title: Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer's disease.
abstract: Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well described early macroscopic events in Alzheimer's disease. The relationships between these three types of alterations have been documented in previous studies, but their chronology still remains to be established. The present study used multi-modal fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging longitudinal data to address this question in patients with amnestic mild cognitive impairment. We found unidirectional, specific sequential relationships between: (i) baseline hippocampal atrophy and both cingulum bundle (r = 0.70; P = 3 × 10⁻³) and uncinate fasciculus (r = 0.75; P = 7 × 10⁻⁴) rate of atrophy; (ii) baseline cingulum bundle atrophy and rate of decline of posterior (r = 0.72; P = 2 × 10⁻³); and anterior (r = 0.74; P = 1 × 10⁻³) cingulate metabolism; and (iii) baseline uncinate white matter atrophy and subgenual metabolism rate of change (r = 0.65; P = 6 × 10⁻³). Baseline local grey matter atrophy was not found to contribute to hypometabolism progression within the posterior and anterior cingulate as well as subgenual cortices. These findings suggest that hippocampal atrophy progressively leads to disruption of the cingulum bundle and uncinate fasciculus, which in turn leads to glucose hypometabolism of the cingulate and subgenual cortices, respectively. This study reinforces the relevance of remote mechanisms above local interactions to account for the pattern of metabolic brain alteration observed in amnestic mild cognitive impairment, and provides new avenues to assess the sequence of events in complex diseases characterized by multiple manifestations.
authors.affiliation: Inserm-EPHE-Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, Bd H. Becquerel, BP 5229, 14074 Caen Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Villain
authors.forename: Marine
authors.initials: M
authors.lastname: Fouquet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Baron
authors.forename: Florence
authors.initials: F
authors.lastname: Mézenge
authors.forename: Brigitte
authors.initials: B
authors.lastname: Landeau
authors.forename: Vincent
authors.initials: V
authors.lastname: de La Sayette
authors.forename: Fausto
authors.initials: F
authors.lastname: Viader
authors.forename: Francis
authors.initials: F
authors.lastname: Eustache
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desgranges
authors.forename: Gaël
authors.initials: G
authors.lastname: Chételat
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D001284:Atrophy; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors