Objective: World Trade Center (WTC) responders are susceptible to both cognitive and neuropsychiatric impairments, particularly chronic posttraumatic stress disorder. The present study examined self-reported behavioral impairments in a sample of 732 WTC responders, 199 of whom were determined to have high risk of WTC-related cortical atrophy by an artificial neural network. Results: We found that responders at increased risk of cortical atrophy showed behavioral impairment across five domains: motivation, mood, disinhibition, empathy, and psychosis (14.6% vs 3.9% in the low-risk group; P = 3.90 × 10−7). Factor analysis models revealed that responders at high risk of cortical atrophy tended to have deficits generalized across all aspects of behavioral impairment with focal dysfunction in sensory psychosis. We additionally describe how relationships are modulated by exposure severity and pharmacological treatments. Discussion: Our findings suggest a potential link between sensory deficits and the development of cortical atrophy in WTC responders and may indicate symptoms consistent with a clinical portrait of parietal dominant Alzheimer's disease or a related dementia (ADRD). Results underscore the importance of investigating neuropsychiatric symptomatology in clinical evaluations of possible ADRD.
LivingstonGHuntleyJSommerladA, et al.Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446.
2.
LivingstonGSommerladAOrgetaV, et al.Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734.
3.
MorleyJEMorrisJCBerg-WegerM, et al.Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference. J Am Med Dir Assoc. 2015;16(9):731-739.
4.
GedaYERobertsROMielkeMM, et al.Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study. Am J Psychiatry. 2014;171(5):572-581.
5.
GallagherDFischerCEIaboniA. Neuropsychiatric symptoms in mild cognitive impairment. Can J Psychiatr. 2017;62(3):161-169.
6.
ApostolovaLGCummingsJL. Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dement Geriatr Cogn Disord. 2008;25(2):115-126.
7.
DinizBSButtersMAAlbertSMDewMAReynoldsCF3rd. Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. 2013;202(5):329-335.
8.
DinizBSReynoldsCF3rdButtersMA, et al.The effect of gender, age, and symptom severity in late-life depression on the risk of all-cause mortality: the Bambui Cohort Study of Aging. Depress Anxiety. 2014;31(9):787-795.
9.
WoolleyJDKhanBKMurthyNKMillerBLRankinKP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011;72(2):126-133.
10.
RosenbergPBMielkeMMApplebyBSOhESGedaYELyketsosCG. The association of neuropsychiatric symptoms in MCI with incident dementia and Alzheimer disease. Am J Geriatr Psychiatr. 2013;21(7):685-695.
11.
ModregoPJFerrandezJ. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol. 2004;61(8):1290-1293.
12.
IsmailZElbayoumiHFischerCE, et al.Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatr. 2017;74(1):58-67.
13.
FalgasNAllenIESpinaS, et al.The severity of neuropsychiatric symptoms is higher in early-onset than late-onset Alzheimer's Disease. Eur J Neurol. 2021.
14.
McEwenBS. The brain on stress: toward an integrative approach to brain, body, and behavior. Perspect Psychol Sci. 2013;8(6):673-675.
15.
PluvinageJVWyss-CorayT. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nat Rev Neurosci. 2020;21(2):93-102.
16.
SmithEHolmesLLarkinB. Health trends among 9/11 responders from 2011-2021: a review of World trade center health program statistics. Prehospital Disaster Med. 2021:1-6.
17.
CloustonSAPHallCBKritikosM, et al.Cognitive impairment and World trade centre-related exposures. Nat Rev Neurol. 2021.
18.
CloustonSPietrzakRHKotovR, et al.Traumatic exposures, posttraumatic stress disorder, and cognitive functioning in World Trade Center responders. Alzheimers Dement (N Y). 2017;3(4):593-602.
19.
PietrzakRHFederASinghR, et al.Trajectories of PTSD risk and resilience in World Trade Center responders: an 8-year prospective cohort study. Psychol Med. 2014;44(1):205-219.
20.
KritikosMCloustonSAPDiminichED, et al.Pathway analysis for plasma beta-amyloid, tau and neurofilament light (ATN) in World trade center responders at midlife. Neurol Ther. 2020;9(1):159-171.
21.
Calderon-GarciduenasLTorres-JardonRKuleszaRJ, et al.Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress. Environ Res. 2020;183:109137.
22.
CloustonSAPDeriYHortonM, et al.Reduced cortical thickness in World Trade Center responders with cognitive impairment. Alzheimers Dement (Amst). 2020;12(1):e12059.
23.
