Mild Behavioral Impairment: An Early Sign and Predictor of Alzheimer's
Disease Dementia

Fei      Jiang; Cheng      Cheng; Jinsong      Huang; Qiaoling      Chen; Weidong      Le
Abstract

Background: Alzheimer's disease (AD) is the most common form of dementia in the elderly population and places heavy burdens on medical care and nursing. Recently, the psychiatric and behavioral symptoms of prodromal AD, especially mild behavioral impairment (MBI), have attracted much attention. In 2012, Alzheimer's Association International Conference, MBI was proposed as a syndrome with psychiatric and behavioral disturbance before the onset of typical clinical cognitive symptoms in dementia. Increasing lines of evidence have indicated the link between MBI and early AD pathologies including Aβ and tau.
Objective: This narrative review aims to summarize the advantages of MBI over other concept of psychiatric and behavioral symptoms associated with AD in the early prediction of AD dementia. We also discuss the possible common genetic basis and pathological mechanisms underlying the interactions between MBI and AD.
Methods: Papers cited here were retrieved from PubMed up to February 2022. We selected a total of 95 articles for summary and discussion.
Results: The occurrence of MBI is mainly due to the overlapped genetic and pathological risk factors with AD and is related to the brain's response to environmental stressors. MBI may be a warning sign for the early pathology of AD, and more attention should be paid on the number and duration of MBI symptoms.
Conclusion: MBI may be an early sign and predictor of Alzheimer's disease dementia. Early intervention for MBI may have a positive effect on alleviating long-term cognitive decline.
Keywords: Mild behavioral impairment, Alzheimer's disease, psychosis, early cognitive deficit, early predictor, early intervention, biological mechanisms.
[1]
Jmi G, Robbana L, Ghali F, et al. The burden of caregivers of patients with alzheimer. Eur Psychiatry  2020; 41(S1): S654-54.
 [http://dx.doi.org/10.1016/j.eurpsy.2017.01.1097]

[2]
Linden DEJ. Genetic risk for Alzheimer disease affects the brain throughout the lifespan. Neurol Genet  2020; 6(5): e516.
 [http://dx.doi.org/10.1212/NXG.0000000000000516] [PMID: 33134514]

[3]
Török N, Tanaka M, Vécsei L. Searching for peripheral biomarkers in neurodegenerative diseases: The tryptophan-kynurenine metabolic pathway. Int J Mol Sci  2020; 21(24): E9338.
 [http://dx.doi.org/10.3390/ijms21249338] [PMID: 33302404]

[4]
Battaglia S, Garofalo S, di Pellegrino G. Context-dependent extinction of threat memories: Influences of healthy aging. Sci Rep  2018; 8(1): 12592.
 [http://dx.doi.org/10.1038/s41598-018-31000-9] [PMID: 30135561]

[5]
Eikelboom WS, van Rooij JGJ, van den Berg E, et al. Neuropsychiatric symptoms complicating the diagnosis of alzheimer’s disease: A case report. J Alzheimers Dis  2018; 66(4): 1363-9.
 [http://dx.doi.org/10.3233/JAD-180700] [PMID: 30412494]

[6]
Cieslak A, Smith EE, Lysack J, Ismail Z. Case series of mild behavioral impairment: Toward an understanding of the early stages of neurodegenerative diseases affecting behavior and cognition. Int Psychogeriatr  2018; 30(2): 273-80.
 [http://dx.doi.org/10.1017/S1041610217001855] [PMID: 29017626]

[7]
Zhu L, Sun L, Sun L, Xiao S. Case of early-onset Alzheimer’s disease with atypical manifestation. Gen Psychiatr  2021; 34(1): e100283.
 [http://dx.doi.org/10.1136/gpsych-2020-100283] [PMID: 33585790]

[8]
Suárez GA, Henley SM, Walton J, Crutch SJ. Posterior cortical atrophy: An atypical variant of Alzheimer disease. Psychiatr Clin North Am  2015; 38(2): 211-20.
 [http://dx.doi.org/10.1016/j.psc.2015.01.009] [PMID: 25998111]

[9]
Petersen RC, Wiste HJ, Weigand SD, et al. NIA-AA alzheimer’s disease framework: Clinical characterization of stages. Ann Neurol  2021; 89(6): 1145-56.
 [http://dx.doi.org/10.1002/ana.26071] [PMID: 33772866]

