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Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria
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BACKGROUND: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. METHODS: Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: "mild cognitive impairment," "dementia," "prodromal dementia," "preclinical dementia," "Alzheimer's," "depression," "dysphoria," "mania," "euphoria," "bipolar disorder," and "irritability." RESULTS: Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. CONCLUSION: Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies.
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“Cognitive decline encompasses mental health conditions like anxiety [45,46].”
From The Effect of Anxiety and Nutritional Habits on the Body Distortion of Athletes. (2025) · cites this paper as [45]
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“Experiential avoidance seeks to control the way or frequency of aversive private experiences [37] and has been associated with anxiety [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54].”
From The Effect of Anxiety and Nutritional Habits on the Body Distortion of Athletes. (2025) · cites this paper as [45]
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Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults
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“dysregulation (mood and anxiety symptoms) (7); impulse dyscontrol/agitation/abnormal reward salience (changes in response inhibition and self-regulation); social inappropriateness (impaired social cognition) (8); and abnormal thoughts/perception (psychosis) (9), assessed individually and collectively for their”
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“Moreover, studying these individuals may help us identify the causal pathway between anxiety, depression, and other affective symptoms and cognitive impairment [34].”
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“In the ISTAART-AA MBI criteria, symptoms are divided into the following domains: decreased motivation [46, 47], affective dysregulation [48, 49], impulse dyscontrol [4, 50], social inappropriateness [51, 52], and abnormal though or perception [53, 54].”
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“cognitive decline and dementia, biomarker of cognitive decline, or even a potential manifestation of prodromal dementia (Ismail et al., 2018; Taragano et al., 2018; Creese et al., 2019).”
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“Thus, the MBI requirement for later life emergent and sustained NPS may better reflect true NPS that result from neurodegeneration and proteinopathies associated with dementia, removing symptoms that may be a result of non-dementia etiologies [38].”
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“According to previous reviews, depression in early life might be a risk factor for dementia, and late life onset of depression might be a prodromal symptom [4, 27].”
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“Decreasing the likelihood of infections or other medical conditions, change in living situation or relationships, or medication adjustments and side effects contributing to NPS ascertainment likely results in fewer MBI false positives (Ismail et al., 2017a).”
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“Within the MBI diagnostic framework [10], relevant NPS are categorized into five domains, namely: decreased drive and motivation (apathy) [13], emotional dysregulation (mood and anxiety symptoms) [14], impulse dyscontrol (agitation, aggression, impulsivity, abnormal reinforcement, and reward) [15], social inappropriat…”
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“A previously described PET imaging protocol [32] was also completed for determining amyloid burden using the radiotracer [ 18 F]-Florbetapir (AV45).”
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“…in functionally independent community dwelling older adults, in contrast to thoseNPS that aremore specific to dementia (e.g. resisting care, rummaging, and importuning); it has a reference period of 6 months rather than 2 to 4 weeks, as is the case with most other scales (Ismail et al., 2017a).”
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“Thus, further research using the MBI-C is required, as the nature of the queries (i.e., later life onset of sustained symptoms) may be a very salient feature of dementia prognostication and early detection, when interventions may be more effective (Mortby, et al., 2018).”
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“However, the rate of recognition of pre-existing psychiatric symptomatology in the clinic is still low and only a few studies use a scale for NPS as the screening standard, to date [17, 18].”
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“Nonetheless, whether DSM criteria apply or not, depressive symptoms are debilitating and worth assessing and addressing (Ismail et al., 2018).”
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“This is also exemplified by adolescents, alluded to above, as typical changes in irritability across the lifespan often coincide with significant changes in neurobiological development and decline [9, 10].”
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BackgroundADHD and Neurodegenerative Disease Risk: A Critical Examination of the Evidence
Becker, S., Sharma, M. J., & Callahan, B. L. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.826213 · Cited by 25
“This is rather problematic in the context of examining relationships between ADHD and neurodegeneration, because ADHD-like experiences (inattention, distractibility, impulsivity, and emotional dysregulation) can be neuropsychiatric indicators of neurodegenerative disease onset (Ismail et al., 2018; Bateman et al., 202…”
BackgroundZhou, S., Wang, Q., Zhang, J., Wáng, Q., Hou, F., Han, X., Hu, S., Shen, G., & Zhang, Y. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.939150 · Cited by 25
Artificial neural networks-based classification of emotions using wristband heart rate monitor data
Chen, Y.-C., Hsiao, C.-C., Zheng, W.-D., Lee, R.-G., & Lin, R. (2019) · Medicine · doi:10.1097/md.0000000000016863 · Cited by 23
“Emotional changes may also present as prodromal symptoms of various psychiatric disorders [6] and neurodegenerative diseases.([7]) Neurotransmitters such as acetylcholine,([8]) serotonin, noradrenaline, and dopamine, are involved in the behavioral control([9]) of emotions.”
