Associations of Neuropsychiatric Features with Cerebrospinal Fluid Biomarkers of Amyloidogenesis and Neurodegeneration in Dementia with Lewy Bodies Compared with Alzheimer’s Disease and Cognitively Healthy People
Restricted accessResearch articleFirst published online June 1, 2021
Associations of Neuropsychiatric Features with Cerebrospinal Fluid Biomarkers of Amyloidogenesis and Neurodegeneration in Dementia with Lewy Bodies Compared with Alzheimer’s Disease and Cognitively Healthy People
Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases.
Objective:
We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer’s disease (AD) and cognitively healthy people.
Methods:
Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42, Aβ40, Aβ38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEɛ4 carrier status.
Results:
Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOEɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis.
Conclusion:
Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.
ModreanuR, CerqueraSC, MartíMJ, RíosJ, Sánchez-GómezA, CámaraA, FernándezM, ComptaY (2017) Cross-sectional and longitudinal associations of motor fluctuations and non-motor predominance with cerebrospinal τ and Aβ as well as dementia-risk in Parkinson’s disease. J Neurol Sci373, 223–229.
2.
De OliveiraFF, MachadoFC, SampaioG, MarinSMC, Naffah-MazzacorattiMG, BertolucciPHF (2020) Neuropsychiatric feature profiles of patients with Lewy body dementia. Clin Neurol Neurosurg194, 105832.
3.
DolatshahiM, PourmirbabaeiS, KamalianA, Ashraf-GanjoueiA, YaseriM, AarabiMH (2018) Longitudinal alterations of alpha-synuclein, amyloid beta, total, and phosphorylated tau in cerebrospinal fluid and correlations between their changes in Parkinson’s disease. Front Neurol9, 560.
4.
BlonieckiV, AarslandD, BlennowK, CummingsJ, FalahatiF, WinbladB, Freund-LeviY (2017) Effects of risperidone and galantamine treatment on Alzheimer’s disease biomarker levels in cerebrospinal fluid. J Alzheimers Dis57, 387–393.
5.
JackCRJr, KnopmanDS, JagustWJ, ShawLM, AisenPS, WeinerMW, PetersenRC, TrojanowskiJQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s cascade. Lancet Neurol9, 119–128.
6.
TangW, HuangQ, WangY, WangZY, YaoYY (2014) Assessment of CSF Aβ42 as an aid to discriminating Alzheimer’s disease from other dementias and mild cognitive impairment: A meta-analysis of 50 studies. J Neurol Sci345, 26–36.
7.
MackinRS, InselP, ZhangJ, MohlenhoffB, GalaskoD, WeinerM, MattsonM (2015) Cerebrospinal fluid α-synuclein and Lewy body-like symptoms in normal controls, mild cognitive impairment, and Alzheimer’s disease. J Alzheimers Dis43, 1007–1016.
8.
SelkoeDJ (2006) The ups and downs of Aβ. Nat Med12, 758–759.
9.
OliveiraFF, ChenES, SmithMC, BertolucciPH (2017) Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia. Rev Bras Psiquiatr39, 95–103.
10.
GonneaudJ, Arenaza-UrquijoEM, FouquetM, PerrotinA, FradinS, La SayetteV, EustacheF, ChételatG (2016) Relative effect of APOEɛ4 on neuroimaging biomarker changes across the lifespan. Neurology87, 1696–1703.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCRJr, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement7, 263–269.
14.
ChavesMLF, CamozzatoAL, GodinhoC, KochhannR, SchuhA, AlmeidaVL, KayeJ (2007) Validity of the Clinical Dementia Rating Scale for the detection and staging of dementia in Brazilian patients. Alzheimer Dis Assoc Disord21, 210–217.
15.
BertolucciPHF, BruckiSMD, CampacciSR, JulianoY (1994) The mini-mental state examination in an outpatient population: Influence of literacy. Arq Neuropsiquiatr52, 1–7.
16.
