Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer’s disease (AD) and mild cognitive impairment (MCI).
Objective:
The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI.
Methods:
For this systematic review, four databases, PubMed (1946–2018), Cochrane (2005–2018), EMBASE (1947–2018), and PsycINFO (1806–2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded.
Results:
In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology.
Conclusion:
Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized “objective” approach for the evaluation of NPS.
JostBC, GrossbergGT (1996) The evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study, J Am Geriatr Soc44, 1078–1081.
2.
SteinbergM, ShaoH, ZandiP, LyketsosCG, Welsh-BohmerKA, NortonMC, BreitnerJC, SteffensDC, TschanzJT (2008) Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study, Int J Geriatr Psychiatry23, 170–177.
3.
LyketsosCG, LopezO, JonesB, FitzpatrickAL, BreitnerJ, DeKoskyS (2002) Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study, JAMA288, 1475–1483.
4.
HerrmannN, LanctôtKL, SambrookR, LesnikovaN, HébertR, McCrackenP, RobillardA, NguyenE (2006) The contribution of neuropsychiatric symptoms to the cost of dementia care, Int J Geriatr Psychiatry21, 972–976.
5.
PetersME, SchwartzS, HanD, RabinsPV, SteinbergM, TschanzJT, LyketsosCG (2015) Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County Dementia Progression Study, Am J Psychiatry172, 460–465.
6.
FischerCE, IsmailZ, SchweizerTA (2012) Impact of neuropsychiatric symptoms on caregiver burden in patients with Alzheimer’s disease, Neurodegener Dis Manag2, 269–277.
7.
CummingsJL (1997) The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology4810S–16S.
8.
MoherD, LiberatiA, TetzlaffJ, AltmanDG,
PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med6, e1000097.
9.
EngelborghsS, MaertensK, VloeberghsE, AertsT, SomersN, MarienP, De DeynPP (2006) Neuropsychological and behavioural correlates of CSF biomarkers in dementia, Neurochem Int48, 286–295.
KrambergerMG, JelicV, KareholtI, EnacheD, Eriksdotter JonhagenM, WinbladB, AarslandD (2012) Cerebrospinal fluid Alzheimer markers in depressed elderly subjects with and without Alzheimer’s disease, Dement Geriatr Cogn Disord Extra2, 48–56.
12.
RamakersIH, VerheyFR, ScheltensP, HampelH, SoininenH, AaltenP, RikkertMO, VerbeekMM, SpiruL, BlennowK, TrojanowskiJQ, ShawLM, VisserPJ,
Alzheimer’s Disease Neuroimaging Initiative and DESCRIPA Investigators (2013) Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment, Psychol Med43, 911–920.
13.
AuningE, SelnesP, GrambaiteR, Saltyte BenthJ, HaramA, Lovli StavA, BjornerudA, HessenE, HolPK, Muftuler londalenA, FladbyT, AarslandD (2015) Neurobiological correlates of depressive symptoms in people with subjective and mild cognitive impairment, Acta Psychiatr Scand131, 139–147.
14.
KuoHC, YenHC, HuangCC, HsuWC, WeiHJ, LinCL (2015) Cerebrospinal fluid biomarkers for neuropsychological symptoms in early stage of late-onset Alzheimer’s disease, Int J Neurosci125, 747–754.
15.
WolfsgruberS, JessenF, KopparaA, KleineidamL, SchmidtkeK, FrolichL, KurzA, SchulzS, HampelH, HeuserI, PetersO, ReischiesFM, JahnH, LuckhausC, HullM, GertzHJ, SchroderJ, PantelJ, RienhoffO, RutherE, HennF, WiltfangJ, MaierW, KornhuberJ, WagnerM (2015) Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI, Neurology84, 1261–1268.
16.
BarcaML, PerssonK, EldholmR, BenthJS, KerstenH, KnapskogAB, SaltvedtI, SelbaekG, EngedalK (2017) Trajectories of depressive symptoms and their relationship to the progression of dementia, J Affect Disord222, 146–152.
17.
TautvydaiteD, AntoniettiJP, HenryH, von GuntenA, PoppJ (2017) Relations between personality changes and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, J Psychiatr Res90, 12–20.
18.
DauvilliersYA, LehmannS, JaussentI, GabelleA (2014) Hypocretin and brain beta-amyloid peptide interactions in cognitive disorders and narcolepsy, Front Aging Neurosci6, 119.
19.
