Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer’s disease (AD), likely reflecting synaptic dysfunction and/or degeneration.
Objective:
To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients.
Methods:
The cohort included hip fracture patients with (n = 70) and without delirium (n = 58), CUA undergoing elective surgery (n = 127), and AD patients (n = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers.
Results:
No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p = 0.001) and CUA (p = 0.035) in age-adjusted sensitivity analyses.
Conclusion:
The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium.
InouyeSK, WestendorpRG, SaczynskiJS (2014) Delirium in elderly people. Lancet383, 911–922.
2.
(2013), Diagnostic and Statistical Manual of Mental Disorders, Washington, DC.
3.
KhanBA, ZawahiriM, CampbellNL, FoxGC, WeinsteinEJ, NazirA, FarberMO, BuckleyJD, MaclullichA, BoustaniMA (2012) Delirium in hospitalized patients: Implications of current evidence on clinical practice and future avenues for research–a systematic evidence review. J Hosp Med7, 580–589.
4.
GualN, MorandiA, PérezLM, BrítezL, BurbanoP, ManF, InzitariM (2018) Risk factors and outcomes of delirium in older patients admitted to postacute care with and without dementia. Dement Geriatr Cogn Disord45, 121–129.
5.
DavisDHJ, TerreraGM, KeageH, RahkonenT, OinasM, MatthewsFE, CunninghamC, PolvikoskiT, SulkavaR, MacLullichAMJ, BrayneC (2012) Delirium is a strong risk factor for dementia in the oldest-old: A population-based cohort study. Brain135, 2809–2816.
6.
KrogsethM, WatneLO, JulieboV, SkovlundE, EngedalK, FrihagenF, WyllerTB (2016) Delirium is a risk factor for further cognitive decline in cognitively impaired hip fracture patients. Arch Gerontol Geriatr64, 38–44.
7.
KrogsethM, WyllerTB, EngedalK, JulieboV (2011) Delirium is an important predictor of incident dementia among elderly hip fracture patients. Dement Geriatr Cogn Disord31, 63–70.
8.
FongTG, DavisD, GrowdonME, AlbuquerqueA, InouyeSK (2015) The interface between delirium and dementia in elderly adults. Lancet Neurol14, 823–832.
9.
HalaasNB, BlennowK, IdlandAV, WyllerTB, RæderJ, FrihagenF, StaffAC, ZetterbergH, WatneLO (2018) Neurofilament light in serum and cerebrospinal fluid of hip fracture patients with delirium. Dement Geriatr Cogn Disord46, 346–357.
10.
CunninghamEL, McGuinnessB, McAuleyDF, ToombsJ, MawhinneyT, O’BrienS, BeverlandD, SchottJM, LunnMP, ZetterbergH, PassmoreAP (2019) CSF beta-amyloid 1-42 concentration predicts delirium following elective arthroplasty surgery in an observational cohort study. Ann Surg269, 1200–1205.
11.
FongTG, VasunilashornSM, LibermannT, MarcantonioER, InouyeSK (2019) Delirium and Alzheimer disease: A proposed model for shared pathophysiology. Int J Geriatr Psychiatry34, 781–789.
12.
SelkoeDJ (2002) Alzheimer’s disease is a synaptic failure. Science298, 789–791.
13.
Jarquin-ValdiviaAA, MajorRJ (2019) A unifying hypothesis for delirium and hospital-acquired weakness as synaptic dysfunctions. Med Hypotheses124, 105–109.
MaldonadoJR (2018) Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry33, 1428–1457.
16.
HuangKP, HuangFL, JägerT, LiJ, ReymannKG, BalschunD (2004) Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci24, 10660–10669.
17.
RepresaA, DeloulmeJC, SensenbrennerM, Ben-AriY, BaudierJ (1990)Neurogranin: Immunocytochemical localization of a brain-specific protein kinase C substrate. J Neurosci10, 3782–3792.