[10]
Battaglia S, Fabius JH, Moravkova K, Fracasso A, Borgomaneri S. The neurobiological correlates of gaze perception in healthy individuals and neurologic patients. Biomedicines  2022; 10(3): 627.
 [http://dx.doi.org/10.3390/biomedicines10030627] [PMID: 35327431]

[11]
Taragano FE, Allegri RF, Krupitzki H, et al. Mild behavioral impairment and risk of dementia: A prospective cohort study of 358 patients. J Clin Psychiatry  2009; 70(4): 584-92.
 [http://dx.doi.org/10.4088/JCP.08m04181] [PMID: 19323967]

[12]
Carla SD. Mild Behavioral Impairment. Tijdschrift voor VerpleeghuisGeneeskunde  2006; 31(4): 152-6.
 [http://dx.doi.org/10.1007/BF03075177]

[13]
Taragano FE, Allegri RF, Lyketsos C. Mild behavioral impairment: A prodromal stage of dementia. Dement Neuropsychol  2008; 2(4): 256-60.
 [http://dx.doi.org/10.1590/S1980-57642009DN20400004] [PMID: 29213581]

[14]
Creese B, Brooker H, Ismail Z, et al. Mild behavioral impairment as a marker of cognitive decline in cognitively normal older adults. Am J Geriatr Psychiatry  2019; 27(8): 823-34.
 [http://dx.doi.org/10.1016/j.jagp.2019.01.215] [PMID: 30902566]

[15]
Sannemann L, Schild AK, Altenstein S, et al. Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study. Alzheimers Res Ther  2020; 12(1): 131.
 [http://dx.doi.org/10.1186/s13195-020-00701-7] [PMID: 33066827]

[16]
Johansson M, Stomrud E, Insel PS, et al. Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer’s disease. Transl Psychiatry  2021; 11(1): 76.
 [http://dx.doi.org/10.1038/s41398-021-01206-z] [PMID: 33500386]

[17]
Ismail Z, Agüera OL, Brodaty H, et al. The mild behavioral impairment checklist (MBI-C): A rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimers Dis  2017; 56(3): 929-38.
 [http://dx.doi.org/10.3233/JAD-160979] [PMID: 28059789]

[18]
Kassam F, Chen HY, Nosheny RL, et al. Cognitive profile of mild behavioral impairment (MBI) in brain health registry participants. Alzheimers Dement  2020; 16(S6)
 [http://dx.doi.org/10.1002/alz.047673]

[19]
Soo SA, Ng KP, Wong F, et al. Mild behaviour impairment checklist (MBI‐C): Is there a difference in ratings between patient and close informant? Alzheimers Dement  2020; 16(S6)
 [http://dx.doi.org/10.1002/alz.039239]

[20]
DeMichele-Sweet MAA, Klei L, Creese B, et al. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry  2021; 26(10): 5797-811.
 [http://dx.doi.org/10.1038/s41380-021-01152-8] [PMID: 34112972]

[21]
Scassellati C, Ciani M, Maj C, et al. Behavioral and Psychological Symptoms of Dementia (BPSD): Clinical characterization and genetic correlates in an Italian Alzheimer’s disease cohort. J Pers Med  2020; 10(3): E90.
 [http://dx.doi.org/10.3390/jpm10030090] [PMID: 32823921]

[22]
Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet  2009; 41(10): 1088-93.
 [http://dx.doi.org/10.1038/ng.440] [PMID: 19734902]

[23]
Porcelli S, Calabrò M, Crisafulli C, et al. Alzheimer’s disease and neurotransmission gene variants: Focus on their effects on psychiatric comorbidities and inflammatory parameters. Neuropsychobiology  2019; 78(2): 79-85.
 [http://dx.doi.org/10.1159/000497164] [PMID: 31096213]

[24]
Andrews SJ, Ismail Z, Anstey KJ, Mortby M. Association of Alzheimer’s genetic loci with mild behavioral impairment. Am J Med Genet B Neuropsychiatr Genet  2018; 177(8): 727-35.
 [http://dx.doi.org/10.1002/ajmg.b.32684] [PMID: 30378268]

[25]
Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet  2011; 43(5): 436-41.
 [http://dx.doi.org/10.1038/ng.801] [PMID: 21460841]

