轻度行为损害与阿尔茨海默病相关研究的进展

摘要/Abstract

摘要：

轻度行为损害（mild behavioral impairment，MBI）是中老年（50岁以上）发生的一系列精神行为症状，以情感失调和冲动失控为主，包括抑郁、躁狂以及幻觉、妄想等，是认知下降的早期预警信号，与阿尔茨海默病（Alzheimer′s disease，AD）的病理进程相关，且可早于痴呆症状出现多年。MBI在认知功能正常人群中的患病率约10%，而在轻度认知功能障碍（mild cognitive impairment， MCI）人群中该比例显著升高至14%~50%。然而，在临床实践中，由于MBI症状的复杂性和非特异性，其与AD间的潜在关联常被低估或忽视。近年来，随着AD诊断标志物的深入研究，MBI与AD的内在联系已逐步被揭示。横断面研究证实，MBI与脑脊液Aβ42水平降低及脑内Aβ沉积负荷增加显著相关。纵向研究进一步揭示，MBI症状与高Aβ沉积程度及认知衰退速率呈正相关，但与tau蛋白病理间的关联仍存在争议。MBI与AD特征性脑萎缩存在空间一致性，如海马体、杏仁核和内嗅皮层等。上述证据链共同支持MBI作为AD临床前阶段神经精神标志物的重要地位。为了更好地在早期识别AD，本文旨在强调临床实践中需建立神经精神症状-认知衰退多维评估框架，提醒临床医生对老年期的异常精神行为提高重视，以提升AD临床前阶段的识别率。

关键词:轻度行为损害,阿尔茨海默病,精神行为症状,生物标志物,神经影像学,认知下降

Abstract:

Mild behavioral impairment (MBI) refers to a series of neuropsychiatric symptoms in adults aged ≥50 years, primarily characterized by affective dysregulation and impulse control deficits, including depression, mania, hallucinations, and delusions. As an early harbinger of cognitive decline, MBI is intrinsically linked to the pathological progression of Alzheimer's disease (AD) and may appear several years before the onset of dementia symptoms. Its prevalence is approximately 10% in cognitively normal populations, increasing to 14%-50% among individuals with mild cognitive impairment (MCI). However, in clinical practice, the potential associations between MBI and AD are often underestimated or overlooked due to the complexity and non-specificity of MBI symptoms. In recent years, with in-depth research on AD biomarkers, the intrinsic relationship between MBI and AD has been gradually revealed. Cross-sectional studies have confirmed that MBI is significantly associated with reduced cerebrospinal fluid (CSF) Aβ42 levels and elevated cerebral Aβ deposition burden. Longitudinal evidence further demonstrates positive associations between MBI severity, high Aβ deposition, and accelerated cognitive decline, though its links with tau pathology remain controversial. MBI shows spatial consistency with AD-characteristic brain atrophy, such as in the hippocampus, amygdala, and entorhinal cortex. Collectively, this evidence solidifies the important role of MBI as a neuropsychiatric biomarker in the preclinical stage of AD. To optimize early AD detection, this review aims to highlight the need to establish a multidimensional assessment framework integrating neuropsychiatric symptoms and cognitive decline in clinical practice and remind clinicians to heighten vigilance toward abnormal neuropsychiatric behaviors in the elderly, thereby improving the detection rate of the preclinical stage of AD.

Key words:Mild behavioral impairment,Alzheimer's disease,Neuropsychiatric symptoms,Biomarkers,Neuroima-ging,Cognitive decline

中图分类号:

R749.16
R446

李雨航, 肖世富, 岳玲. 轻度行为损害与阿尔茨海默病相关研究的进展[J]. 诊断学理论与实践, 2025, 24(05): 548-554.

LI Yuhang, XIAO Shifu, YUE Ling. Advances in research on association between mild behavioral impairment and Alzheimer′s disease[J]. Journal of Diagnostics Concepts & Practice, 2025, 24(05): 548-554.