18.
Garrido-GarcíaA, de AndrésR, Jiménez-PompaA, SorianoP, Sanz-FuentesD, Martínez-BlancoE, Díez-GuerraFJ (2019) Neurogranin expression is regulated by synaptic activity and promotes synaptogenesis in cultured hippocampal neurons. Mol Neurobiol56, 7321–7337.
19.
MonsN, EnderlinV, JaffardR, HigueretP (2001) Selective age-related changes in the PKC-sensitive, calmodulin-binding protein, neurogranin, in the mouse brain. J Neurochem79, 859–867.
20.
ReddyPH, ManiG, ParkBS, JacquesJ, MurdochG, WhetsellWJr., KayeJ, ManczakM (2005) Differential loss of synaptic proteins in Alzheimer’s disease: Implications for synaptic dysfunction.J Alzheimers Dis7, 103–117; discussion 173-180.
21.
WellingtonH, PatersonRW, PorteliusE, TörnqvistU, MagdalinouN, FoxNC, BlennowK, SchottJM, ZetterbergH (2016) Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology86, 829–835.
22.
PalmqvistS, InselPS, StomrudE, JanelidzeS, ZetterbergH, BrixB, EichenlaubU, DageJL, ChaiX, BlennowK, MattssonN, HanssonO (2019) Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol Med11, e11170.
23.
PorteliusE, ZetterbergH, SkillbäckT, TörnqvistU, AndreassonU, TrojanowskiJQ, WeinerMW, ShawLM, MattssonN, BlennowK (2015)Cerebrospinal fluid neurogranin: Relation to cognition and neurodegeneration in Alzheimer’s disease. Brain138, 3373–3385.
24.
KvartsbergH, DuitsFH, IngelssonM, AndreasenN, ÖhrfeltA, AnderssonK, BrinkmalmG, LannfeltL, MinthonL, HanssonO, AndreassonU, TeunissenCE, ScheltensP, Van der FlierWM, ZetterbergH, PorteliusE, BlennowK (2015) Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease. Alzheimers Dement11, 1180–1190.
25.
BlennowK, Diaz-LucenaD, ZetterbergH, Villar-PiqueA, KarchA, VidalE, HermannP, SchmitzM, Ferrer AbizandaI, ZerrI, LlorensF (2019) CSF neurogranin as a neuronal damage marker in CJD: A comparative study with AD. J Neurol Neurosurg Psychiatry90, 846–853.
26.
SatoC, BarthélemyNR, MawuenyegaKG, PattersonBW, GordonBA, Jockel-BalsarottiJ, SullivanM, CrispMJ, KastenT, KirmessKM, KanaanNM, YarasheskiKE, Baker-NighA, BenzingerTLS, MillerTM, KarchCM, BatemanRJ (2018) Tau kinetics in neurons and the human central nervous system. Neuron97, 1284–1298.e1287.
27.
WatneLO, TorbergsenAC, ConroyS, EngedalK, FrihagenF, HjorthaugGA, JulieboV, RaederJ, SaltvedtI, SkovlundE, WyllerTB (2014) The effect of a pre- and postoperative orthogeriatric service on cognitive function in patients with hip fracture: Randomized controlled trial (Oslo Orthogeriatric Trial). BMC Med12, 63.
28.
WyllerTB, WatneLO, TorbergsenA, EngedalK, FrihagenF, JuliebøV, SaltvedtI, SkovlundE, RæderJ, ConroyS (2012) The effect of a pre- and post-operative orthogeriatric service on cognitive function in patients with hip fracture. The protocol of the Oslo Orthogeriatrics Trial. BMC Geriatr12, 36.
29.
InouyeSK, van DyckCH, AlessiCA, BalkinS, SiegalAP, HorwitzRI (1990) Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med113, 941–948.
30.