[26]
Bensamoun D, Guignard R, Furst AJ, et al. Associations between neuropsychiatric symptoms and cerebral amyloid deposition in cognitively impaired elderly people. J Alzheimers Dis  2016; 49(2): 387-98.
 [http://dx.doi.org/10.3233/JAD-150181] [PMID: 26484900]

[27]
Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry  2014; 85(4): 449-55.
 [http://dx.doi.org/10.1136/jnnp-2013-306110] [PMID: 24133289]

[28]
Krell RJ, Lowe VJ, Neureiter J, et al. Depressive and anxiety symptoms and cortical amyloid deposition among cognitively normal elderly persons: The mayo clinic study of aging. Int Psychogeriatr  2018; 30(2): 245-51.
 [http://dx.doi.org/10.1017/S1041610217002368] [PMID: 29198244]

[29]
Babulal GM, Stout SH, Head D, et al. Neuropsychiatric symptoms and alzheimer’s disease biomarkers predict driving decline: Brief report. J Alzheimers Dis  2017; 58(3): 675-80.
 [http://dx.doi.org/10.3233/JAD-170067] [PMID: 28453487]

[30]
Bloniecki V, Aarsland D, Cummings J, Blennow K, Freund LY. Agitation in dementia: Relation to core cerebrospinal fluid biomarker levels. Dement Geriatr Cogn Disord Extra  2014; 4(2): 335-43.
 [http://dx.doi.org/10.1159/000363500] [PMID: 25298777]

[31]
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol  2015; 14(4): 388-405.
 [http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]

[32]
Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature  2019; 575(7784): 669-73.
 [http://dx.doi.org/10.1038/s41586-019-1769-z] [PMID: 31748742]

[33]
Maphis N, Xu G, Kokiko CON, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain  2015; 138(Pt 6): 1738-55.
 [http://dx.doi.org/10.1093/brain/awv081] [PMID: 25833819]

[34]
Porcelli S, Crisafulli C, Donato L, et al. Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in Alzheimer’s disease. J Neurol Sci  2016; 370: 162-6.
 [http://dx.doi.org/10.1016/j.jns.2016.09.053] [PMID: 27772752]

[35]
Cuello AC. Early and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum? Trends Pharmacol Sci  2017; 38(11): 956-66.
 [http://dx.doi.org/10.1016/j.tips.2017.07.005] [PMID: 28867259]

[36]
Pascoal TA, Benedet AL, Ashton NJ, et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med  2021; 27(9): 1592-9.
 [http://dx.doi.org/10.1038/s41591-021-01456-w] [PMID: 34446931]

[37]
Parbo P, Ismail R, Sommerauer M, et al. Does inflammation precede tau aggregation in early Alzheimer’s disease? A PET study. Neurobiol Dis  2018; 117: 211-6.
 [http://dx.doi.org/10.1016/j.nbd.2018.06.004] [PMID: 29902557]

[38]
Müller N. Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. Schizophr Bull  2018; 44(5): 973-82.
 [http://dx.doi.org/10.1093/schbul/sby024] [PMID: 29648618]

[39]
Severance EG, Dickerson F, Yolken RH. Complex gastrointestinal and Endocrine Sources of Inflammation in Schizophrenia. Front Psychiatry  2020; 11: 549.
 [http://dx.doi.org/10.3389/fpsyt.2020.00549] [PMID: 32625121]

[40]
Upthegrove R, Khandaker GM. Cytokines, oxidative stress and cellular markers of inflammation in schizophrenia. Curr Top Behav Neurosci  2020; 44: 49-66.
 [http://dx.doi.org/10.1007/7854_2018_88] [PMID: 31115797]

[41]
Sharma A. Systems genomics support for immune and inflammation hypothesis of depression. Curr Neuropharmacol  2016; 14(7): 749-58.
 [http://dx.doi.org/10.2174/1570159X14666160106155331] [PMID: 26733279]

[42]
Yao H, Mizoguchi Y, Monji A, et al. Low-grade inflammation is associated with apathy indirectly via deep white matter lesions in community-dwelling older adults: The sefuri study. Int J Mol Sci  2019; 20(8): E1905.
 [http://dx.doi.org/10.3390/ijms20081905] [PMID: 30999680]

[43]
Masters MC, Morris JC, Roe CM. “Noncognitive” symptoms of early Alzheimer disease: A longitudinal analysis. Neurology  2015; 84(6): 617-22.
 [http://dx.doi.org/10.1212/WNL.0000000000001238] [PMID: 25589671]

