title: The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function.
abstract: Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), β-amyloid peptides 1-42 (Aβ(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel-process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of Aβ(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/Aβ(1-42)-associated cognitive change across all brain regions examined. Significant direct effects of alterations in Aβ(1-42) levels on hypometabolism were observed in a single brain region: middle/inferior temporal gyrus. Results support a temporal framework model in which reduced CSF amyloid-related biomarkers occur earlier in the pathogenic pathway, ultimately leading to detrimental cognitive effects. Also consistent with this temporal framework model, baseline markers of neurofibrillary degeneration predicted changes in brain glucose metabolism in turn causing longitudinal cognitive changes, suggesting that tau-related burden precedes neurometabolic dysfunction. While intriguing, the hypothesized mediational relationships require further validation.
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA; Alzheimer's Disease Research Center, University of Wisconsin, Madison, WI, USA. Electronic address: nmdowlin@biostat.wisc.edu.
authors.forename: N Maritza
authors.initials: NM
authors.lastname: Dowling
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin, Madison, WI, USA; Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin, Madison, WI, USA; Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Carey E
authors.initials: CE
authors.lastname: Gleason
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000503:physiopathology; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
keywords: Alzheimer's disease; Beta amyloid; CSF biomarkers; FDG-PET; Longitudinal mediation; Parallel process latent growth; Structural equation modeling; Tau