Cerebrospinal Fluid Abnormalities and Rate of Decline in Everyday Function Across the Dementia Spectrum

Abstract

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).Design: Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau 181 ), and ␤-amyloid 1-42 (A␤ 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.Setting: Fifty-eight sites in the United States and Canada.Participants: 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: A␤ 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 A␤ 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 A␤ 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 A␤ 42 abnormalities are at greatest risk of functional loss.

Biomarkers and Functional Decline in Prodromal Alzheimer’s Disease

“…Baseline biomarker measures as a predictive factor of functional decline is a novel area of research, with very few studies having explored such relationships and of those comparable; our findings are congruent [14][15][16][41][42][43]. Two separate studies found regional cortical thinning and decreased CSF A1-42 to predict IADL decline across the AD spectrum [15,41].…”

“…Two separate studies found regional cortical thinning and decreased CSF A1-42 to predict IADL decline across the AD spectrum [15,41]. Likewise, correlations between cerebral atrophy and IADL decline in MCI individuals have been reported [14], with rate of decline found to increase three fold in APOE-4 positive individuals [42].…”

“…Previously published data suggest that early biomarker measures may indicate future IADL regression usually in late prodromal and early stage disease populations [13][14][15][16]. However to date, no study has sought to put together a comprehensive picture of how multiple baseline AD biomarker measures may impact on downstream IADL decline, specifically within a prodromal population.…”

Mild cognitive impairment (MCI) twenty years on

“…Numerous studies have now shown difficulties in everyday functioning to be a feature of MCI, and associated furthermore with MCI biomarkers (Ritchie et al, 2001;2010;Touchon and Ritchie, 1999;Aretouli and Brandt, 2010;Okonkwo et al, 2010a;2010b).…”

P4–200: SIST‐M‐IR activities of daily living items that best discriminate the clinically normal elderly from those with mild cognitive impairment

“…On the other hand, these items might be useful in combination with other items derived from similar analyses in preclinical and prodromal AD clinical trials, which consist of similar samples, as sensitive IADL outcome measures. IADL impairment in individuals across the early AD spectrum, including CN, MCI, and mild AD dementia, has been associated with multiple AD biomarkers, including measures of atrophy, hypometabolism, cortical amyloid, and cerebrospinal fluid amyloid-beta 1-42, total tau, and phospho-tau [28][29][30][31][32][33]. The current study did not include AD biomarkers in the classification of diagnoses (the classification was based solely on clinical information).…”