Frequently Asked Questions

This study identified 4 neuropsychiatric symptom clusters in participants with amnestic mild cognitive impairment or dementia due to Alzheimer disease. The final principal components model explained 62.4% of the variance and included: hyperactivity (disinhibition, irritability, aberrant motor behaviors, agitation/aggression), psychosis (hallucinations, delusions, euphoria), neurovegetative (appetite abnormalities, apathy), and affective (depression, anxiety, nighttime behavior).

Psychosis symptoms were relatively uncommon in this cohort and were not included in the longitudinal imaging analyses. Only 13.9% of participants at baseline, 18.2% at 1 year, and 14.3% at 2 years had psychosis cluster scores greater than 0, so the authors excluded this cluster from further imaging analyses because the low frequency limited power to detect brain associations.

The hyperactivity cluster was longitudinally associated with lower volumes in 3 regions: the left middle temporal cortex, right nucleus accumbens, and left ventral diencephalon. Specifically, the standardized associations were b2=-0.28 for right nucleus accumbens (95% CI, -0.48 to -0.08; P=.007), b2=-0.24 for left middle temporal (95% CI, -0.45 to -0.03; P=.025), and b2=-0.25 for left ventral diencephalon (95% CI, -0.44 to -0.05; P=.013).

The neurovegetative cluster was longitudinally associated with lower volumes in the left fusiform, left middle temporal, and right nucleus accumbens. The strongest associations were with the right nucleus accumbens (b2=-0.55, 95% CI, -0.75 to -0.35; P<.001) and left middle temporal cortex (b2=-0.50, 95% CI, -0.72 to -0.28; P<.001), with an additional association for left fusiform volume (b2=-0.36, 95% CI, -0.58 to -0.14; P=.002).

The affective cluster was associated with lower volumes in several cortical and subcortical regions: left rostral anterior cingulate, right entorhinal cortex, right medial orbitofrontal cortex, right pars opercularis, and left putamen. The reported longitudinal associations were b2=-0.42 for left rostral anterior cingulate (95% CI, -0.67 to -0.16; P=.002), b2=-0.51 for right entorhinal (95% CI, -0.84 to -0.17; P=.004), b2=-0.47 for right medial orbitofrontal (95% CI, -0.75 to -0.20; P=.001), b2=-0.44 for right pars opercularis (95% CI, -0.69 to -0.18; P=.001), and b2=-0.44 for left putamen (95% CI, -0.72 to -0.17; P=.002).

Yes. All symptom clusters were longitudinally associated with instrumental activities of daily living (iADLs) after adjustment for age, education, MoCA score, time, cholinesterase inhibitor use, and sex. The hyperactivity, neurovegetative, and affective clusters also longitudinally predicted basic activities of daily living (ADLs), and the authors reported that higher subscale scores for these clusters were significantly associated with worse iADL (b2 range, -0.17 to -0.24) and ADL (b2 range, -0.19 to -0.20) outcomes.

This was a longitudinal cohort study using Phase 1 data from the Ontario Neurodegenerative Disease Research Initiative. The study included participants aged 45-90 years with amnestic mild cognitive impairment or dementia due to Alzheimer disease who underwent assessments of neuropsychiatric symptoms, structural MRI, and function at baseline and again at 1-year and 2-year follow-up visits.

Of 126 participants, 111 had sufficient Neuropsychiatric Inventory Questionnaire data for principal components analysis. MRI data were available for 126 participants at baseline, 109 at 1 year, and 85 at 2 years, with 96 and 73 participants providing sufficient paired symptom and MRI data at the first and second follow-up visits, respectively.

The main limitations were limited diagnostic specificity, low frequency of psychosis symptoms, restriction to mostly mild-to-moderate disease, and the assumption that symptom cluster structure remained stable over time. The cohort did not require pathologic confirmation or imaging/CSF biomarker-supported diagnosis, included few atypical Alzheimer disease variants, and had fewer than 20% of participants with psychosis-cluster symptoms at each time point, which prevented meaningful longitudinal imaging analysis of psychosis.

The authors also noted that follow-up subscale scores were based on the cluster structure derived at baseline, and that factor solutions at later visits were less stable because of smaller samples and increasing data sparsity from attrition. As a result, the findings are most generalizable to patients in early or mid-clinical stages of Alzheimer disease.