BackgroundEffects of Mindfulness-based Interventions on Dementia Patients: A Meta-analysis
Wang, F. L., Tang, Q. Y., Zhang, L. L., Yang, J., Li, Y., Peng, H., & Wang, S. H. (2020) · Western Journal of Nursing Research · doi:10.1177/0193945920916750 · Cited by 23
“Moreover, recent studies have found that emotional distress is not only a clinical symptom of dementia but may also be an important risk factor for the rapid development of mild cognitive impairment and preclinical Alzheimer’s disease to dementia (Ismail et al., 2018; Li & Li, 2018; Pietrzak et al., 2015).”
BackgroundRao, A. R., Chatterjee, P., Thakral, M., Dwivedi, S. N., & Dey, A. B. (2020) · PLoS ONE · doi:10.1371/journal.pone.0234514 · Cited by 23
“There are numerous mechanisms which try to explain the cognitive decline in individuals with diabetes mellitus, these include insulin dysregulation, pro-inflammatory pathways, vascular risk factors, oxidative stress and lipoprotein receptors[26], which are similar to the causal pathway between NPS and cognitive declin…”
BackgroundAnker, E., Ginsberg, Y., & Heir, T. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03223-0 · Cited by 25
Anxiety disorders, benzodiazepine prescription, and incident dementia
Brieler, J. A., Salas, J., Amick, M., Sheth, P., Garrett, E. K., Morley, J. E., & Scherrer, J. F. (2023) · Journal of the American Geriatrics Society · doi:10.1111/jgs.18515 · Cited by 23
“19 Inconsis-tent findings may be due to variations in how anxiety is measured and the degree of control for confounding factors.”
BackgroundChange in Purpose in Life Before and After Onset of Cognitive Impairment
Sutin, A. R., Luchetti, M., Stéphan, Y., & Terracciano, A. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.33489 · Cited by 22
Sun, Z., Ping, P., Li, Y., Feng, L., Liu, F., Zhao, Y., Yao, Y., Zhang, P., & Fu, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.870442 · Cited by 21
“, 2014), suggesting that with the development of the biological-psychological-social medical model, Qi depression caused by an accumulation of negative emotions has been proven to be closely related to the progression of cognitive decline (Zhou et al., 2006; Ismail et al., 2018; Zhang et al., 2021).”
BackgroundKwon, K. J., Kim, H. Y., Han, S., & Shin, C. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111338 · Cited by 23
“This lack of efficacy may be attributed to the challenges in applying common psychiatric diagnostic criteria and clinical features to a population with neurodegenerative diseases [27].”
BackgroundRavona‐Springer, R., Heymann, A. D., Lin, H., Liu, X., Berman, Y., Schwartz, J., Soleimani, L., Sano, M. C., & Beeri, M. S. (2020) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2020.09.022 · Cited by 20
“This battery covers four cognitive domains: (1) Memory [Alzheimer’s Disease Assessment Scale (ADAS) Word List Immediate Recall, Delayed Recall, and Recognition], (2) Attention/ working memory [Diamond Cancellation, Digit Span forward, and backward], (3) Executive functions [Trails Making Test A and B, Digit Symbol Sub…”
BackgroundMethodLi, F., Kong, X., Zhu, H., Xu, H., Wu, B., Cao, Y., & Li, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1011510 · Cited by 20
“) in this study although they may be associated with cognitive function after stroke (Ismail et al., 2018; Weaver et al., 2021).”
BackgroundTurnbull, A. G., Anthony, M., Tadin, D., Porsteinsson, A. P., Heffner, K. L., & Lin, F. V. (2022) · Cortex · doi:10.1016/j.cortex.2022.10.015 · Cited by 20
The Dichotomy of Alzheimer’s Disease Pathology: Amyloid-β and Tau
Ashford, J. W. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181198 · Cited by 19
“Accordingly, some A PP related mechanisms which have an early, adverse effect on the function of the frontal lobe could lead to symptoms of mild behavioral impairment, including personality changes, apathy, and depression, which are related to prodromal and mild AD [72, 73].”
Detection of anxiety symptoms and disorders in older adults: a diagnostic accuracy systematic review
Atchison, K., Wu, P., Samii, L., Walsh, M., Ismail, Z., Iaboni, A., & Goodarzi, Z. (2024) · Age and Ageing · doi:10.1093/ageing/afae122 · Cited by 23
Liew, T. M., Yu, J., Mahendran, R., Ng, T. P., Kua, E. H., & Feng, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170947 · Cited by 18
“This finding is consistent with the current evidence that NPS in early NCD can be associated with worse cognitive outcome [27, 29, 30].”
