Restricted accessResearch articleFirst published online 2025-1
Cross-sectional and prognostic associations of baseline [ 18 F]GTP1 tau PET signal and white matter lesion volumes for cognitive and functional decline in prodromal-to-mild Alzheimer's disease
In Alzheimer's disease (AD), tau and white matter lesion pathology are associated with clinical severity and subsequent decline, but their relative relationships with clinical assessments remain uncertain.
Objective
To examine cross-sectional and prognostic associations between baseline [18F]GTP1 tau positron emission tomography (PET) standardized uptake value ratio (SUVRs) and T1 white matter hypointensity (WMHypo) volumes with clinical indices.
Methods
We analyzed participants with biomarker-confirmed prodromal (n = 127) or mild (n = 233) AD with baseline [18F]GTP1 tau PET and MRI and longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SB), 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Mini-Mental Status Examination (MMSE), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) data.
Results
Higher baseline [18F]GTP1 SUVRs were independently associated with poorer baseline performance and faster rates of subsequent decline on all five clinical outcome measures. Higher baseline WMHypo volumes were independently associated with poorer baseline performance on the CDR-SB, ADAS-Cog13, RBANS, and MMSE and faster rates of subsequent decline on the CDR-SB and ADCS-ADL.
Conclusions
The independent associations of tau and white matter lesion pathology with clinical decline in AD suggest future prognostic models should include both imaging modalities.
QuerfurthHWLaFerlaFM. Alzheimer's disease. N Engl J Med2010; 362: 329–344.
2.
VillemagneVLBarkhofFGaribottoV, et al.Molecular imaging approaches in dementia. Radiology2021; 298: 517–530.
3.
BarberRScheltensPGholkarA, et al.White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry1999; 67: 66–72.
4.
McAleeseKEWalkerLGrahamS, et al.Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol2017; 134: 459–473.
5.
SchneiderJAArvanitakisZBangW, et al.Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology2007; 69: 2197–2204.
6.
GrimmerTFaustMAuerF, et al.White matter hyperintensities predict amyloid increase in Alzheimer's disease. Neurobiol Aging2012; 33: 2766–2773.
7.
Erten-LyonsDWoltjerRKayeJ, et al.Neuropathologic basis of white matter hyperintensity accumulation with advanced age. Neurology2013; 81: 977–983.
8.
McAleeseKEFirbankMDeyM, et al.Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol Commun2015; 3: 60.
9.
AlbanSLLynchKMRingmanJM, et al.The association between white matter hyperintensities and amyloid and tau deposition. Neuroimage Clin2023; 38: 103383.
10.
Graff-RadfordJArenaza-UrquijoEMKnopmanDS, et al.White matter hyperintensities: relationship to amyloid and tau burden. Brain2019; 142: 2483–2491.
11.
RoseboroughARamirezJBlackSE, et al.Associations between amyloid beta and white matter hyperintensities: a systematic review. Alzheimers Dement2017; 13: 1154–1167.
12.
OssenkoppeleRSmithRMattsson-CarlgrenN, et al.Accuracy of tau positron emission tomography as a prognostic marker in preclinical and prodromal Alzheimer disease: a head-to-head comparison against amyloid positron emission tomography and magnetic resonance imaging. JAMA Neurol2021; 78: 961–971.
13.
TengEManserPTSanabria BohorquezS, et al.Baseline [(18)F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer's disease. Alzheimers Res Ther2021; 13: 196.
14.
DoraiswamyPMSperlingRAColemanRE, et al.Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology2012; 79: 1636–1644.
15.
FifordCMSudreCHYoungAL, et al.Presumed small vessel disease, imaging and cognition markers in the Alzheimer's disease neuroimaging initiative. Brain Commun2021; 3: fcab226.
16.
NelsonPTAlafuzoffIBigioEH, et al.Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol2012; 71: 362–381.
17.
HanseeuwBJBetenskyRAJacobsHIL, et al.Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol2019; 76: 915–924.
18.
BosIVerheyFRRamakersI, et al.Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline. Alzheimers Res Ther2017; 9: 101.
19.
YassiNHilalSXiaY, et al.Influence of comorbidity of cerebrovascular disease and amyloid-beta on Alzheimer's disease. J Alzheimers Dis2020; 73: 897–907.
20.
EdwardsLThomasKRWeigandAJ, et al.White matter hyperintensity volume and amyloid-PET synergistically impact memory independent of tau-PET in older adults without dementia. J Alzheimers Dis2023; 94: 695–707.
