100 research outputs found

    Rates of Decline in Alzheimer Disease Decrease with Age

    No full text
    <div><p>Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ<sub>1–42</sub>, tau, and phospho-tau<sub>181p</sub> (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.</p> </div

    Number of participants in each age group, for each class of measure analyzed, separately for longitudinal and baseline analyses.

    No full text
    <p>Clin  =  clinical measure: ADAS-Cog, CDR-SB, MMSE. CSF data were obtained at baseline for approximately half the study sample. Note that in each age bracket, age extends up to, but does not include, the highest age indicated (age groups do not overlap).</p

    Mixed effects model fit for annual rates of clinical decline, allowing for linear change with age.

    No full text
    <p>Data points plotted, with 95% confidence intervals, are independent estimates of rates of change for successive 5-year intervals for a mixed effects model fit without an age-dependent term. Slopes and p-values of the linear fits for each diagnostic group are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042325#pone-0042325-t003" target="_blank">Table 3</a>. Legend: red  = AD; blue  =  MCI; green  = HC.</p

    Estimated sample sizes with respect to age, per arm, to detect a 25% reduction in rate of change in MCI participants relative to age-matched change in HCs, at the p<0.05 level with 80% power assuming a 24 month trial with scans every six months.

    Get PDF
    <p>Sample sizes are estimated using a linear mixed effects model with fixed intercepts (no relative change at baseline) and random slopes and linear dependence on age applied to all data available up through 36 months. Dashed lines show the 95% confidence intervals.</p

    MCI participant demographic and baseline data.

    No full text
    <p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone-0047739-t001" target="_blank">Tables 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone-0047739-t003" target="_blank">3</a> for key. MCI: mild cognitive impairment.</p>‡<p>Two MCI participants were not classified for MRI<sup>+/−</sup> due to technical issues; both had cognitive data and were Aβ<sup>+</sup>; 1 was ptau<sup>−</sup>, the other ptau<sup>+</sup>.</p>*<p>166 (53.4%) of the 311 MCI subjects had CSF Aβ data. All have ptau; includes the two in <sup>‡</sup>.</p>$<p>167 (53.7%) of the 311 MCI subjects had CSF ptau data. One of these does not have Aβ data, but has cognitive data and is ptau<sup>+</sup>MRI<sup>+</sup>. The 167 include the two in <sup>‡</sup>.</p><p>∧Only 75 MRI<sup>−</sup> had CSF Aβ and ptau data; only 89 MRI<sup>+</sup> had CSF Aβ data; 90 MRI<sup>+</sup> had ptau data.</p

    Annual atrophy rates for MCI participants, with 95% confidence intervals, for AD-relevant cortical and subcortical ROIs, grouped with respect to baseline Aβ, ptau, and volumetric MRI status (top row).

    No full text
    <p>In the bottom row, all participants are Aβ-positive. N is the number of participants. Numerical values are in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone.0047739.s001" target="_blank">File S1</a>, Tables S1A–F.</p

    Slopes and p-values for annual atrophy rates as a function of age shown in Figure 1.

    No full text
    <p>Bold underlined entries highlight slope values that significantly differ from zero. The three right hand columns give p-values for differences in slopes between cohorts. Two-sample t-test for independent samples with unequal variances (Satterthwaite’s method <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042325#pone.0042325-Rosner1" target="_blank">[37]</a>) was used to calculate p-values for pair-wise comparisons (last three columns).</p

    Slopes and p-values for annual rates of clinical decline as a function of age shown in Figure 2.

    No full text
    <p>Bold underlined entries highlight slope values that significantly differ from zero. The three right hand columns give p-values for differences in slopes between cohorts. P-values for the last three columns were calculated as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042325#pone-0042325-t002" target="_blank">Table 2</a>.</p

    Estimated sample sizes with respect to age, per arm, to detect a 25% reduction in rate of change in MCI participants relative to age-matched change in HCs, at the p<0.05 level with 80% power assuming a 24 month trial with scans every six months.

    No full text
    <p>Sample sizes are estimated using a linear mixed effects model with fixed intercepts (no relative change at baseline) and random slopes and linear dependence on age applied to all data available up through 36 months. Dashed lines show the 95% confidence intervals.</p

    P-values for significance of difference in sample size estimates (Table 3, Figure 3) from pairs of measures (rows) using particular enrichment specifications (columns).

    No full text
    <p>Values significant at the 5% level are underlined and bold. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone-0047739-t003" target="_blank">Tables 3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone-0047739-t004" target="_blank">4</a> legends for key.</p><p>Calculation of p-values described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047739#pone.0047739-Holland1" target="_blank">[50]</a>.</p
    corecore