Special Issue on mild behavioral impairment and non-cognitive prodromes to dementia
Mortby, M. E., Lyketsos, C. G., Geda, Y. E., & Ismail, Z. (2018) · International Psychogeriatrics · doi:10.1017/s1041610218000108 · Cited by 19
“In their paper relating depression and anxiety to cortical amyloid deposition in cognitively normal elderly, Krell-Roesch et al. (2018) provided evidence of an association between anxious and depressive symptoms and cortical amyloid deposition.”
BackgroundYao, C. W., Pelletier, A., Fereshtehnejad, S., Cross, N. E., Dang‐Vu, T. T., & Postuma, R. B. (2021) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.9562 · Cited by 17
Khoury, R., & Grossberg, G. T. (2018) · CNS Drugs · doi:10.1007/s40263-018-0590-9 · Cited by 16
Emotion dysregulation in idiopathic rapid eye movement sleep behavior disorder
Jun, J., Kim, R., Jung, H.-M., Byun, J., Seok, J. M., Kim, T., Lim, J., Sunwoo, J., Kim, H., Schenck, C. H., et al. (2019) · SLEEP · doi:10.1093/sleep/zsz224 · Cited by 17
Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes
Guerrero‐Berroa, E., Ravona‐Springer, R., Schmeidler, J., Heymann, A. D., Soleimani, L., Sano, M. C., LeRoith, D., Preiss, R., Zukran, R., Silverman, J. M., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170778 · Cited by 17
Harris, B. N., Roberts, B. R., DiMarco, G. M., Maldonado, K. A., Okwunwanne, Z., Savonenko, A. V., & Soto, P. L. (2022) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2022.114126 · Cited by 19
β-amyloid pathology is not associated with depression in a large community sample autopsy study
Saldanha, N. M., Suemoto, C. K., Rodriguez, R. D., Leite, R. E. P., Nascimento, C. F., Ferretti‐Rebustini, R. E. D. L., da Silva, M. M., Pasqualucci, C. A., Nitríni, R., Filho, W. J., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.09.062 · Cited by 16
Neuropsychiatric Profile as a Predictor of Cognitive Decline in Mild Cognitive Impairment
Roberto, N., Portella, M. J., Marquié, M., Alegret, M., Hernández, I., Mauleón, A., Rosende‐Roca, M., Ruiz, C. A., Antonio, E. E., Tartari, J. P., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.718949 · Cited by 16
The pathway to secondary prevention of Alzheimer's disease
McDade, E., Bednar, M. M., Brashear, H. R., Miller, D. S., Maruff, P., Randolph, C., Ismail, Z., Carrillo, M. C., Weber, C. J., Bain, L. J., et al. (2020) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12069 · Cited by 20
Mild behavioural impairment-apathy and core Alzheimer's disease cerebrospinal fluid biomarkers
Vellone, D. A., Leon, R., Goodarzi, Z., Forkert, N. D., Smith, E. E., & Ismail, Z. (2025) · Brain · doi:10.1093/brain/awaf194 · Cited by 14
“33 Furthermore, there might be slightly different effect sizes for biomarker associations with different MBI domains, dependent on the time course of domain emergence relative to the deposition of amyloid and the phosphorylation of tau.”
Chatzidimitriou, E., Ioannidis, P., Μoraitou, D., Konstantinopoulou, E., & Aretouli, E. (2023) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2023.1087765 · Cited by 16
“Irritability has also been reported as a common neuropsychiatric symptom and often as a pre-dementia risk marker (Ismail et al., 2018).”
BackgroundA narrative review on mild behavioural impairment: an exploration into its scientific perspectives
Cozza, M., & Boccardi, V. (2023) · Aging Clinical and Experimental Research · doi:10.1007/s40520-023-02472-1 · Cited by 18
Babulal, G. M., Chen, L., Murphy, S. A., Doherty, J. M., Johnson, A. M., & Morris, J. C. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.07.012 · Cited by 15
Li, E., Ai, F., Tian, Q., Yang, H., Tang, P., & Guo, B. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-06657-y · Cited by 16
“Depressive symptoms are widespread in older adults with cognitive impairment, and the overall comorbidity rate has reached 32% [3, 4].”
Ram, D., George, M., & Gowdappa, B. (2018) · Indian Journal of Psychiatry · doi:10.4103/psychiatry.indianjpsychiatry_183_18 · Cited by 14
“[17,18] Emotional dysregulation has been identified as a risk factor for cognitive impairment in adults.[19] Improving cognitive control over and persistence of emotional responses is often the target for cognitive-based psychotherapeutic approaches for the treatment of affective illnesses.”