[44]
Ledo JH, Azevedo EP, Beckman D, et al. Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by alzheimer’s amyloid-β oligomers in mice. J Neurosci  2016; 36(48): 12106-16.
 [http://dx.doi.org/10.1523/JNEUROSCI.1269-16.2016] [PMID: 27903721]

[45]
Lasselin J, Elsenbruch S, Lekander M, et al. Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior. Brain Behav Immun  2016; 57: 30-7.
 [http://dx.doi.org/10.1016/j.bbi.2016.01.003] [PMID: 26790758]

[46]
Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology  2011; 77(3): 212-8.
 [http://dx.doi.org/10.1212/WNL.0b013e318225ae07] [PMID: 21753171]

[47]
Chen Y, Dang M, Zhang Z. Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: A systematic review of symptom-general and-specific lesion patterns. Mol Neurodegener  2021; 16(1): 38.
 [http://dx.doi.org/10.1186/s13024-021-00456-1] [PMID: 34099005]

[48]
Albaret G, Sifré E, Floch P, et al. Alzheimer’s disease and helicobacter pylori infection: Inflammation from stomach to brain? J Alzheimers Dis  2020; 73(2): 801-9.
 [http://dx.doi.org/10.3233/JAD-190496] [PMID: 31868664]

[49]
Lin C, Zhao S, Zhu Y, et al. Microbiota-gut-brain axis and toll-like receptors in Alzheimer’s disease. Comput Struct Biotechnol J  2019; 17: 1309-17.
 [http://dx.doi.org/10.1016/j.csbj.2019.09.008] [PMID: 31921396]

[50]
Holzer P, Farzi A, Hassan AM, Zenz G, Jačan A, Reichmann F. Visceral inflammation and immune activation stress the brain. Front Immunol  2017; 8: 1613.
 [http://dx.doi.org/10.3389/fimmu.2017.01613] [PMID: 29213271]

[51]
Dinan TG, Cryan JF, Stanton C. Gut microbes and brain development have black box connectivity. Biol Psychiatry  2018; 83(2): 97-9.
 [http://dx.doi.org/10.1016/j.biopsych.2017.11.005] [PMID: 29223221]

[52]
Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav  2014; 13(1): 69-86.
 [http://dx.doi.org/10.1111/gbb.12109] [PMID: 24286462]

[53]
Kennedy KM, Gerlach MJ, Adam T, et al. Fetal meconium does not have a detectable microbiota before birth. Nat Microbiol  2021; 6(7): 865-73.
 [http://dx.doi.org/10.1038/s41564-021-00904-0] [PMID: 33972766]

[54]
Ting SK, Hao Y, Chia PS, Tan EK, Hameed S. Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer’s disease. Sci Rep  2016; 6(1): 20858.
 [http://dx.doi.org/10.1038/srep20858] [PMID: 26868671]

[55]
Fischer CE, Qian W, Schweizer TA, et al. Lewy bodies, vascular risk factors, and subcortical arteriosclerotic leukoencephalopathy, but not alzheimer pathology, are associated with development of psychosis in alzheimer’s disease. J Alzheimers Dis  2016; 50(1): 283-95.
 [http://dx.doi.org/10.3233/JAD-150606] [PMID: 26682680]

[56]
Steinberg M, Hess K, Corcoran C, et al. Vascular risk factors and neuropsychiatric symptoms in Alzheimer’s disease: The Cache County Study. Int J Geriatr Psychiatry  2014; 29(2): 153-9.
 [http://dx.doi.org/10.1002/gps.3980] [PMID: 23681754]

[57]
Kim J, Schweizer TA, Fischer CE, Munoz DG. The role of cerebrovascular disease on cognitive and functional status and psychosis in severe alzheimer’s disease. J Alzheimers Dis  2017; 55(1): 381-9.
 [http://dx.doi.org/10.3233/JAD-160506] [PMID: 27662301]

[58]
Yatawara C, Hiu S, Tan L, Kandiah N. Neuropsychiatric symptoms in South-East Asian patients with mild cognitive impairment and dementia: Prevalence, subtypes, and risk factors. Int J Geriatr Psychiatry  2018; 33(1): 122-30.
 [http://dx.doi.org/10.1002/gps.4693] [PMID: 28239920]