LoebC, GandolfoC (1983) Diagnostic evaluation of degenerative and vascular dementia. Stroke14, 399–401.
17.
CamozzattoAL, KochhannR, SimeoniC, KonrathCA, FranzAP, CarvalhoA, ChavesML (2008) Reliability of the Brazilian Portuguese version of the Neuropsychiatric Inventory (NPI) for patients with Alzheimer’s disease and their caregivers. Int Psychogeriatr20, 383–393.
18.
TeunissenCE, PetzoldA, BennettJL, BervenFS, BrundinL, ComabellaM, FranciottaD, FrederiksenJL, FlemingJO, FurlanR, HintzenRQ, HughesSG, JohnsonMH, KrasulovaE, KuhleJ, MagnoneMC, RajdaC, RejdakK, SchmidtHK, van PeschV, WaubantE, WolfC, GiovannoniG, HemmerB, TumaniH, DeisenhammerF (2009) A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology73, 1914–1922.
OliveiraFF, MachadoFC, SampaioG, MarinSMC, ChenES, SmithMC, BertolucciPHF (2015) Contrasts between patients with Lewy body dementia syndromes and}-ɛ3/ɛ3 patients with late-onset Alzheimer disease dementia. Neurologist20, 35–41.
21.
RamakersIHGB, VerheyFRJ, ScheltensP, HampelH, SoininenH, AaltenP, RikkertMO, VerbeekMM, SpiruL, BlennowK, TrojanowskiJQ, ShawLM, VisserPJ (2013) Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment. Psychol Med43, 911–920.
22.
ShowrakiA, MurariG, IsmailZ, BarfettJJ, FornazzariL, MunozDG, SchweizerTA, FischerCE (2019) Cerebrospinal fluid correlates of neuropsychiatric symptoms in patients with Alzheimer’s disease/mild cognitive impairment: A systematic review. J Alzheimers Dis71, 477–501.
23.
VergalloA, GiampietriL, PagniC, GiorgiFS, NicolettiV, MiccoliM, LibertiniP, PetrozziL, BonuccelliU, TognoniG (2019) Association between CSF beta-amyloid and apathy in early-stage Alzheimer disease. J Geriatr Psychiatry Neurol32, 164–169.
24.
DuitsFH, TeunissenCE, BouwmanFH, VisserPJ, MattsonN, ZetterbergH, BlennowK, HanssonO, MinthonL, AndreasenN, MarcussonJ, WallinA, RikkertMO, TsolakiM, ParnettiL, HerukkaSK, HampelH, De LeonMJ, SchröderJ, AarslandD, BlankensteinMA, ScheltensP, van der FlierWM (2014) The cerebrospinal fluid “Alzheimer profile”: Easily said, but what does it mean?Alzheimers Dement10, 713–723.
25.
VranováHP, HénykováE, KaiserováM, MenšíkováK, VaštíkM, MarešJ, HluštíkP, ZapletalováJ, StrnadM, StejskalD, KaňovskýP (2014) Tau protein, beta-amyloid1–42 and clusterin CSF levels in the differential diagnosis of Parkinsonian syndrome with dementia. J Neurol Sci343, 120–124.
26.
SkillbäckT, FarahmandBY, RosénC, MattsonN, NäggaK, KilanderL, ReligaD, WimoA, WinbladB, SchottJM, BlennowK, EriksdotterM, ZetterbergH (2015) Cerebrospinal fluid tau and amyloid-β1 - 42 in patients with dementia. Brain138, 2716–2731.
27.
ZhangW, ZhangQ, YangQ, LiuP, SunT, XuY, QianX, QiuW, MaC (2020) Contribution of Alzheimer’s disease neuropathologic change to the cognitive dysfunction in human brains with Lewy body-related pathology. Neurobiol Aging91, 56–65.
28.
