Dementia Insights: Mild Behavioral Impairment

New-onset persistent personality and behavior changes after age 50, rather than signaling a new-onset psychiatric disorder, could be an early manifestation of a neurodegenerative disease. With the prevalence of dementia on the rise worldwide, early detection of individuals at risk is an important focus for clinicians and researchers. Mild cognitive impairment (MCI) often is a transitional state between normal cognition and dementia. MCI can be preceded or accompanied by behavioral changes. Mild behavioral impairment (MBI) is a neurobehavioral syndrome that can reveal high risk for incident dementia by leveraging risk associated with new-onset and persistent neuropsychiatric symptoms (NPS).

NPS and Their Relation to Cognitive Decline:

The Birth of MBI

NPS occur in almost all individuals with dementia and include delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, irritability, and changes in sleep and eating patterns. These symptoms can fluctuate during the disease course, can exacerbate disease progression, and are associated with more rapid cognitive decline. However, NPS can emerge in advance of dementia, the assessment of which is an important factor to consider during intake history. When NPS emerge de novo after age 50, persist for longer than 6 months, represent a change from longstanding personality or behavior, and are not explained by another psychiatric disorder, they meet criteria for MBI.¹

New-onset NPS and the term MBI originally were framed in the context of frontotemporal dementia,² in which cognitive and behavioral changes, including disinhibition and apathy, were core criteria. When individuals with a primary complaint of NPS were followed for 3 years, however, only 36% were diagnosed with frontotemporal dementia; 28% were diagnosed with Alzheimer disease (AD), 18% with vascular dementia, and 18% with another form of dementia.² More recently, among 1998 cognitively normal participants, 59% developed NPS before cognitive symptoms, including 30% who eventually developed AD.³ These studies, among others, suggest that NPS can be an early marker of any dementia type, including AD, which has not traditionally been associated with a behavioral prodrome.

Because MCI and MBI can occur individually or together, it is important to determine whether there are differences in disease progression in people with 1 prodromal syndrome or a combination. Over a 3-year period, individuals who presented at baseline with or without an MBI diagnosis and an MCI diagnosis at a subsequent visit were followed until they progressed to a dementia diagnosis. Those with a combination of MCI and MBI were more likely to progress to dementia and less likely to revert to normal cognition than those with MCI who did not meet MBI criteria.⁴

Earlier along the cognitive continuum, subjective cognitive decline (SCD) is linked to risk of progression to MCI and dementia. As with MCI, individuals with both SCD and MBI exhibit a higher risk of progression to dementia than do those with SCD or MBI alone (ie, MBI in normal cognition).⁵

Acknowledging risks of both MBI and SCD, the National Institute on Aging–Alzheimer’s Association Research Framework and clinical staging include MBI and SCD in stage 2, representing the neurobehavioral and neurocognitive axes of dementia risk.⁶ Based on the need for early identification and treatment, the opportunity exists to flag people with SCD or MBI, or both, for further assessment. These individuals may be referred to research opportunities and begin modifying lifestyle factors, such as improving cardiovascular health, sleep health, diet, and exercise, as appropriate, and can be worked up with biomarkers for potential participation in disease-modifying treatment trials.

Clinical Features of MBI

The clinical features of MBI and criteria were developed and validated by an international panel led by the International Society to Advance Alzheimer’s Research and Treatment (ISTAART) NPS Professional Interest Area.⁷ In addition to symptoms beginning de novo after age 50 and being persistent, the ISTAART-MBI diagnostic criteria require demonstration that a change has occurred in at least 1 of the 5 core domains of NPS: decreased drive or motivation (ie, apathy), affective dysregulation (ie, mood or anxiety symptoms), impulse dyscontrol (eg, agitation, impulsivity), social inappropriateness (eg, impaired social cognition), and abnormal perception or thought (ie, delusions or hallucinations) (Table). To estimate the pooled prevalence of symptoms in each MBI domain, a recent meta-analysis of 10 studies with 9758 cognitively normal older adults, 1057 older adults with SCD, and 1252 older adults with MCI was conducted.⁸ Affective dysregulation, characterized by symptoms of anxiety, dysphoria, changeability, or euphoria,⁷ was the most commonly affected domain, with a prevalence of 32.8% (95% CI, 24.4%-42.5%).⁸ Impulse dyscontrol, characterized by agitation, irritability, poor frustration tolerance, or disinhibition,⁷ had a prevalence of 26.7% (95% CI, 18.2%-37.2%).⁸ Decreased motivation, characterized by apathy, aspontaneity, or indifference,⁷ had a prevalence of 12.6% (95% CI, 6.9%-6.0%).⁸ Social inappropriateness, characterized by lack of empathy, loss of insight, loss of social graces or tact, rigidity, or exaggeration of previous personality traits,⁷ had a prevalence of 6.0% (95% CI, 3.4%-10.4%).⁸ Abnormal perception or thought, characterized by delusions or hallucinations,⁷ had a prevalence of 2.8% (95% CI, 1.7%-4.7%).⁸ Importantly, the prevalence of MBI increases with greater cognitive impairment and is lower in normal cognition and higher in MCL. For more detailed information about domain differences, see the 2023 review by Jin et al.⁹