图/表2

表1

MBI的流行病学研究

时间	研究者	使用工具	研究对象	MBI流行病学数据
2018	Sheikn等^{[ 13 ]}	NPI	MCI	MCI 49%~85%；非MCI 28%~75%
2019	Matsuoka等^{[ 12 ]}	NPI	精神科和记忆门诊	精神科门诊，SCD 19.6%，MCI 50.0% 记忆诊所，SCD 76.5%，MCI 85.3%
2020	Rao等^{[ 14 ]}	NPI	记忆门诊	遗忘型MCI 41.13%
2020	Kassam等^{[ 7 ]}	MBI-C	所有认知状态人群	认知正常10%；MCI 14%
2022	Xu等^{[ 15 ]}	MBI-C	临床患者	MCI超过50%
2021	肖辛怡等^{[ 16 ]}	NPI	记忆门诊	MCI 42.6%；痴呆78.3%
2023	曾黎等^{[ 17 ]}	MBI-C	农村老人	农村老人32.97%
2024	Leow等^{[ 18 ]}	MBI-C	新加坡社区	MBI-C平均得分（2.52±4.54）分
2024	Cherkasov等^{[ 19 ]}	MBI-C	50岁以上老人	50岁以上65%
2024	Richey等^{[ 20 ]}	NPI-Q	社区老人	有头部损伤史的31.3%；没有头部损伤史的 26.0%