O’SullivanR, MeagherD, LeonardM, WatneLO, HallRJ, MaclullichAM, TrzepaczP, AdamisD (2015) A comparison of the revised Delirium Rating Scale (DRS-R98) and the Memorial Delirium Assessment Scale (MDAS) in a palliative care cohort with DSM-IV delirium. Palliat Support Care13, 937–944.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
33.
InouyeSK, Leo-SummersL, ZhangY, BogardusSTJr., LeslieDL, AgostiniJV (2005) A chart-based method for identification of delirium: Validation compared with interviewer ratings using the confusion assessment method. J Am Geriatr Soc53, 312–318.
34.
BraekhusA, UlsteinI, WyllerTB, EngedalK (2011) The Memory Clinic–outpatient assessment when dementia is suspected. Tidsskr Nor Laegeforen131, 2254–2257.
35.
KnapskogAB, BraekhusA, EngedalK (2019) The effect of changing the amyloid beta42 cut-off of cerebrospinal fluid biomarkers on Alzheimer disease diagnosis in a memory clinic population in Norway. Alzheimer Dis Assoc Disord33, 72–74.
36.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCRJr., KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
37.
WatneLO, HallRJ, MoldenE, RaederJ, FrihagenF, MacLullichAM, JulieboV, NymanA, MeagherD, WyllerTB (2014) Anticholinergic activity in cerebrospinal fluid and serum in individuals with hip fracture with and without delirium. J Am Geriatr Soc62, 94–102.
38.
HanssonO, ZetterbergH, BuchhaveP, LondosE, BlennowK, MinthonL (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurol5, 228–234.
39.
KvartsbergH, LashleyT, MurrayCE, BrinkmalmG, CullenNC, HöglundK, ZetterbergH, BlennowK, PorteliusE (2019) The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer’s disease. Acta Neuropathol137, 89–102.
40.
BreitbartW,
RosenfeldB,
RothA,
SmithMJ,
CohenK,
PassikS (1997) The memorial delirium assessment scale. J Pain Symptom Manage13, 128–137.
WanderlindML, GonçalvesR, TomasiCD, Dal-PizzolF, RitterC (2020) Association of neurogranin with delirium among critically ill patients. Biomark Med14, 1613–1617.
44.
KvartsbergH, PorteliusE, AndreassonU, BrinkmalmG, HellwigK, LelentalN, KornhuberJ, HanssonO, MinthonL, SpitzerP, MalerJM, ZetterbergH, BlennowK, LewczukP (2015) Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls. Alzheimers Res Ther7, 40.
45.
De VosA, BjerkeM, BrounsR, De RoeckN, JacobsD, Van den AbbeeleL, GuldolfK, ZetterbergH, BlennowK, EngelborghsS, VanmechelenE (2017) Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke. BMC Neurol17, 170.
46.
RichwineAF, ParkinAO, BuchananJB, ChenJ, MarkhamJA, JuraskaJM, JohnsonRW (2008) Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation. Psychoneuroendocrinology33, 1369–1377.
47.
ScheffSW, PriceDA, SchmittFA, DeKoskyST, MufsonEJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology68, 1501–1508.
48.
MolinuevoJL, AytonS, BatrlaR, BednarMM, BittnerT, CummingsJ, FaganAM, HampelH, MielkeMM, MikulskisA, O’BryantS, ScheltensP, SevignyJ, ShawLM, SoaresHD, TongG, TrojanowskiJQ, ZetterbergH, BlennowK (2018) Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol136, 821–853.
49.
AlbaneseE, BanderjeeS, DhanasiriS, FernandezJL, FerriC, KnappM, McCroneP, PrinceM, SnellT, StewartR (2007) Personal Social Services Research Unit (PSSRU) at the London School of Economics and the Institute of Psychiatry at King’s College London, pp. 4, 18-19.
50.
DavidssonP, BlennowK (1998) Neurochemical dissection of synaptic pathology in Alzheimer’s disease. Int Psychogeriatr10, 11–23.