MBI Biomarkers and Mechanisms

MBI may be associated with AD pathology and biomarkers of neurodegeneration. For example, MBI is associated with atrophy in the hippocampus, parahippocampal gyrus, entorhinal cortex, and temporal lobe.¹⁰ The core domain of impulse dyscontrol is associated with decreased white matter integrity in several white matter tracts associated with learning and memory.¹¹ MBI in older adults without dementia is associated with reduced functional connectivity in networks disrupted in AD, including the default mode network,¹ salience network,¹ and frontoparietal control network.¹² Imaging and fluid biomarker studies have assessed amyloid/tau/neuroimaging (ATN) biomarkers in MBI. MBI Checklist (MBI-C) scores are associated with increased global and striatal amyloid binding,¹³ tau–positron emission tomography tracer uptake in the medial temporal cortex, and cerebrospinal fluid p-tau₁₈₁ levels.¹⁴ MBI is associated with progression to neuropathologically confirmed AD (hazard ratio, 1.59), but only in people who score higher in AD neuropathologic change categories.¹⁵ In 139 Alzheimer’s Disease Neuroimaging Initiative participants, MBI scores were associated cross-sectionally with a lower plasma AΒ42/40 ratio, linking MBI to a greater brain amyloid burden.¹⁶ In another Alzheimer’s Disease Neuroimaging Initiative cohort of 571 individuals, MBI was associated cross-sectionally with higher plasma p-tau181 levels and with increasing levels over time, in addition to decline in memory and executive function.¹⁷ Therefore, there is cross-sectional and longitudinal evidence linking MBI to AD–ATN biomarkers.

Evidence of the role of deficient serotonergic (5-hydroxytryptamine [5HT]) neurotransmission in NPS in AD is accumulating. 5HT receptor and transporter density decreases with age. Serotonergic neurons have cell bodies in brainstem raphe nuclei and are involved in spatial navigation, decision-making, social relationships, working memory, attention, and reversal learning in both humans and animals. These associations of 5HT with cognition and mood suggest a potential role for changes in 5HT in underlying NPS of AD.¹⁸ Neuropathology studies link NPS to loss of cortical 5HT innervation, cholinergic–serotonergic imbalance, reduced 5HT1A receptor binding in the temporal cortex, and lower cell counts in the dorsal raphe nucleus. Observational evidence suggests that use of selective serotonin reuptake inhibitors may be associated with lower risk of incident AD.

The evidence suggests that MBI is associated with AD pathology in cognitively unimpaired persons and those with MCI, and that NPS (although MBI has not been studied specifically) may be associated with decreased 5HT function. Both of these insights point to novel avenues for AD prevention by treating MBI and NPS with pharmacologic or nonpharmacologic interventions.

Measurement of MBI

The 5 core domains are reflected in the tools repurposed and created for identifying MBI. The Neuropsychiatric Inventory Questionnaire (NPI-Q)¹⁹ is an informant-rated instrument that assesses the severity and distress of 12 symptom domains over the past month in individuals with dementia. MBI status can be generated from the NPI-Q, using a published algorithm.⁵ Decreased motivation is represented by the apathy and indifference items in the NPI-Q; affective dysregulation by the depression or dysphoria, anxiety, and elation or euphoria items; impulse dyscontrol by the agitation or aggression, irritability or lability, and motor disturbance items; social inappropriateness by the disinhibition item; and psychotic symptoms by the delusion and hallucination items.⁴ Item scores are added to create a total score. A score above 0 at 2 consecutive assessment time periods (at least 6 months apart) is consistent with MBI. This method has been used extensively, especially because many longitudinal studies have used the NPI-Q, before the development of MBI.^1,4,5 However, the NPI-Q was created for use in the setting of dementia, rather than among individuals with normal cognition.The MBI-C was developed to assess for later-life onset and persistence of NPS in the 5 MBI domains. The MBI-C consists of 34 yes/no questions developed for community-dwelling older adults without dementia, followed by a severity rating of 1 (mild), 2 (moderate), or 3 (severe).²⁰ An item is answered “yes” when the symptom is present and has been persistent for 6 months or longer. The questionnaire is primarily answered by care partners who know the individual well. The MBI-C was validated against the NPI-Q in 1238 individuals presenting with SCD, MCI, or dementia at an academic cognitive clinic. According to analysis using Spearman correlation testing, there was a significant positive correlation between the MBI-C and the NPI-Q, both in total, with a correlation of .67 (ρ (227), P<.00001), and in domain scores. Both questionnaires observed at least 1 NPS in a majority of participants (MBI-C, 89.87%; NPI-Q, 67.98%).²¹

Clinical Recommendations for Practitioners

The best way to manage AD in the long run is to prevent it, and with rapid improvements in blood-based biomarkers and anti-amyloid therapies, there are increasing opportunities to intervene earlier in the AD continuum. MBI is a clinical syndrome associated with increased AD risk and biological mechanisms. Identifying new psychiatric symptoms in older adults may help identify persons at risk. There may be different prodromal symptoms in different people, possibly reflecting different mechanisms of AD risk. Therefore, individuals with MBI may particularly benefit from psychologic or psychopharmacologic interventions to decrease risk.

We recommend standard diagnosis and treatment of late-life psychiatric syndromes, including major depression, anxiety disorders, and late-life psychotic disorders. We also recommend vigilance for new symptoms in older adults that may represent MBI, with special attention to prognosis and prompt treatment. Efficient mining of big data such as electronic health records may assist with identification.

Conclusion

Practitioners should ask patients and their care partners about later-life changes in behavior and personality, which might prompt a more detailed workup. By understanding the importance of NPS in the neurodegenerative disease continuum, we can identify persistent late-onset NPS as a risk factor and determine which individuals may be at a higher risk for developing dementia.⁴ Referral to preventive and early-stage cognitive impairment treatment trials or specialized memory and dementia practitioners will allow individuals and families to begin preparation and conversations about their care wishes before cognitive symptom onset.