表1

图1

参考文献59

[1]	JIANG F, CHENG C, HUANG J, et al. Mild behavioral impairment: An early sign and predictor of Alzheimer's disease dementia[J].Curr Alzheimer Res,2022,19(6):407-419. doi:10.2174/1567205019666220805114528pmid:35929623
[2]	TARAGANO F E, ALLEGRI R F, KRUPITZKI H, et al. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients[J].J Clin Psychiatry,2009 Apr,70(4):584-92.
[3]	汤占斌, 李国忠. 精神行为异常与阿尔茨海默病的关系及干预方法[J].脑与神经疾病杂志,2019,27(5):327-331.
	TANG Z, LI G. The relationship between neuropsychiatric symptoms and Alzheimer's disease and their interventions[J].J Brain Nerv Dis,2019,27(5):327-331.
[4]	MORTBY M E, ISMAIL Z, ANSTEY K J. Prevalence estimates of mild behavioral impairment in a population-based sample of pre-dementia states and cognitively healthy older adults[J].Int Psychogeriatr,2018,30(2):221-232. doi:10.1017/S1041610217001909pmid:28931446
[5]	MALLO S C, ISMAIL Z, PEREIRO A X, et al. Assessing mild behavioral impairment with the mild behavioral impairment-checklist in people with mild cognitive impairment[J].J Alzheimers Dis,2018,66(1):83-95. doi:10.3233/JAD-180131pmid:30175974
[6]	KIANIMEHR G, FATEHI F, NOROOZIAN M. Prevalence of mild behavioral impairment in patients with mild cognitive impairment[J].Acta Neurol Belg,2022,122(6):1493-1497.
[7]	KASSAM F, CHEN H, NOSHENY R L, et al. Cognitive profile of people with mild behavioral impairment in Brain Health Registry participants[J].Int Psychogeriatr,2023,35(11):643-652.
[8]	MATUSKOVA V, VEVEROVA K, JESTER D J, et al. Mild behavioral impairment in early Alzheimer's disease and its association with APOE and BDNF risk genetic polymorphisms[J].Alzheimers Res Ther,2024,16(1):21. doi:10.1186/s13195-024-01386-ypmid:38279143
[9]	TSAI C F, HUANG M H, LIN Y S, et al. Health-related quality of life and mild behavioral impairment in older adults without dementia[J].Int J Geriatr Psychiatry,2023,38(9):e6003.
[10]	CREESE B, BROOKER H, ISMAIL Z, et al. Mild beha-vioral impairment as a marker of cognitive decline in cognitively normal older adults[J].Am J Geriatr Psychiatry,2019,27(8):823-834.
[33]	RAMAKERS I H, VERHEY F R, SCHELTENS P, et al. Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment[J].Psychol Med,2013,43(5):911-920. doi:10.1017/S0033291712001870pmid:22954311
[34]	SUN L, LI W, QIU Q, et al. Anxiety adds the risk of cognitive progression and is associated with axon/synapse degeneration among cognitively unimpaired older adults[J].EBioMedicine,2023,94:104703.
[35]	BABULAL G M, GHOSHAL N, HEAD D, et al. Mood changes in cognitively normal older adults are linked to Alzheimer disease biomarker levels[J].Am J Geriatr Psychiatry,2016,24(11):1095-1104. doi:S1064-7481(16)30082-3pmid:27426238
[36]	BLASKO I, KEMMLER G, JUNGWIRTH S, et al. Plasma amyloid beta-42 independently predicts both late-onset depression and Alzheimer disease[J].Am J Geriatr Psychiatry,2010,18(11):973-982. doi:10.1097/JGP.0b013e3181df48bepmid:20808106
[37]	LUSSIER F Z, PASCOAL T A, CHAMOUN M, et al. Mild behavioral impairment is associated with β-amyloid but not tau or neurodegeneration in cognitively intact elderly individuals[J].Alzheimers Dement,2020,16(1):192-199. doi:10.1002/alz.12007pmid:31914223
[38]	GATCHEL J R, RABIN J S, BUCKLEY R F, et al. Longitudinal association of depression symptoms with cognition and cortical amyloid among community-dwelling older adults[J].JAMA Netw Open,2019,2(8):e198964.
[39]	JOHANSSON M, STOMRUD E, LINDBERG O, et al. Apathy and anxiety are early markers of Alzheimer's di-sease[J].Neurobiol Aging,2020,85:74-82.
[40]	LEWCZUK P, ERMANN N, ANDREASSON U, et al. Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease[J].Alzheimers Res Ther,2018,10(1):71. doi:10.1186/s13195-018-0404-9pmid:30055655
[41]	JOHANSSON M, STOMRUD E, INSEL P S, et al. Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease[J].Transl Psychiatry,2021,11(1):76.
[42]	KNOPMAN D S, LUNDT E S, THERNEAU T M, et al. Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects[J].Brain,2019,142(4):1148-1160. doi:10.1093/brain/awz025pmid:30759182
