Cerebrospinal fluid abnormalities and rate of decline in everyday function across the dementia spectrum: normal aging, mild cognitive impairment, and Alzheimer disease.
OBJECTIVE
To investigate the effect of cerebrospinal fluid (CSF) abnormalities on the rate of decline in everyday function in normal aging, mild cognitive impairment (MCI), and mild Alzheimer disease (AD).


METHODS
Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau(181)), and beta-amyloid 1-42 (Abeta(42)) concentrations were performed in CSF obtained from participants in the Alzheimer's Disease Neuroimaging Initiative. Random effects regressions were used to examine the relationship among CSF abnormalities, cognitive impairment (assessed with the Alzheimer Disease Assessment Scale-cognitive subscale [ADAS-Cog]), and functional decline (assessed with the Pfeffer Functional Activities Questionnaire) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment.


METHODS
Fifty-eight sites in the United States and Canada.


METHODS
One hundred fourteen cognitively intact adults, 195 patients with MCI, and 100 patients with mild AD. Main Outcome Measure Decline in the Pfeffer Functional Activities Questionnaire score.


RESULTS
Abnormalities in all CSF analytes were associated with functional decline in MCI, and all but the t-tau:Abeta(42) ratio were associated with functional decline in controls. No abnormal CSF analyte was associated with functional decline in AD. Among controls, p-tau(181) concentration was the most sensitive to functional decline, whereas in MCI it was Abeta(42) concentration. Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI, whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status. Across all diagnostic groups, persons with both tau and Abeta(42) abnormalities exhibited the steepest rate of functional decline.


CONCLUSIONS
Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI. However, they do not predict further functional degradation in patients with AD. Persons with comorbid tau and Abeta(42) abnormalities are at greatest risk of functional loss.
Okonkwo
Ozioma C
OC
Department of Neurology, Johns Hopkins School of Medicine, 1620 McElderry St, Reed Hall East 2, Baltimore, MD 21205, USA. ozioma@jhmi.edu
Alosco
Michael L
ML
Griffith
H Randall
HR
Mielke
Michelle M
MM
Shaw
Leslie M
LM
Trojanowski
John Q
JQ
Tremont
Geoffrey
G
D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D003072:Cognition Disorders / Q000134:cerebrospinal fluid*; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D011795:Surveys and Questionnaires; D013912:Threonine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D013912:Threonine