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Alzheimer’s disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework.
Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.
1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p < .001). Word List Delayed Recall (β = −.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p < .001) and 4 (β = −2.23, p < .001).
We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.
Neuropsychiatric symptoms are a common problem in dementia. Epidemiological studies indicate that approximately 60% of demented subjects in the community exhibit some degree of psychopathology. Among specific populations of subjects diagnosed with frontotemporal dementia (FTD) or advanced Alzheimer's disease (AD), the prevalence of behavioral pathology increases to 95%. The most frequently reported behavioral symptoms include apathy, agitation and depression.
The significant contributions of neuropsychiatric symptoms to the more common dementia syndromes are reflected by their prominent role in the diagnosis of these conditions. Behavioral symptoms are primary components of the diagnostic criteria for FTD and dementia with Lewy bodies (DLB) and are among the secondary supportive factors in the diagnostic criteria for AD and vascular dementia (VaD). Disturbances in behavior have also been reported in mild cognitive impairment (MCI), Parkinson's disease with dementia (PDD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).
While the severity of a dementing illness is often determined using cognitive criteria, behavioral disturbances are responsible for a substantial proportion of the morbidity caused by different dementia syndromes. Caregivers for patients with dementia find behavioral abnormalities significantly more troubling than cognitive deficits. The presence of neuropsychiatric symptoms correlates with increased rates of institutionalization, cost of care and caregiver stress and burden.
The behavioral disruptions seen in dementia are not simply an inevitable consequence of worsening cognitive impairment. Although neuropsychiatric symptoms are often seen with greater frequency and severity in the later stages of dementing illnesses, the clinical course of different behavioral symptoms is often heterogeneous and does not correlate closely with the severity of cognitive or functional impairment.
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