[43]	JACK C R, WISTE H J, BOTHA H, et al. The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes[J].Brain,2019,142(10):3230-3242. doi:10.1093/brain/awz268pmid:31501889
[11]	PERIN S, HARRINGTON K D, LIM Y Y, et al. Amyloid burden and incident depressive symptoms in preclinical Alzheimer's disease[J].J Affect Disord,2018,229:269-274.
[12]	MATSUOKA T, ISMAIL Z, NARUMOTO J. Prevalence of mild behavioral impairment and risk of dementia in a psychiatric outpatient clinic[J].J Alzheimers Dis,2019,70(2):505-513. doi:10.3233/JAD-190278pmid:31177229
[13]	SHEIKH F, ISMAIL Z, MORTBY M E, et al. Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden[J].Int Psychogeriatr,2018,30(2):233-244. doi:10.1017/S104161021700151Xpmid:28879833
[14]	RAO A R, CHATTERJEE P, THAKRAL M, et al. Beha-vioural issues in late life may be the precursor of dementia- A cross sectional evidence from memory clinic of AIIMS, India[J].PLoS One,2020,15(6):e0234514.
[15]	XU Y, JIANG C, WU J, et al. Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer's disease[J].CNS Neurosci Ther,2022,28(4):580-592.
[16]	肖辛怡, 严玉宁, 魏文石. 记忆门诊就诊者神经精神症状观察及认知水平分析[J].中国社区医师,2021,37(34):52-53.
	XIAO X Y, YAN Y N, WEI W S. Observation of neuropsychiatric symptoms and analysis of cognitive level in memory outpatients[J].Chin Community Physicians,2021,37(34):52-53.
[17]	曾黎, 唐吉, 唐小艳, 等. 贵州省部分农村地区老年人轻度行为损害流行现状及影响因素分析[J].中国预防医学杂志,2023,24(6):580-586.
	ZENG L, TANG J, TANG X Y, et al. Prevalence and influencing factors of mild behavioral impairmentamong older adults in some rural areas of Guizhou Province[J].Chin Prev Med,2023,24(6):580-586.
[18]	LEOW Y J, SOO S A, KUMAR D, et al. Mild behavioral impairment and cerebrovascular profiles are associated with early cognitive impairment in a community-based southeast asian cohort[J].J Alzheimers Dis,2024,97(4):1727-1735. doi:10.3233/JAD-230898pmid:38306040
[19]	CHERKASOV N S, KOLYKHALOV I V. Diagnostic approa-ches to assessing mild behavioral impairment in patients with mild cognitive impairment[J].Zh Nevrol Psikhiatr Im S S Korsakova,2024,124(4. Vyp. 2):49-55.
[44]	LEUZY A, SMITH R, OSSENKOPPELE R, et al. Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders[J].JAMA Neurol,2020,77(8):955-965. doi:10.1001/jamaneurol.2020.0989pmid:32391858
[45]	BLONIECKI V, ZETTERBERG H, AARSLAND D, et al. Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?[J].Alzheimers Res Ther,2020,12(1):153. doi:10.1186/s13195-020-00718-ypmid:33203439
[46]	MATTSSON N, CULLEN N C, ANDREASSON U, et al. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease[J].JAMA Neurol,2019,76(7):791-799. doi:10.1001/jamaneurol.2019.0765pmid:31009028
[47]	CHAUDHRY A, ANTHANASIOU-FRAGKOULI A, HOULDEN H. DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder[J].J Neurol,2021,268(8):3031-3041.
[48]	ROHRER J D, WOOLLACOTT I O, DICK K M, et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia[J].Neurolo-gy,2016,87(13):1329-1336.
[49]	MEETER L H, DOPPER E G, JISKOOT L C, et al. Neurofilament light chain: a biomarker for genetic frontotemporal dementia[J].Ann Clin Transl Neurol,2016,3(8):623-636.
[50]	NAUDE J P, GILL S, HU S, et al. Plasma neurofilament light: A marker of neurodegeneration in mild behavioral impairment[J].J Alzheimers Dis,2020,76(3):1017-1027. doi:10.3233/JAD-200011pmid:32597801
[51]	CREESE B, ARATHIMOS R, BROOKER H, et al. Genetic risk for Alzheimer's disease, cognition, and mild behavioral impairment in healthy older adults[J].Alzheimers Dement (Amst),2021,13(1):e12164.
[52]	VIJVERBERG E G B, SCHOUWS S, MEESTERS P D, et al. Cognitive deficits in patients with neuropsychiatric symptoms: a comparative study between behavioral variant frontotemporal dementia and primary psychiatric disorders[J].J Clin Psychiatry,2017,78(8):e940-e946.
[53]	温扬, 魏文石. 轻度行为损害的量表评估及与载脂蛋白E基因多态性的关系研究[J].中华老年心脑血管病杂志,2021,23(2):140-143.