BrunnströmH, HanssonO, ZetterbergH, LondosE, EnglundE (2013) Correlations of CSF tau and amyloid levels with Alzheimer pathology in neuropathologically verified dementia with Lewy bodies. Int J Geriatr Psychiatry28, 738–744.
29.
MattsonN, InselP, NoshenyR, ZetterbergH, TrojanowskiJQ, ShawLM, TosunD, WeinerM (2013) CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders. Transl Psychiatry3, e293.
30.
JackCRJr, WisteHJ, WeigandSD, RoccaWA, KnopmanDS, MielkeMM, LoweVJ, SenjemML, GunterJL, PreboskeGM, PankratzVS, VemuriP, PetersenRC (2014) Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: A cross-sectional study. Lancet Neurol13, 997–1005.
31.
MulugetaE, LondosE, BallardC, AlvesG, ZetterbergH, BlennowK, SkogsethR, MinthonL, AarslandD (2011) CSF amyloid β38 as a novel diagnostic marker for dementia with Lewy bodies. J Neurol Neurosurg Psychiatry82, 160–164.
SlaetsS, VanmechelenE, Le BastardN, DecraemerH, VandijckM, MartinJJ, De DeynPP, EngelborghsS (2014) Increased CSF α-synuclein levels in Alzheimer’s disease: Correlation with tau levels. Alzheimers Dement10, S290–S298.
34.
OosterveldLP, VerberkIMW, MajbourNK, El-AgnafOM, WeinsteinHC, BerendseHW, TeunissenCE, van de BergWDJ (2020) CSF or serum neurofilament light added to α-synuclein panel discriminates Parkinson’s from controls. Mov Disord35, 288–295.
35.
SkillbäckT, FarahmandB, BartlettJW, RosénC, MattsonN, NäggaK, KilanderL, ReligaD, WimoA, WinbladB, RosengrenL, SchottJM, BlennowK, EriksdotterM, ZetterbergH (2014) CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology83, 1945–1953.
36.
HampelH, ToschiN, BaldacciF, ZetterbergH, BlennowK, KilimannI, TeipelSJ, CavedoE, SantosAM, EpelbaumS, LamariF, GenthonR, DuboisB, FlorisR, GaraciF, ListaS (2018) Alzheimer’s disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1–42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40. Alzheimers Dement14, 492–501.
37.
ffytcheDH, PereiraJB, BallardC, ChaudhuriKR, WeintraubD, AarslandD (2017) Risk factors for early psychosis in PD: Insights from the Parkinson’s Progression Markers Initiative. J Neurol Neurosurg Psychiatry88, 325–331.
38.
McKeithIG (2006) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the Consortium on DLB International Workshop. J Alzheimers Dis9, 417–423.
39.
GonzalesMM, InselPS, NelsonC, TosunD, SchöllM, MattssonN, SacuiuS, BickfordD, WeinerMW, MackinRS (2018) Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment. Int J Geriatr Psychiatry33, 1305–1311.
40.
EngelborghsS, MaertensK, VloeberghsE, AertsT, SomersN, MariënP, De DeynPP (2006) Neuropsychological and behavioural correlates of CSF biomarkers in dementia. Neurochem Int48, 286–295.
41.
KimJ, FischerCE, SchweizerTA, MunozDG (2017) Gender and pathology-specific effect of apolipoprotein E genotype on psychosis in Alzheimer’s disease. Curr Alzheimer Res14, 834–840.
42.
De OliveiraFF, BertolucciPHF, ChenES, SmithMAC (2014) Assessment of sleep satisfaction in patients with dementia due to Alzheimer’s disease. J Clin Neurosci21, 2112–2117.
43.
PoulinSP, BergeronD, DickersonBC (2017) Risk factors, neuroanatomical correlates, and outcome of neuropsychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis60, 483–493.
44.
De OliveiraFF, BertolucciPHF, ChenES, SmithMAC (2014) Pharmacological modulation of cognitive and behavioral symptoms in patients with dementia due to Alzheimer’s disease. J Neurol Sci336, 103–108.