[59]
Shu J, Qiang Q, Yan Y, et al. Distinct patterns of brain atrophy associated with mild behavioral impairment in cognitively normal elderly adults. Int J Med Sci  2021; 18(13): 2950-6.
 [http://dx.doi.org/10.7150/ijms.60810] [PMID: 34220322]

[60]
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. Front Aging Neurosci  2021; 13: 643271.
 [http://dx.doi.org/10.3389/fnagi.2021.643271] [PMID: 34108874]

[61]
Misquitta K, Dadar M, Louis Collins D, Tartaglia MC. White matter hyperintensities and neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s disease. Neuroimage Clin  2020; 28: 102367.
 [http://dx.doi.org/10.1016/j.nicl.2020.102367] [PMID: 32798911]

[62]
Li X, Xiong Z, Liu Y, et al. Case report of first-episode psychotic symptoms in a patient with early-onset Alzheimer’s disease. BMC Psychiatry  2020; 20(1): 128.
 [http://dx.doi.org/10.1186/s12888-020-02537-9] [PMID: 32183776]

[63]
Gill S, Wang M, Mouches P, et al. Neural correlates of the impulse dyscontrol domain of mild behavioral impairment. Int J Geriatr Psychiatry  2021; 36(9): 1398-406.
 [http://dx.doi.org/10.1002/gps.5540] [PMID: 33778998]

[64]
Cotta Ramusino M, Perini G, Vaghi G, et al. Correlation of frontal atrophy and csf tau levels with neuropsychiatric symptoms in patients with cognitive impairment: A memory clinic experience. Front Aging Neurosci  2021; 13: 595758.
 [http://dx.doi.org/10.3389/fnagi.2021.595758] [PMID: 33746732]

[65]
Förstl H, Burns A, Levy R, Cairns N, Luthert P, Lantos P. Neuropathological correlates of behavioural disturbance in confirmed Alzheimer’s disease. Br J Psychiatry  1993; 163(3): 364-8.
 [http://dx.doi.org/10.1192/bjp.163.3.364] [PMID: 8401967]

[66]
Taragano FE, Allegri RF, Heisecke SL, 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 Alzheimers Dis  2018; 62(1): 227-38.
 [http://dx.doi.org/10.3233/JAD-170632] [PMID: 29439333]

[67]
Dietlin S, Soto M, Kiyasova V, et al. Neuropsychiatric symptoms and risk of progression to Alzheimer’s disease among mild cognitive impairment subjects. J Alzheimers Dis  2019; 70(1): 25-34.
 [http://dx.doi.org/10.3233/JAD-190025] [PMID: 31127783]

[68]
Mallo SC, Pereiro AX, Campos‐Magdaleno M, et al. Neuropsy-chiatric symptoms in subjective cognitive complaints (SCC) and mild cognitive impairment (MCI): Detecting changes over time with the Mild Behavioral Impairment Checklist (MBI‐C). Alzheimers Dement  2020; 16(S6)
 [http://dx.doi.org/10.1002/alz.041963]

[69]
Ahn S, Mathiason MA, Yu F. Longitudinal cognitive profiles by anxiety and depressive symptoms in american older adults with subjective cognitive decline. J Nurs Scholarsh  2021; 53(6): 698-708.
 [http://dx.doi.org/10.1111/jnu.12692] [PMID: 34342395]

[70]
Perri R, Turchetta CS, Caruso G, Fadda L, Caltagirone C, Carlesimo GA. Neuropsychological correlates of cognitive, emotional-affective and auto-activation apathy in Alzheimer's disease. Neuropsychologia  2018; 118(B): 12-21.
 [http://dx.doi.org/10.1016/j.neuropsychologia.2018.01.039]

[71]
Shao Y, Xu H, Wang J, et al. Agitation and apathy increase risk of dementia in psychiatric inpatients with late-onset psychiatric symptoms. BMC Psychiatry  2021; 21(1): 214.
 [http://dx.doi.org/10.1186/s12888-021-03210-5] [PMID: 33910556]

[72]
Geda YE, Roberts RO, Mielke MM, et al. Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: A population-based study. Am J Psychiatry  2014; 171(5): 572-81.
 [http://dx.doi.org/10.1176/appi.ajp.2014.13060821] [PMID: 24700290]

