Regular Research Article| Volume 30, ISSUE 8, P925-934, August 2022

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An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death

  • Jiayue Qiu
    School of Dental Medicine (JQ), University of Pennsylvania, Philadelphia, PA
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  • Felicia C. Goldstein
    Send correspondence and reprint requests to Felicia C. Goldstein, Ph.D., Department of Neurology, Emory University School of Medicine, 1841 Clifton Road, N.E., Atlanta 30329, Georgia.
    Department of Neurology (FCG), Emory University School of Medicine, Atlanta, GA

    Goizueta Alzheimer's Disease Research Center (FCG, JJH), Emory University School of Medicine, Atlanta, GA
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  • John J. Hanfelt
    Send correspondence and reprint requests to John J. Hanfelt, Ph.D., Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, 1518 Clifton Road, N.E., Atlanta 30322, Georgia.
    Goizueta Alzheimer's Disease Research Center (FCG, JJH), Emory University School of Medicine, Atlanta, GA

    Department of Biostatistics and Bioinformatics (JJH), Emory University Rollins School of Public Health, Atlanta, GA
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Published:January 02, 2022DOI:


      • What is the primary question addressed by this study?The purpose of this study was to examine neuropsychiatric symptom complexes in a population with mild cognitive impairment and assess whether these complexes were associated with more rapid progression to dementia or death without dementia.
      • What is the main finding of this study?In addition to a subgroup with mild or no neuropsychiatric symptoms, three subgroups were identified based on mood, hyperactive, or psychotic symptoms, and these three subgroups were at higher risk of dementia.
      • What is the meaning of the finding?Our results suggest that the structure of neuropsychiatric symptoms warrants further consideration in classification models of mild cognitive impairment to better predict the risk of disease progression.



      To explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying.


      Latent class analysis using 7,971 participants with MCI.


      Participants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers.


      Persons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater.


      Neuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit.


      In addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an “affect” or “negative mood” subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a “hyperactive” subgroup (14%) with agitation, irritability, and disinhibition; and 3) a “psychotic with additional severe NPS” subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the “mild NPS” class, with the “psychotic with additional severe NPS” subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia.


      Our findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.

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      Linked Article

      • To Cluster or Not Cluster, That is the Question
        The American Journal of Geriatric PsychiatryVol. 30Issue 8
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          It is becoming increasingly clear that Alzheimer's disease (AD) symptoms are not purely cognitive and that neuropsychiatric symptoms (NPS) are a frequent prodrome of AD. This has implications for prognosis and treatment, since NPS are frequently the first symptom of future cognitive and/or functional decline 1 and late-life NPS may be targets for AD prevention. Recent studies have largely (but not universally) reported NPS to be associated with risk of progression to mild cognitive impairment (MCI) or AD, and NPS including depression, anxiety, sleep disturbances and apathy have been implicated.
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