Alzheimer's disease (AD) is pathologically defined by the accumulation of amyloid-β and phosphorylated tau and subsequent neuronal death. These neuropathological changes typically accumulate in the medial temporal lobe before spreading to other cortical regions (Braak staging pattern). Recent studies using postmortem brain tissue and neuroimaging data have revealed AD subtypes with distinct neuropathological patterns. Hippocampal-sparing (HpSp) subtype of AD shows the preservation of medial temporal lobe volume, compared to typical AD; however, underlying changes in the brain microstructure remain largely unclear.
Objective
We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate the microstructural signatures in each AD subtype.
Methods
We defined typical and HpSp AD based on visual assessment scales of brain MRI, among individuals with mild cognitive impairment who were positive for core AD cerebrospinal fluid markers. We set regions of interest in Braak stage (BS)-related areas (hippocampus (BS II), precuneus (BS V), and postcentral gyrus (BS VI)) and compared NODDI metrics, including intracellular volume fraction, orientation dispersion index, and isotropic volume fraction (Viso), among typical AD, HpSp AD, and non-AD control groups.
Results
NODDI metrics in the hippocampus were significantly different between the typical and HpSp AD groups. Notably, the hippocampal NODDI values in the HpSp AD group were comparable to those of the control group. Viso values in the precuneus were significantly higher in HpSp AD, compared to typical AD.
Conclusions
This suggests that AD subtypes have distinct patterns of microstructural changes in BS-related brain regions.
BraakHBraakE. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol1991; 82: 239–259.
2.
ScheltensPLeysDBarkhofF, et al.Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry1992; 55: 967–972.
3.
Jack JrCRBennettDABlennowK, et al.NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement2018; 14: 535–562.
4.
van DyckCHSwansonCJAisenP, et al.Lecanemab in early Alzheimer's disease. N Engl J Med2023; 388: 9–21.
5.
MurrayMEGraff-RadfordNRRossOA, et al.Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol2011; 10: 785–796.
6.
FerreiraDNordbergAWestmanE. Biological subtypes of Alzheimer disease: a systematic review and meta-analysis. Neurology2020; 94: 436–448.
7.
JohnsonKASchultzABetenskyRA, et al.Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol2016; 79: 110–119.
8.
OssenkoppeleRPichet BinetteAGrootC, et al.Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med2022; 28: 2381–2387.
9.
NelsonPTBraakHMarkesberyWR. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol2009; 68: 1–14.
10.
BraakHThalDRGhebremedhinE, et al.Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol2011; 70: 960–969.
11.
HymanBTVan HoesenGWDamasioAR, et al.Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science1984; 225: 1168–1170.
12.
TakedaS. Progression of Alzheimer's disease, tau propagation, and its modifiable risk factors. Neurosci Res2019; 141: 36–42.
13.
VogelJWYoungALOxtobyNP, et al.Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med2021; 27: 871–881.
14.
FerreiraDVerhagenCHernández-CabreraJA, et al.Distinct subtypes of Alzheimer's disease based on patterns of brain atrophy: longitudinal trajectories and clinical applications. Sci Rep2017; 7: 46263.
15.
KamiyaKHoriMAokiS. NODDI In clinical research. J Neurosci Methods2020; 346: 108908.
16.
ParkerTDSlatteryCFZhangJ, et al.Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging. Hum Brain Mapp2018; 39: 3005–3017.
17.
TakahashiHTakamiYTakedaS, et al.Imaging biomarker for early-stage Alzheimer disease: utility of hippocampal histogram analysis of diffusion metrics. AJNR Am J Neuroradiol2024; 45: 320–327.
18.
McKeithIGBoeveBFDicksonDW, et al.Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology2017; 89: 88–100.
19.
GorelickPBScuteriABlackSE, et al.Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American stroke association. Stroke2011; 42: 2672–2713.
20.
MoriEIshikawaMKatoT, et al.Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir (Tokyo)2012; 52: 775–809.
21.
FazekasFChawlukJBAlaviA, et al.MR Signal abnormalities at 1.5T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol1987; 149: 351–356.
22.
TeunissenCEPetzoldABennettJL, et al.A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology2009; 73: 1914–1922.
23.
NakajimaTTakedaSItoY, et al.A novel chronic dural port platform for continuous collection of cerebrospinal fluid and intrathecal drug delivery in free-moving mice. Fluids Barriers CNS2022; 19: 31.
24.
HarperLFumagalliGGBarkhofF, et al.MRI Visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases. Brain2016; 139: 1211–1225.
25.
HarperLBarkhofFFoxNC, et al.Using visual rating to diagnose dementia: a critical evaluation of MRI atrophy scales. J Neurol Neurosurg Psychiatry2015; 86: 1225–1233.
26.