BackgroundA Protective Role of Translocator Protein in Alzheimer’s Disease Brain
Jung, M. E. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200217105950 · Cited by 17
Imtiaz, D., Anwar, Y., & Khan, A. A. (2020) · Smart Health · doi:10.1016/j.smhl.2020.100140 · Cited by 14
Janicki, M. P., Hendrix, J. A., McCallion, P., & Panel, A. T. N. C. E. C. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12335 · Cited by 14
Ismail, Z., Gatchel, J. R., Bateman, D. R., Barcelos‐Ferreira, R., Cantillon, M., Jaeger, J., Donovan, N. J., & Mortby, M. E. (2018) · International Psychogeriatrics · doi:10.1017/s1041610218000637 · Cited by 14
Management of Psychiatric Symptoms in Dementia
Ayhan, Y., Yoseph, S. A., & Miller, B. L. (2022) · Neurologic Clinics · doi:10.1016/j.ncl.2022.05.001 · Cited by 13
Granata, N., Torlaschi, V., Zanatta, F., Giardini, A., Maestri, R., Pavesi, C., Sommaruga, M., Gazzi, L., Bertolotti, G., Braga, S. S., et al. (2022) · Psychology Health & Medicine · doi:10.1080/13548506.2022.2077394 · Cited by 13
“These data are in line with the existing literature about the prevalence of emotional distress in people with cognitive impairment (Ismail et al., 2018; Rock et al., 2014).”
ResultMarrie, R. A., Maxwell, C. J., Rotstein, D., Tsai, C.-C., & Tremlett, H. L. (2023) · Revue Neurologique · doi:10.1016/j.neurol.2023.07.002 · Cited by 12
Pierobon, A., Granata, N., Torlaschi, V., Vailati, C., Radici, A., Maestri, R., Pavesi, C., Sommaruga, M., Gazzi, L., Bertolotti, G., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235570 · Cited by 12
“In fact, affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often revealing in advance neurodegenerative changes and a progressive cognitive decline [35].”
BackgroundEffect of Hearing Ability and Mild Behavioural Impairment on MoCA and Memory Index Scores
Gosselin, P. A., Ismail, Z., Faris, P., Benkoczi, C. L., Fraser, T. L., Cherry, S. W., Faulkner, T. I., & Islam, M. S. (2019) · Canadian Geriatrics Journal · doi:10.5770/cgj.22.374 · Cited by 12
“MoCA Memory Index 8(6-12) 11(9-14) 7(5-11) MWU=62 .”
BackgroundInfluentialInamura, K., Shinagawa, S., Nagata, T., Tagai, K., Nukariya, K., & Shigeta, M. (2022) · Psychogeriatrics · doi:10.1111/psyg.12818 · Cited by 10
Metadata
- Authors
- Ismail, Z., Gatchel, J., Bateman, D. R., Barcelos-Ferreira, R., Cantillon, M., Jaeger, J., Donovan, N. J., Mortby, M. E., & Mortby, M. E.
- Affiliations
- University of Calgary (CA)
- Harvard University (US)
- Indiana University Indianapolis (US)
- Rutgers, The State University of New Jersey (US)
- Albert Einstein College of Medicine (US)
- Brigham and Women's Hospital (US)
- Australian National University (AU)
- Corresponding author
- Mortby, Moyra E.
- Mortby, Moyra Elizabeth
- ORCID
- Venue
- International Psychogeriatrics
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 30
- Issue
- 2
- Pages
- 185-196
- ISSN
- 1041-6102 (ISSN-L)
- PMC
- PMC7864664
- OpenAlex
- W2756173155
- Cited by
- 221
- References
- 115
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 26 · 2023: 34 · 2022: 23 · 2021: 26 · 2020: 35 · 2019: 17 · 2018: 13
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-01-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- International Psychogeriatrics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- Alzheimer's Association
- BrightFocus Foundation
- Consortium canadien en neurodégénérescence associée au vieillissement
- Rogers Family Foundation
- Alzheimer Society
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council (1102028)
- National Institute on Aging (K23AG058805)
- National Institute of Mental Health (R25MH094612)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- mild behavioral impairment, neuropsychiatric symptoms, prodromal dementia, depression, anxiety, irritability, euphoria, dysphoria, mania, bipolar disorder, mild cognitive impairment, cognitive decline, dementia prevention, neurodegeneration, older adults
- MeSH terms
- Affective Symptoms, Aged, Anxiety, Dementia, Depression, Emotions, Euphoria, Humans, Irritable Mood, Neuropsychological Tests, Cognitive Dysfunction, Symptom Assessment
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