KuanPFCloustonSYangXKotovRBrometELuftBJ. Molecular linkage between post-traumatic stress disorder and cognitive impairment: a targeted proteomics study of World Trade Center responders. Transl Psychiatry. 2020;10(1):269.
CloustonSDeriYHortonM, et al.Reduced cortical thickness in World Trade Center responders with cognitive impairment: neuroimaging/differential diagnosis. Alzheimer's Dementia. 2020;16:e039996.
26.
CloustonSAPKritikosMHuangC, et al.Reduced cerebellar cortical thickness in World Trade Center responders with cognitive impairment. Transl Psychiatry. 2022;12(1):107.
27.
CloustonSAPKritikosMDeriY, et al.A cortical thinning signature to identify World Trade Center responders with possible dementia. Intell Based Med. 2021;5:100032.
28.
ChenAPFCloustonSAPKritikosM, et al.A deep learning approach for monitoring parietal-dominant Alzheimer's disease in World Trade Center responders at midlife. Brain Commun. 2021;3(3):fcab145.
29.
NaudeJGillSHuS, et al.Plasma neurofilament light: a marker of cognitive decline in mild behavioural impairment. J Alzheimers Dis. 2020;76(3):1017-1027.
30.
LussierFZPascoalTAChamounM, et al.Mild behavioral impairment is associated with β‐amyloid but not tau or neurodegeneration in cognitively intact elderly individuals. Alzheimer's Dementia. 2020;16(1):192-199.
31.
JohanssonMStomrudEInselPS, et al.Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease. Transl Psychiatry. 2021;11(1):76.
32.
MatuskovaVIsmailZNikolaiT, et al.Mild behavioral impairment is associated with atrophy of entorhinal cortex and hippocampus in a memory clinic cohort. Front Aging Neurosci. 2021;13:236.
33.
CreeseBArathimosRBrookerH, et al.Genetic risk for Alzheimer's disease, cognition, and mild behavioral impairment in healthy older adults. Alzheimers Dement (Amst). 2021;13(1):e12164.
34.
MiaoRChenH-YGillSNaudeJSmithEEIsmailZ. Plasma β-amyloid in mild behavioural impairment-neuropsychiatric symptoms on the Alzheimer's continuum. J Geriatr Psychiatr Neurol. 2021. in press.
35.
GillSWangMMouchesP, et al.Neural correlates of the impulse dyscontrol domain of mild behavioral impairment. Int J Geriatr Psychiatr. 2021;36(9):1398-1406.
36.
HardyCJDYongKXXGollJCCrutchSJWarrenJD. Impairments of auditory scene analysis in posterior cortical atrophy. Brain. 2020;143(9):2689-2695.
37.
OldsJJHillsWLWarnerJ, et al.Posterior cortical atrophy: characteristics from a clinical data registry. Front Neurol. 2020;11:358.
38.
WitoonpanichPCashDMShakespeareTJ, et al.Olfactory impairment in posterior cortical atrophy. J Neurol Neurosurg Psychiatry. 2013;84(5):588-590.
39.
MillerZARosenbergLSantos-SantosMA, et al.Prevalence of mathematical and visuospatial learning disabilities in patients with posterior cortical atrophy. JAMA Neurol. 2018;75(6):728-737.
40.
IsmailZAguera-OrtizLBrodatyH, 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):929-938.
41.
IsmailZSmithEEGedaY, et al.Neuropsychiatric symptoms as early manifestations of emergent dementia: provisional diagnostic criteria for mild behavioral impairment. Alzheimer's Dementia. 2016;12(2):195-202.
42.
IsmailZMcGirrAGillSHuSForkertNDSmithEE. Mild behavioral impairment and subjective cognitive decline predict cognitive and functional decline. J Alzheimers Dis. 2021;80(1):459-469.
43.
MatsuokaTIsmailZNarumotoJ. Prevalence of mild behavioral impairment and risk of dementia in a psychiatric outpatient clinic. J Alzheimers Dis. 2019;70(2):505-513.
44.
CreeseBBrookerHIsmailZ, et al.Mild behavioral impairment as a marker of cognitive decline in cognitively normal older adults. Am J Geriatr Psychiatr. 2019;27(8):823-834.
45.
BlanchardEBJones-AlexanderJBuckleyTCFornerisCA. Psychometric properties of the PTSD checklist (PCL). Behav Res Ther. 1996;34(8):669-673.
46.
LongJSFreeseJ. Regression Models for Categorical Dependent Variables Using Stata; 2006. Stata Press.
47.