[73]
Acosta I, Borges G, Aguirre-Hernandez R, Sosa AL, Prince M. Neuropsychiatric symptoms as risk factors of dementia in a Mexican population: A 10/66 Dementia Research Group study. Alzheimers Dement  2018; 14(3): 271-9.
 [http://dx.doi.org/10.1016/j.jalz.2017.08.015] [PMID: 29028481]

[74]
Edwards ER, Spira AP, Barnes DE, Yaffe K. Neuropsychiatric symptoms in mild cognitive impairment: Differences by subtype and progression to dementia. Int J Geriatr Psychiatry  2009; 24(7): 716-22.
 [http://dx.doi.org/10.1002/gps.2187] [PMID: 19140134]

[75]
Canevelli M, Blasimme A, Vanacore N, Bruno G, Cesari M. Mild behavioral impairment: Ethical, methodological and clinical reflections. Neurosci Biobehav Rev  2016; 69: 402-3.
 [http://dx.doi.org/10.1016/j.neubiorev.2016.08.025] [PMID: 27570153]

[76]
Reisberg B, Shao Y, Moosavi M, et al. Psychometric cognitive decline precedes the advent of subjective cognitive decline in the evolution of alzheimer’s disease. Dement Geriatr Cogn Disord  2020; 49(1): 16-21.
 [http://dx.doi.org/10.1159/000507286] [PMID: 32388509]

[77]
Wolfsgruber S, Kleineidam L, Guski J, et al. Minor neuropsychological deficits in patients with subjective cognitive decline. Neurology  2020; 95(9): e1134-43.
 [http://dx.doi.org/10.1212/WNL.0000000000010142] [PMID: 32636322]

[78]
Pan Y, Shea YF, Li S, et al. Prevalence of mild behavioural impairment: A systematic review and meta-analysis. Psychogeriatrics  2021; 21(1): 100-11.
 [http://dx.doi.org/10.1111/psyg.12636] [PMID: 33260271]

[79]
Sheikh F, Ismail Z, Mortby ME, et al. Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden. Int Psychogeriatr  2018; 30(2): 233-44.
 [http://dx.doi.org/10.1017/S104161021700151X] [PMID: 28879833]

[80]
Ismail Z, McGirr A, Gill S, Hu S, Forkert ND, Smith EE. Mild behavioral impairment and subjective cognitive decline predict cognitive and functional decline. J Alzheimers Dis  2021; 80(1): 459-69.
 [http://dx.doi.org/10.3233/JAD-201184] [PMID: 33554909]

[81]
Tascone LDS, Bottino CMC. Neurobiology of neuropsychiatric symptoms in Alzheimer’s disease: A critical review with a focus on neuroimaging. Dement Neuropsychol  2013; 7(3): 236-43.
 [http://dx.doi.org/10.1590/S1980-57642013DN70300002] [PMID: 29213845]

[82]
Cicognola C, Hansson O, Scheltens P, et al. Cerebrospinal fluid N-224 tau helps discriminate Alzheimer’s disease from subjective cognitive decline and other dementias. Alzheimers Res Ther  2021; 13(1): 38.
 [http://dx.doi.org/10.1186/s13195-020-00756-6] [PMID: 33557920]

[83]
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov  2011; 10(9): 698-712.
 [http://dx.doi.org/10.1038/nrd3505] [PMID: 21852788]

[84]
Naude JP, Gill S, Hu S, et al. Plasma neurofilament light: A marker of neurodegeneration in mild behavioral impairment. J Alzheimers Dis  2020; 76(3): 1017-27.
 [http://dx.doi.org/10.3233/JAD-200011] [PMID: 32597801]

[85]
Mallo SC, Valladares RS, Facal D, Lojo SC, Fernández IMJ, Pereiro AX. Neuropsychiatric symptoms as predictors of conversion from MCI to dementia: A machine learning approach. Int Psychogeriatr  2020; 32(3): 381-92.
 [http://dx.doi.org/10.1017/S1041610219001030] [PMID: 31455461]

[86]
Choy G, Khalilzadeh O, Michalski M, et al. Current applications and future impact of machine learning in radiology. Radiology  2018; 288(2): 318-28.
 [http://dx.doi.org/10.1148/radiol.2018171820] [PMID: 29944078]

[87]
Giger ML. Machine learning in medical imaging J Am Coll Radiol  2018; 15(3)(Pt B): 512-20.
 [http://dx.doi.org/10.1016/j.jacr.2017.12.028] [PMID: 29398494]