ScheltensPErkinjuntiTLeysD, et al.White matter changes on CT and MRI: an overview of visual rating scales. European Task Force on Age-Related White Matter Changes. Eur Neurol1998; 39: 80–89.
27.
KoedamELLehmannMvan der FlierWM, et al.Visual assessment of posterior atrophy development of a MRI rating scale. Eur Radiol2011; 21: 2618–2625.
28.
FerreiraDCavallinLGranbergT, et al.Quantitative validation of a visual rating scale for frontal atrophy: associations with clinical status, APOE e4, CSF biomarkers and cognition. Eur Radiol2016; 26: 2597–2610.
29.
TapiolaTAlafuzoffIHerukkaSK, et al.Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol2009; 66: 382–389.
30.
JenkinsonMBeckmannCFBehrensTE, et al.FSL. Neuroimage2012; 62: 782–790.
31.
AnderssonJLSkareSAshburnerJ. How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging. Neuroimage2003; 20: 870–888.
32.
BasserPJMattielloJLeBihanD. Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B1994; 103: 247–254.
33.
FrisoniGBJack JrCRBocchettaM, et al.The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity. Alzheimers Dement2015; 11: 111–125.
34.
WatsonCAndermannFGloorP, et al.Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology1992; 42: 1743–1750.
35.
DestrieuxCFischlBDaleA, et al.Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage2010; 53: 1–15.
36.
ByunMSKimSEParkJ, et al.Heterogeneity of regional brain atrophy patterns associated with distinct progression rates in Alzheimer's disease. PLoS One2015; 10: e0142756.
37.
SlatteryCFZhangJPatersonRW, et al.Apoe influences regional white-matter axonal density loss in Alzheimer's disease. Neurobiol Aging2017; 57: 8–17.
38.
DouaudGJbabdiSBehrensTE, et al.DTI Measures in crossing-fibre areas: increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer's disease. Neuroimage2011; 55: 880–890.
39.
KamagataKHatanoTOkuzumiA, et al.Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson disease. Eur Radiol2016; 26: 2567–2577.
40.
BroadRJGabelMCDowellNG, et al.Neurite orientation and dispersion density imaging (NODDI) detects cortical and corticospinal tract degeneration in ALS. J Neurol Neurosurg Psychiatry2019; 90: 404–411.
41.
SoneDSatoNOtaM, et al.Abnormal neurite density and orientation dispersion in unilateral temporal lobe epilepsy detected by advanced diffusion imaging. Neuroimage Clin2018; 20: 772–782.
42.
MastropietroARizzoGFontanaL, et al.Microstructural characterization of corticospinal tract in subacute and chronic stroke patients with distal lesions by means of advanced diffusion MRI. Neuroradiology2019; 61: 1033–1045.
43.
KamiyaKHoriMIrieR, et al.Diffusion imaging of reversible and irreversible microstructural changes within the corticospinal tract in idiopathic normal pressure hydrocephalus. Neuroimage Clin2017; 14: 663–671.
44.
KraguljacNVGuerreriMStricklandMJ, et al.Neurite orientation dispersion and density imaging in psychiatric disorders: a systematic literature review and a technical note. Biol Psychiatry Glob Open Sci2023; 3: 10–21.
45.
FuXShresthaSSunM, et al.Microstructural white matter alterations in mild cognitive impairment and Alzheimer's disease: study based on Neurite Orientation Dispersion and Density Imaging (NODDI). Clin Neuroradiol2020; 30: 569–579.
46.
FerreiraDMohantyRMurrayME, et al.The hippocampal sparing subtype of Alzheimer's disease assessed in neuropathology and in vivo tau positron emission tomography: a systematic review. Acta Neuropathol Commun2022; 10: 166.
47.
WenJZhangHAlexanderDC, et al.Neurite density is reduced in the presymptomatic phase of C9orf72 disease. J Neurol Neurosurg Psychiatry2019; 90: 387–394.
48.
DongJWJelescuIOAdes-AronB, et al.Diffusion MRI biomarkers of white matter microstructure vary nonmonotonically with increasing cerebral amyloid deposition. Neurobiol Aging2020; 89: 118–128.
49.
MontalVVilaplanaEAlcoleaD, et al.Cortical microstructural changes along the Alzheimer's disease continuum. Alzheimers Dement2018; 14: 340–351.
50.
TherriaultJPascoalTALussierFZ, et al.Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging2022; 2: 526–535.
51.
VahermaaVAydoganDBRaijT, et al.Freesurfer 7 quality control: key problem areas and importance of manual corrections. Neuroimage2023; 279: 120306.
52.
SalaANordbergARodriguez-VieitezE. Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity. Mol Psychiatry2021; 26: 5864–5874.
53.
SternY. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol2012; 11: 1006–1012.
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