21.
TengEManserPTPickthornK, et al.Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: a randomized clinical trial. JAMA Neurol2022; 79: 758–767.
22.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 270–279.
23.
McKhannGMKnopmanDSChertkowH, et al.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 Dement2011; 7: 263–269.
24.
FolsteinMFFolsteinSEMcHughPR. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975; 12: 189–198.
25.
MorrisJC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr1997; 9: 173–176. discussion 177–178.
26.
RandolphCTierneyMCMohrE, et al.The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol1998; 20: 310–319.
27.
Sanabria BohorquezSMarikJOgasawaraA, et al.[(18)F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer's disease. Eur J Nucl Med Mol Imaging2019; 46: 2077–2089.
28.
FischlBSalatDHBusaE, et al.Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron2002; 33: 341–355.
29.
OlssonEKlassonNBergeJ, et al.White matter lesion assessment in patients with cognitive impairment and healthy controls: reliability comparisons between visual rating, a manual, and an automatic volumetrical MRI method-the Gothenburg MCI study. J Aging Res2013; 2013: 198471.
30.
DadarMMaranzanoJDucharmeS, et al.Validation of T1w-based segmentations of white matter hyperintensity volumes in large-scale datasets of aging. Hum Brain Mapp2018; 39: 1093–1107.
31.
CedresNFerreiraDMachadoA, et al.Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities. Aging (Albany NY)2020; 12: 894–901.
32.
BergLMillerJPStorandtM, et al.Mild senile dementia of the Alzheimer type: 2. Longitudinal Assessment. Ann Neurol1988; 23: 477–484.
33.
MohsRCKnopmanDPetersenRC, et al.Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord1997; 11: S13–S21.
34.
GalaskoDBennettDSanoM, et al.An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord1997; 11: S33–S39.
35.
TengEWardMManserPT, et al.Cross-sectional associations between [(18)F]GTP1 tau PET and cognition in Alzheimer's disease. Neurobiol Aging2019; 81: 138–145.
36.
DubbelmanMAMimmackKJSpragueEH, et al.Regional cerebral tau predicts decline in everyday functioning across the Alzheimer's disease spectrum. Alzheimers Res Ther2023; 15: 120.
37.
RoyKPepinLCPhiliossaintM, et al.Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum. J Alzheimers Dis2014; 42: 291–300.
38.
HalawaOAGatchelJRAmariglioRE, et al.Inferior and medial temporal tau and cortical amyloid are associated with daily functional impairment in Alzheimer's disease. Alzheimers Res Ther2019; 11: 14. 20190131.
39.
MarshallGAGatchelJRDonovanNJ, et al.Regional tau correlates of instrumental activities of daily living and apathy in mild cognitive impairment and Alzheimer's disease dementia. J Alzheimers Dis2019; 67: 757–768.
40.
van den BergEGeerlingsMIBiesselsGJ, et al.White matter hyperintensities and cognition in mild cognitive impairment and Alzheimer's disease: a domain-specific meta-analysis. J Alzheimers Dis2018; 63: 515–527.
41.
OgamaNSakuraiTNakaiT, et al.Impact of frontal white matter hyperintensity on instrumental activities of daily living in elderly women with Alzheimer disease and amnestic mild cognitive impairment. PLoS One2017; 12: e0172484.
42.
YoonBShimYSKimYD, et al.Correlation between instrumental activities of daily living and white matter hyperintensities in amnestic mild cognitive impairment: results of a cross-sectional study. Neurol Sci2013; 34: 715–721.
43.
RoseboroughADSaadLGoodmanM, et al.White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: a meta-analysis, systematic review, and recommendations for future study harmonization. Alzheimers Dement2023; 19: 194–207.
44.
BangenKJThomasKRWeigandAJ, et al.Pattern of regional white matter hyperintensity volume in mild cognitive impairment subtypes and associations with decline in daily functioning. Neurobiol Aging2020; 86: 134–142.
45.
Garnier-CrussardABougachaSWirthM, et al.White matter hyperintensity topography in Alzheimer's disease and links to cognition. Alzheimers Dement2022; 18: 422–433.
46.
LaoPJBoehmeAKMoralesC, et al.Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample. Neurobiol Aging2022; 117: 83–96.
47.
MorrisonCDadarMManeraAL, et al.Racial differences in white matter hyperintensity burden in older adults. Neurobiol Aging2023; 122: 112–119.
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