XIAO LUO1, Yerfan Jiaerken2, Minming Zhang2, Juan Zhou3
1Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, 2The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, 3Duke-National University of Singapore Medical School, Singapore, Singapore
Subjective memory concern (SMC) refers to elderly who perceive decline in memory but exhibit a normal performance at objective neuropsychological assessments . Previous work demonstrate that SMC is associated with higher amyloid burden and may be accompanied with behavioral symptoms such as depression [2, 3]. However, most studies were cross-sectional and thus failed to identify SMC individuals who subsequently converted to mild cognitive impairment (MCI) or Alzheimer's disease (AD). Given the possible additive effect of cerebrovascular disease on neurodegeneration, it is largely unknown whether individuals with SMC have greater white matter hyperintensities (WMH) at baseline and over time. More importantly, few studies have investigated whether and how WMH, together with brain atrophy, amyloid burden and behavioral disturbance, relate to clinical progression and cognitive decline in SMC. To cover this gap, here we sought to test the hypothesis that WMH plays an important role in the clinical progression of SMC.
We analyzed data from 170 cognitively intact elderly in the ADNI database, including 69 SMC individuals and 101 normal controls (NC) matched in age, gender, education, and vascular risk factors. Clinical progression was determined by global clinical dementia rating (CDR). Out of 69 SMC individuals, 54 subjects were divided into stable SMC (S-SMC) and 19 progressive SMC (P-SMC, who convert to MCI patients over time). We segmented WMH from individual FLAIR image and quantified the periventricular WMH (PWMH) and deep WMH (DWMH) for both time points of each participant. Grey matter (GM) probability maps at baseline and follow-up was also derived. To examine the interaction between group and time, we performed ANOVA analysis followed by post-doc paired T-tests on WMH measures (p<0.05 Bonferroni corrected) and GM probability maps (p < 0.001 height and p<0.05 extent corrected) separately.
Moreover, the global mean Florbetapir PET amyloid deposition, behavioral symptoms (depression and Neuropsychiatric Inventory, NPI) and cognition were assessed at baseline and compared between S-SMC and P-SMC. We built logistic regression model to evaluate whether amyloid SUVR, WMH burden, GM atrophy, and behavioral problems at baseline are predictive of clinical progression in SMC (i.e., changes in global CDR over two years as dependent variables), controlling for demographic and vascular risk factors.
At baseline, the three groups did not differ in global cognitive ability (MMSE), functional activities, NPI scores, and CDR scores. At baseline, both SMC groups had higher amyloid deposition, and PWMH burden compared to NC while P-SMC had higher DWMH and depression score than NC (Fig.1 left). Longitudinally, although both SMC groups had increased PWMH volume, P-SMC group had greater increase in DWMH volume relative to the other groups (Fig. 1 right). Furthermore, though no group difference at baseline, accelerated atrophy in the middle temporal gyrus (MTG) and precuneus was found in P-SMC compared to NC and S-SMC (Fig. 2); while S-SMC did not differ from NC in terms of atrophy.
More importantly, logistic regression analysis revealed that baseline depression score and PWMH volume (but not atrophy and amyloid) predicted the two-year clinical progression of SMC participants (91.2% accuracy). Similarly, increased PWMH burden predicted general cognitive decline over time (MMSE) in SMC individuals (Model R2=0.07). Greater amyloid burden at baseline was associated with faster brain atrophy in MTG and precuneus regions over time across SMC individuals.
·Figure 2. Individuals with progressive subjective memory concern (SMC) had accelerate atrophy compared to stable SMC and controls.
·Figure 1. Baseline and progression of WMH volume in individuals with subjective memory concern during two-year follow-up.
Progressive SMC is accompanied with higher DWMH burden and more brain atrophy in the temporal and precuneus regions over time. SMC individuals with more severe depression problems and greater WMH burden are at higher risk of disease progression and cognitive decline. Our findings shed new insights on the important role of cerebrovascular disease in the preclinical stage of the disease.
Disorders of the Nervous System:
Alzheimer's Disease and Other Dementias 1
Modeling and Analysis Methods:
Classification and Predictive Modeling 2
1|2Indicates the priority used for review