[88]
LeCun Y, Bengio Y, Hinton G. Deep learning. Nature  2015; 521(7553): 436-44.
 [http://dx.doi.org/10.1038/nature14539] [PMID: 26017442]

[89]
Fisher CK, Smith AM, Walsh JR, Coalition Against Major D. Machine learning for comprehensive forecasting of Alzheimer’s Disease progression. Sci Rep  2019; 9(1): 13622.
 [http://dx.doi.org/10.1038/s41598-019-49656-2] [PMID: 31541187]

[90]
Li Z, Jiang X, Wang Y, Kim Y. Applied machine learning in Alzheimer’s disease research: Omics, imaging, and clinical data. Emerg Top Life Sci  2021; 5(6): 765-77.
 [http://dx.doi.org/10.1042/ETLS20210249] [PMID: 34881778]

[91]
Lu D, Popuri K, Ding GW, Balachandar R, Beg MF. Multimodal and multiscale deep neural networks for the early diagnosis of alzheimer’s disease using structural MR and FDG-PET images. Sci Rep  2018; 8(1): 5697.
 [http://dx.doi.org/10.1038/s41598-018-22871-z] [PMID: 29632364]

[92]
Westman E, Muehlboeck JS, Simmons A. Combining MRI and CSF measures for classification of Alzheimer’s disease and prediction of mild cognitive impairment conversion. Neuroimage  2012; 62(1): 229-38.
 [http://dx.doi.org/10.1016/j.neuroimage.2012.04.056] [PMID: 22580170]

[93]
Spasov S, Passamonti L, Duggento A, Liò P, Toschi N. A parameter-efficient deep learning approach to predict conversion from mild cognitive impairment to Alzheimer’s disease. Neuroimage  2019; 189: 276-87.
 [http://dx.doi.org/10.1016/j.neuroimage.2019.01.031] [PMID: 30654174]

[94]
Gill S, Mouches P, Wang M, et al. P4-266: Using machine learning to identify neuroimaging and clinical features of Mild Behavioral Impairment (Mbi). Alzheimers Dement  2019; 15: 1383-P83.
 [http://dx.doi.org/10.1016/j.jalz.2019.06.3935]

[95]
Gill S, Mouches P, Hu S, et al. Using machine learning to predict dementia from neuropsychiatric symptom and neuroimaging data. J Alzheimers Dis  2020; 75(1): 277-88.
 [http://dx.doi.org/10.3233/JAD-191169] [PMID: 32250302]

[96]
Kasper S. Targeting cognitive and neuropsychiatric symptoms in early dementia. Eur Neuropsychopharmacol  2012; 22(1): S443.
 [http://dx.doi.org/10.1016/S0924-977X(12)70697-1]

[97]
Dyck CH, Arnsten AFT, Padala PR, et al. Neurobiologic rationale for treatment of apathy in alzheimer’s disease with methylphenidate. Am J Geriatr Psychiatry  2021; 29(1): 51-62.
 [http://dx.doi.org/10.1016/j.jagp.2020.04.026] [PMID: 32461027]

[98]
Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry  2012; 20(2): 104-22.
 [http://dx.doi.org/10.1097/JGP.0b013e31822001a6] [PMID: 21841459]

[99]
Theleritis C, Siarkos K, Katirtzoglou E, Politis A. Pharmacological and nonpharmacological treatment for apathy in alzheimer disease: A systematic review across modalities. J Geriatr Psychiatry Neurol  2017; 30(1): 26-49.
 [http://dx.doi.org/10.1177/0891988716678684] [PMID: 28248559]

[100]
Mortby ME, Adler L, Aguera OL, Bateman DR, Brodaty H, Cantillon M, et al. Apathy as a treatment target in Alzheimer’s disease: Implications for clinical trials. Am J Geriatr Psychiatry  2021; 30(2): 119-47.
 [http://dx.doi.org/10.1016/j.jagp.2021.06.016] [PMID: 34315645]

[101]
Negrón AE, Reichman WE. Risperidone in the treatment of patients with Alzheimer’s disease with negative symptoms. Int Psychogeriatr  2000; 12(4): 527-36.
 [http://dx.doi.org/10.1017/S1041610200006633] [PMID: 11263718]