CloustonSAPHallCBKritikosM, et al.Cognitive impairment and World trade centre-related exposures. Nat Rev Neurol. 2022;18(2):103-116.
48.
CloustonSAPDiminichEDKotovR, et al.Incidence of mild cognitive impairment in World Trade Center responders: Long-term consequences of re-experiencing the events on 9/11/2001. Alzheimers Dement (Amst). 2019;11:628-636.
49.
TeixeiraSMachadoSVelasquesB, et al.Integrative parietal cortex processes: neurological and psychiatric aspects. J Neurol Sci. 2014;338(1-2):12-22.
50.
Cronin-GolombACorkinSGrowdonJH. Visual dysfunction predicts cognitive deficits in Alzheimer's disease. Optom Vis Sci. 1995;72(3):168-176.
51.
MendolaJDCronin-GolombACorkinSGrowdonJH. Prevalence of visual deficits in Alzheimer's disease. Optom Vis Sci. 1995;72(3):155-167.
52.
YongKXXMcCarthyIDPooleT, et al.Navigational cue effects in Alzheimer's disease and posterior cortical atrophy. Ann Clin Transl Neurol. 2018;5(6):697-709.
53.
GoldenHLAgustusJLNicholasJM, et al.Functional neuroanatomy of spatial sound processing in Alzheimer's disease. Neurobiol Aging. 2016;39:154-164.
54.
GoldenHLNicholasJMYongKX, et al.Auditory spatial processing in Alzheimer's disease. Brain. 2015;138(Pt 1):189-202.
55.
D'AntonioFReevesSShengY, et al.Misidentification subtype of alzheimer's disease psychosis predicts a faster cognitive decline. CPT Pharmacometrics Syst Pharmacol. 2019;8(5):308-315.
56.
GottesmanRTKociolekAFernandezK, et al.Association between early psychotic symptoms and alzheimer’s disease prognosis in a community-based cohort. J Alzheim Dis. 2021;81:1131-1139.
57.
GriffithsTDLadMKumarS, et al.How can hearing loss cause dementia?Neuron. 2020;108(3):401-412.
58.
NaasanGShdoSMRodriguezEM, et al.Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms. Brain. 2021;144(3):999-1012.
59.
GiummarraMJLennoxADaliGCostaBGabbeBJ. Early psychological interventions for posttraumatic stress, depression and anxiety after traumatic injury: a systematic review and meta-analysis. Clin Psychol Rev. 2018;62:11-36.
60.
BestEAJuarez-ColungaEJamesKLeBlancWGSerdarB. Biomarkers of exposure to polycyclic aromatic hydrocarbons and cognitive function among elderly in the United States (national health and nutrition examination survey: 2001-2002). PLoS One. 2016;11(2):e0147632.
61.
HaghaniAMorganTEFormanHJFinchCE. Air pollution neurotoxicity in the adult brain: emerging concepts from experimental findings. J Alzheimers Dis. 2020;76(3):773-797.
62.
GordonBABlazeyTMChristensenJ, et al.Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers. Brain. 2019;142(4):1063-1076.
63.
RoussarieJPYaoVRodriguez-RodriguezP, et al.Selective neuronal vulnerability in alzheimer's disease: a network-based analysis. Neuron. 2020;107(5):821-835. e812.
64.
LeeHBRichardsonAKBlackBSShoreADKasperJDRabinsPV. Race and cognitive decline among community-dwelling elders with mild cognitive impairment: findings from the Memory and Medical Care Study. Aging Ment Health. 2012;16(3):372-377.
65.
CohenCIMagaiC. Racial differences in neuropsychiatric symptoms among dementia outpatients. Am J Geriatr Psychiatr. 1999;7(1):57-63.
66.
HowellJCWattsKDParkerMW, et al.Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal fluid biomarkers. Alzheimer's Res Ther. 2017;9(1):88.
67.
SalazarRDwivediAKRoyallDR. Cross-ethnic differences in the severity of neuropsychiatric symptoms in persons with mild cognitive impairment and alzheimer's disease. J Neuropsychiatry Clin Neurosci. 2017;29(1):13-21.
68.
FujimotoHMatsuokaTKatoY, et al.Brain regions associated with anosognosia for memory disturbance in Alzheimer's disease: a magnetic resonance imaging study. Neuropsychiatric Dis Treat. 2017;13:1753-1759.
69.
MondragonJDMauritsNMDe DeynPP. Functional neural correlates of anosognosia in mild cognitive impairment and alzheimer's disease: a systematic review. Neuropsychol Rev. 2019;29(2):139-165.
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