Mild behavioral impairment is associated with plasma p‐tau181 in a dementia‐free population

Abstract

BackgroundMild behavioral impairment (MBI) is a validated neurobehavioral syndrome describing emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. In cognitively normal older adults MBI is associated with positron emission tomography and cerebrospinal fluid measured amyloid‐β and tau, the characteristic hallmarks of Alzheimer’s disease (AD). Plasma p‐tau181 is a blood‐based biomarker recently identified as an accessible alternative for in‐vivo detection of AD pathologies. So far, no study has explored plasma p‐tau181 in MBI. Here, we investigated the cross‐sectional and longitudinal associations of MBI with plasma p‐tau181 in dementia‐free older adults, and the associations of MBI with risk of AD.MethodThe sample included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). MBI status was determined using NPS total score at baseline and year‐one. NPS scores were derived from the Neuropsychiatric Inventory and categorized as persistent NPS (i.e., MBI, score>0 at both visits); transient/impersistent NPS (score>0 at only one visit); and no NPS (score = 0 at both visits). Cross‐sectionally, linear regression models were fitted with p‐tau181 as dependent variable and NPS profile as independent variable. Longitudinally, Cox proportional hazards models examined associations between NPS profile and incident dementia. Multilevel linear mixed effect (MLME) models assessed the associations between NPS status, categorized as within‐person NPS variability (impersistent NPS, not consistent with MBI) and between‐person NPS burden (persistent NPS, consistent with MBI), and p‐tau181 across four years.ResultThe final sample consisted of 571 dementia‐free participants (age 72.2, 46.8% females). Compared to no NPS, participants with persistent NPS but not transient NPS had higher baseline plasma ptau‐181 levels. Longitudinally, persistent NPS were associated with 3.42 times greater risk for dementia compared to no NPS. MLME analyses on annual measures of NPS and p‐tau181 over four years demonstrated that only the between‐person NPS measure was associated with higher p‐tau181 levels.ConclusionThese findings extend the evidence base that MBI is a clinically relevant syndrome associated with the AD pathophysiological process. Incorporating MBI into clinical screening may help to identify those with preclinical or prodromal AD.

Persistence of neuropsychiatric symptoms and dementia prognostication: A comparison of three operational case definitions of mild behavioral impairment

“…In older adults with MCI, only MBI was associated with a lower likelihood of reversion to normal cognition, whereas non‐MBI NPS showed no difference compared to no NPS 18 . This finding suggests that distinguishing MBI from non‐MBI NPS, the latter of which is often captured by the NPI and its derivatives, is essential to fully understand and make use of MBI as a tool for neurodegenerative disease research and for sample enrichment 4 . One issue with using the NPI and its derivatives for MBI is the reference timeframe by which the instruments assess NPS, which spans 1 month 29–31 .…”

“…MBI should be thought of as a subset of NPS that meet the aforementioned criteria (Figure S1), which improve specificity for the NPS identified by MBI representing early‐stage neurodegenerative disease as a complementary behavioral analog to late‐life emergent cognitive symptoms 2 . As such, MBI can improve early dementia risk detection, thereby facilitating research into early neurodegenerative disease mechanisms and the development of preventative or disease‐modifying treatments 3,4 …”

“…2 As such, MBI can improve early dementia risk detection, thereby facilitating research into early neurodegenerative disease mechanisms and the development of preventative or disease-modifying treatments. 3,4 The Mild Behavioral Impairment Checklist (MBI-C) was developed to capture NPS that meet MBI criteria. 5 Studies that used the MBI-C demonstrated poorer cognition and greater β-amyloid (Aβ) and tau pathology, medial temporal lobe atrophy, and Alzheimer's disease (AD) genetic risk in MBI older adults.…”

Persistence of Neuropsychiatric Symptoms and Dementia Prognostication: A Comparison of Three Operational Definitions of Mild Behavioral Impairment

“…2 As such, MBI has the potential to improve early detection of dementia risk, thereby facilitating research into early neurodegenerative disease mechanisms and the development of preventative or disease-modifying treatments. 3,4 The Mild Behavioral Impairment Checklist (MBI-C) was developed specifically to capture NPS that meet the criteria for MBI. 5 Studies that used the MBI-C demonstrated poorer cognition and greater β-amyloid (Aβ) and tau pathology, medial temporal lobe atrophy, and Alzheimer's disease (AD) genetic risk in older adults with MBI.…”

“…19 This finding suggests that distinguishing MBI from non-MBI NPS is essential to fully understand and make use of MBI as a tool for neurodegenerative disease research and for sample enrichment. 4 One issue with using the NPI and its derivatives for MBI is the reference timeframe by which the instruments assess NPS, which spans one month. [28][29][30] In contrast, the MBI-C reference frame is six months, consistent with the symptom persistence criterion for MBI.…”