LiguoriC, RomigiA, NuccetelliM, ZanninoS, SancesarioG, MartoranaA, AlbaneseM, MercuriNB, IzziF, BernardiniS, NittiA, SancesarioGM, SicaF, MarcianiMG, PlacidiF (2014) Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease, JAMA Neurol71, 1498–1505.
20.
GabelleA, JaussentI, HirtzC, VialaretJ, NavucetS, GrasselliC, RobertP, LehmannS, DauvilliersY (2017) Cerebrospinal fluid levels of orexin-A and histamine, and sleep profile within the Alzheimer process, Neurobiol Aging53, 59–66.
21.
LiguoriC, ChiaravallotiA, NuccetelliM, IzziF, SancesarioG, CiminiA, BernardiniS, SchillaciO, MercuriNB, FabioP (2017) Hypothalamic dysfunction is related to sleep impairment and CSF biomarkers in Alzheimer’s disease, J Neurol264, 2215–2223.
22.
ReijsBLR, VosSJB, SoininenH, LotjonenJ, KoikkalainenJ, PikkarainenM, HallA, VanninenR, LiuY, HerukkaSK, Freund-LeviY, FrisoniGB, FrolichL, NobiliF, RikkertMO, SpiruL, TsolakiM, WallinAK, ScheltensP, VerheyF, VisserPJ (2017) Association between later life lifestyle factors and Alzheimer’s disease biomarkers in non-demented individuals: a longitudinal descriptive cohort study, J Alzheimers Dis60, 1387–1395.
23.
KoppelJ, SundayS, ButhornJ, GoldbergT, DaviesP, GreenwaldB (2013) Elevated CSF Tau is associated with psychosis in Alzheimer’s disease, Am J Psychiatry170, 1212–1213.
24.
DonovanNJ, WadsworthLP, LoriusN, LocascioJJ, RentzDM, JohnsonKA, SperlingRA, MarshallGA,
Alzheimer Disease Neuroimaging Initiative
(2014) Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum, Am J Geriatr Psychiatry22, 1168–1179.
25.
MackinRS, InselP, ZhangJ, MohlenhoffB, GalaskoD, WeinerM, MattssonN (2015) Cerebrospinal fluid alpha-synuclein and Lewy body-like symptoms in normal controls, mild cognitive impairment, and Alzheimer’s disease, J Alzheimers Dis43, 1007–1016.
VidoniED, TownleyRA, HoneaRA, BurnsJM,
Alzheimer’s Disease Neuroimaging Initiative
(2011) Alzheimer disease biomarkers are associated with body mass index, Neurology77, 1913–1920.
28.
EwersM, SchmitzS, HanssonO, WalshC, FitzpatrickA, BennettD, MinthonL, TrojanowskiJQ, ShawLM, FaluyiYO, VellasB, DuboisB, BlennowK, BuergerK, TeipelSJ, WeinerM, HampelH,
Alzheimer’s Disease Neuroimaging Initiative
(2012) Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer’s disease, Neurobiol Aging33, 1599–1608.
29.
MathysJ, GholamrezaeeM, HenryH, vonGunten A, PoppJ (2017) Decreasing body mass index is associated with cerebrospinal fluid markers of Alzheimer’s pathology in MCI and mild dementia, Exp Gerontol100, 45–53.
30.
GotovacK, Nikolac PerkovicM, PivacN, BoroveckiF (2016) Biomarkers of aggression in dementia, Prog Neuropsychopharmacol Biol Psychiatry69, 125–130.
IsmailZ, GatchelJ, BatemanDR, Barcelos-FerreiraR, ChantillonM, JaegerJ, DonovanNJ, MortbyME (2018) Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria, Int Psychogeriatr30, 185–196.
33.
IsmailZ, Agüera-OrtizL, BrodatyH, CieslakA, CummingsJ, FischerCE, GauthierS, GedaYE, HerrmannN, KanjiJ (2017) The Mild Behavioral Impairment Checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations, JAlzheimers Dis56, 929–938.
34.
HoogendijkWJ, MeynenG, EndertE, HofmanMA, SwaabDF (2006) Increased cerebrospinal fluid cortisol level in Alzheimer’s disease is not related to depression. Neurobiol Aging27, 780 e781-780.e782.
35.
SellesMC, OliveiraMM, FerreiraST (2018) Brain inflammation connects cognitive and non-cognitive symptoms in Alzheimer’s disease, J Alzheimers Dis25, 25.
36.
CortesN, AndradeV, MaccioniRB (2018) Behavioral and neuropsychiatric disorders in Alzheimer’s disease, J Alzheimers Dis63, 899–910.