[102]
Dollfus S, Olivier V, Chabot B, Déal C, Perrin E. Olanzapine versus risperidone in the treatment of post-psychotic depression in schizophrenic patients. Schizophr Res  2005; 78(2-3): 157-9.
 [http://dx.doi.org/10.1016/j.schres.2005.06.001] [PMID: 16102942]

[103]
Onor ML, Saina M, Trevisiol M, Cristante T, Aguglia E. Clinical experience with risperidone in the treatment of behavioral and psychological symptoms of dementia. Prog Neuropsychopharmacol Biol Psychiatry  2007; 31(1): 205-9.
 [http://dx.doi.org/10.1016/j.pnpbp.2006.09.001] [PMID: 17020789]

[104]
Chan YE, Chen MH, Tsai SJ, et al. Treatment-Resistant depression enhances risks of dementia and alzheimer’s disease: A nationwide longitudinal study. J Affect Disord  2020; 274: 806-12.
 [http://dx.doi.org/10.1016/j.jad.2020.05.150] [PMID: 32664018]

[105]
Cumbo E, Cumbo S, Torregrossa S, Migliore D. Treatment effects of vortioxetine on cognitive functions in mild Alzheimer’s disease patients with depressive symptoms: A 12 month, open-label, observational study. J Prev Alzheimers Dis  2019; 6(3): 192-7.
 [http://dx.doi.org/10.14283/jpad.2019.24] [PMID: 31062834]

[106]
Cirrito JR, Wallace CE, Yan P, et al. Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model. Neurology  2020; 95(19): e2666-74.
 [http://dx.doi.org/10.1212/WNL.0000000000010733] [PMID: 32913022]

[107]
Cirrito JR, Disabato BM, Restivo JL, et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci USA  2011; 108(36): 14968-73.
 [http://dx.doi.org/10.1073/pnas.1107411108] [PMID: 21873225]

[108]
Ilieva K, Atanasova M, Atanasova D, Kortenska L, Tchekalarova J. Chronic agomelatine treatment alleviates icvAβ-induced anxiety and depressive-like behavior through affecting Aβ metabolism in the hippocampus in a rat model of Alzheimer’s disease. Physiol Behav  2021; 239: 113525.
 [http://dx.doi.org/10.1016/j.physbeh.2021.113525] [PMID: 34242671]

[109]
Qiao J, Wang J, Wang H, et al. Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model. Glia  2016; 64(2): 240-54.
 [http://dx.doi.org/10.1002/glia.22926] [PMID: 26446044]

[110]
Wang J, Zhang Y, Xu H, et al. Fluoxetine improves behavioral performance by suppressing the production of soluble β-amyloid in APP/PS1 mice. Curr Alzheimer Res  2014; 11(7): 672-80.
 [http://dx.doi.org/10.2174/1567205011666140812114715] [PMID: 25115542]

[111]
Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature  2004; 430(7000): 631-9.
 [http://dx.doi.org/10.1038/nature02621] [PMID: 15295589]

[112]
Chen J, Zhang F, Zhao L, et al. Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer’s disease and amnestic mild cognitive impairment. Alzheimers Dement (N Y)  2020; 6(1): e12030.
 [http://dx.doi.org/10.1002/trc2.12030] [PMID: 32548235]

[113]
Padala PR, Padala KP, Lensing SY, et al. Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res  2018; 261: 312-8.
 [http://dx.doi.org/10.1016/j.psychres.2017.12.063] [PMID: 29331848]

[114]
Li S, Wu Z, Le W. Traditional Chinese medicine for dementia. Alzheimers Dement  2021; 17(6): 1066-71.
 [http://dx.doi.org/10.1002/alz.12258] [PMID: 33682261]

[115]
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. Front Neurol  2019; 10: 1059.
 [http://dx.doi.org/10.3389/fneur.2019.01059] [PMID: 31632342]

[116]
Battaglia S, Harrison BJ, Fullana MA. Does the human ventromedial prefrontal cortex support fear learning, fear extinction or both? A commentary on subregional contributions. Mol Psychiatry  2022; 27(2): 784-6.
 [http://dx.doi.org/10.1038/s41380-021-01326-4] [PMID: 34667263]

[117]
Battaglia S. Neurobiological advances of learned fear in humans. Adv Clin Exp Med  2022; 31(3): 217.
 [http://dx.doi.org/10.17219/acem/146756]
Cite As
Current Alzheimer Research

Mild Behavioral Impairment: An Early Sign and Predictor of Alzheimer's Disease Dementia

Abstract