	WEN Y, WEI W S. Relationship of mild behavioral impairment checklist-assessed mild behavioral impairment and apoE gene polymorphism[J].Chin J Geriatr Cardiol Heart Brain Vessel Dis,2021,23(2):140-143.
[20]	RICHEY L N, DANESHVARI N O, YOUNG L, et al. Associations of prior head injury with mild behavioral impairment domains[J].J Head Trauma Rehabil,2024,39(2):E48-E58.
[21]	王鹏, 魏泽宜, 王杨, 等. 主观认知下降脑网络改变磁共振成像研究现状与展望[J].中国临床研究,2025,38(4):638-642.
	WANG P, WEI Z Y, WANG Y, et al. The current status and prospects of magnetic resonance imaging research on subjective cognitive decline and changes in brain net-works[J].Chin J Clin Res,2025,38(4):638-642.
[22]	FAN S, LIANG X, YUN T, et al. Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study[J].BMC Geriatr,2020,20(1):510. doi:10.1186/s12877-020-01903-2pmid:33246409
[23]	PAN Y, SHEA Y F, ISMAIL Z, et al. Prevalence of mild behavioural impairment domains: a meta-analysis[J].Psychogeriatrics,2022,22(1):84-98.
[24]	WOLFOVA K, CREESE B, AARSLAND D, et al. Gender/sex differences in the association of mild behavioral impairment with cognitive aging[J].J Alzheimers Dis,2022,88(1):345-355.
[25]	CUI Y, DAI S, MIAO Z, et al. Reliability and validity of the chinese version of the mild behavioral impairment checklist for screening for Alzheimer's disease[J].J Alzheimers Dis,2019,70(3):747-756. doi:10.3233/JAD-190113pmid:31256131
[26]	YOON E J, ISMAIL Z, HANGANU A, et al. Mild beha-vioral impairment is linked to worse cognition and brain atrophy in Parkinson disease[J].Neurology,2019,93(8):e766-e777.
[27]	RUTHIRAKUHAN M, ISMAIL Z, HERRMANN N, et al. Mild behavioral impairment is associated with progression to Alzheimer's disease: A clinicopathological study[J].Alzheimers Dement,2022,18(11):2199-2208. doi:10.1002/alz.12519pmid:35103400
[28]	ISMAIL Z, MCGIRR A, GILL S, et al. Mild behavioral impairment and subjective cognitive decline predict cognitive and functional decline[J].J Alzheimers Dis,2021,80(1):459-469. doi:10.3233/JAD-201184pmid:33554909
[29]	TARAGANO F E, ALLEGRI R F, HEISECKE S L, et al. Risk of conversion to dementia in a mild behavioral impairment group compared to a psychiatric group and to a mild cognitive impairment group[J].J Alzheimers Dis,2018,62(1):227-238. doi:10.3233/JAD-170632pmid:29439333
[30]	GEDA Y E, ROBERTS R O, MIELKE M M, et al. Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study[J].Am J Psychiatry,2014,171(5):572-581.
[31]	GILL S, MOUCHES P, HU S, et al. Using Machine Lear-ning to Predict Dementia from Neuropsychiatric Symptom and Neuroimaging Data[J].J Alzheimers Dis,2020,75(1):277-288.
[32]	RUTHIRAKUHAN M, LANCTÔT K L, DI SCIPIO M, et al. Biomarkers of agitation and aggression in Alzheimer's disease: A systematic review[J].Alzheimers Dement,2018,14(10):1344-1376. doi:S1552-5260(18)30157-2pmid:29940162
[54]	MATUSKOVA V, ISMAIL Z, NIKOLAI T, et al. Mild behavioral impairment is associated with atrophy of entorhinal cortex and hippocampus in a memory clinic cohort[J].Front Aging Neurosci,2021,13:643271.
[55]	GILL S, WANG M, MOUCHES P, et al. Neural correlates of the impulse dyscontrol domain of mild behavioral impairment[J].Int J Geriatr Psychiatry,2021,36(9):1398-1406.
[56]	CAJANUS A, SOLJE E, KOIKKALAINEN J, et al. The association between distinct frontal brain volumes and behavioral symptoms in mild cognitive impairment, Alzheimer's disease, and frontotemporal dementia[J].Front Neurol,2019,10:1059. doi:10.3389/fneur.2019.01059pmid:31632342
[57]	MATSUOKA T, UENO D, ISMAIL Z, et al. Neural correlates of mild behavioral impairment: a functional brain connectivity study using resting-state functional magnetic resonance imaging[J].J Alzheimers Dis,2021,83(3):1221-1231.
[58]	EWERS M, SPERLING R A, KLUNK W E, et al. Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia[J].Trends Neurosci,2011,34(8):430-442. doi:10.1016/j.tins.2011.05.005pmid:21696834
[59]	MAK E, GABEL S, MIRETTE H, et al. Structural neuroi-maging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes[J].Ageing Res Rev,2017,35:250-264.