Institute of Health clinical trials registry number: NCT00297271).

Participants Of the 970 patients in the PRIME study, 189 had MCI at baseline and 781 had dementia. All patients were living in the community, were fluent in English, and provided written informed consent. Four patients with MCI were excluded from analyses because they were taking medication for Alzheimer’s disease or were concurrently participating in a clinical trial of an investigational drug. This paper specifically focused on the remaining 185 patients with MCI at baseline. Diagnoses of MCI were made according to the Petersen criteria by a specialist psychogeriatrician, geriatrician or neurologist (Winblad et al., 2004); subsequent diagnoses of dementia and types were made by specialist clinicians using DSM-IV criteria (American Psychiatric Association, 2000). More specifically, criteria for MCI required that: (i) patients or an informant report signs of cognitive decline; (ii) patients show objective evidence of cognitive decline as measured by the Mini-Mental State Examination (MMSE; Folstein et al., 1975); (iii) patients retain generally preserved functioning in activities of daily living; and (iv) patients do not meet DSM-IV criteria for dementia. Data relating to the subtypes of MCI (Winblad et al., 2004) were not collected. The number of patients at each time point and the reasons that patients were lost to follow up are shown in Figure 1. Patients who Australian & New Zealand Journal of Psychiatry, 48(12)

ANZJP Articles were lost to follow up did not significantly differ from those who completed the study on any of the measured variables (all p>0.06)

Measures and procedure At baseline and at each subsequent visit, a research nurse or specialist clinician administered measures of cognitive ability, functional ability, and neuropsychiatric symptoms. Cognitive ability was assessed using the MMSE (Folstein et al., 1975). Functional ability was assessed using the Functional Autonomy Measurement System (SMAF; Hébert et al., 1988). Neuropsychiatric symptoms, including depression, were assessed using the 12-item Neuropsychiatric Inventory (NPI; Cummings, 1997) with an informant.

Statistical analyses Patients with MCI who developed dementia were compared to patients who did not on demographic variables and measures of cognition (MMSE), decline in cognitive ability over time (decline in MMSE), functional ability (SMAF), decline in functional ability over time (decline in SMAF), neuropsychiatric symptoms (NPI), change in neuropsychiatric symptoms over time (change in NPI), and individual neuropsychiatric symptoms – namely delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behaviour, night-time disturbances, and appetite disturbances. Categorical variables – namely sex and education – were compared using chi-squared analyses. All other variables were compared using independent-samples t-tests. The relationship between neuropsychiatric symptoms and MMSE score was examined using Pearson correlations. A Cox’s proportional hazard model was used to examine which variables predicted a diagnosis of dementia within the 3-year period. Patients who withdrew from the study or died before being institutionalised were classed as censored. Given the statistical constraint of one predictor per 10 events (Peduzzi et al., 1995), analyses focused on age, sex, MMSE), decline in MMSE at 6 months, and depression as predictors. Analyses were also repeated with total NPI score and change in total NPI at 6 months included in the model instead of depression. All statistical procedures were conducted using SPSS version 21.

Results Patient characteristics The baseline characteristics of the patients who developed dementia and those who did not are shown in Table 1. Patients who developed dementia in the 3-year period had a lower MMSE score at baseline, a greater decrease in MMSE score over time, and greater depression at baseline.

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Figure 1.  Flow diagram indicating sample sizes across time points and the reasons that participants were lost to follow up. Baseline n = 185

Institutionalised = 0 Deceased = 1

3 months

Declined/Unable to contact = 34

n = 150 Institutionalised = 0 Deceased = 0 6 months

Declined/Unable to contact = 5

n = 145 Institutionalised = 1 Deceased = 1 1 year n = 141

Declined/Unable to contact = 2

Institutionalised = 4 Deceased = 2

2 years n = 122

Declined/Unable to contact = 13

Institutionalised = 1 Deceased = 1

3 years

Declined/Unable to contact = 9

n = 111

Across all patients, 118 (63.8%) were reported to have at least one neuropsychiatric symptom at baseline. Overall, eight (4.3%) patients were reported to have delusions, two (1.1%) hallucinations, 54 (29.2%) agitation, 61 (33%) depression, 59 (31.9%) anxiety, 10 (5.4%) euphoria, 59 (31.9%) apathy, 25 (13.5%) disinhibition, 67 (36.2%) irritability, 12 (6.5%) aberrant motor behaviour, 34 (18.4%) night-time disturbances, and 26 (14.1%) appetite disturbances. Chi-squared analysis indicated no significant difference in the distribution of symptoms at baseline between patients who developed dementia and those who did not (all chi-squared0.07). Baseline depression and MMSE score were negatively correlated, r=−0.17, p=0.03. There were no statistically significant correlations between other neuropsychiatric symptoms and MMSE score (all r0.09).

one (1.9%) with atypical dementia. The duration until progression to dementia was (mean±SD) 98.1±61.1 weeks.

Progression to dementia

Discussion

Of the 185 patients with MCI at baseline, 52 (28.1%) were diagnosed with dementia over the 3-year period. They comprised 38 (73.1%) patients with Alzheimer’s disease, two (3.8%) with vascular dementia, five (9.6%) with mixed Alzheimer’s and vascular dementia, one (1.9%) with dementia with Lewy Bodies, four (7.7%) with frontotemporal dementia, one (1.9%) with semantic dementia, and

The current study found that approximately 30% of patients with MCI defined by the Petersen criteria progressed to dementia within 3 years. This is consistent with previous research which found annual conversion rates from Petersendefined MCI to dementia of just under 10% (Mitchell and Shiri-Feshki, 2009). As in previous research (Bruscoli and Lovestone, 2004), older age and lower cognitive ability

Predictors of progression to dementia A Cox’s proportional hazard model that included age, sex, baseline MMSE, decline in MMSE at 6 months, and baseline depression as predictors found that only age, MMSE, and decline in MMSE at 6 months predicted the progression from MCI to dementia. Sex and depression were not statistically significant predictors. Results are shown in Table 2. When analyses were repeated with the total NPI score or the change in the total NPI score over 6 months included in the model instead of depression, results were unaltered and neither of these variables emerged as significant predictors.

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Table 1.  Characteristics of patients who did and did not develop dementia. Developed dementia (n=52)

Did not develop dementia (n=133)

Demographics

p-value  

Age (years)

75.3±6.7

76.0±7.0

0.521

Sex (Female)   Education (Some tertiary)

55.8 46.2

42.1 50.0

0.103 0.743

Cognitive ability  MMSE    Decline at 3 months    Decline at 6 months    Decline at 1 year

26.31±2.17 −0.80±2.15 −1.08±2.55 −1.92±3.60

27.26±2.09 −0.07±2.27 0.12±2.05 0.06±2.35

  0.007 0.064 0.001

Progression from mild cognitive impairment to dementia: a 3-year longitudinal study.

To examine characteristics that predict the progression from mild cognitive impairment to dementia...
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