Atrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials

Abstract

There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ∼1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ∼18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195–1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

“…Despite the small sample size and a cross-sectional design, the findings are consistent with the current study that there is an association between higher PiB retention at baseline and increased rates of cortical atrophy. Several longitudinal studies in non-demented older adults also support our finding that higher PiB retention at baseline is associated with greater atrophy rates (Chetelat et al, 2012;Andrews et al, 2013;Dore et al, 2013;Araque Caballero et al, 2015;Petersen et al, 2016).…”

“…Amyloid imaging with PiB retention and its relation to atrophy on MRI has been widely studied in Alzheimer's disease dementia (Archer et al, 2006;Jack et al, 2009;Chetelat et al, 2010), amnestic mild cognitive impairment and preclinical Alzheimer's disease (Andrews et al, 2013;Knopman et al, 2013;Petersen et al, 2013Petersen et al, , 2016Whitwell et al, 2013;Jack et al, 2014;Araque Caballero et al, 2015). Patients with probable DLB and Parkinson's disease dementia with high PiB retention have an Alzheimer's disease-like pattern of atrophy (Shimada et al, 2013) but longitudinal imaging studies investigating whether amyloid-b deposition influences rate of atrophy in patients with probable DLB are lacking.…”

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

“…This has been observed in many large-scale postmortem cohort studies of aging including the religious orders study (Arnold et al, 2013; Bennett, 2006; Schneider et al, 2009), the Nun Study (Tyas et al, 2007), the Baltimore Longitudinal study of Aging (O’Brien et al, 2009), and the Medical Research Council Cognitive Function and Ageing Study (Savva et al, 2009). Further, in human imaging studies using Pittsburgh Compound B positron emission tomography (PET) to assess amyloid deposition, amyloid is found in the brains of approximately 30% of cognitively normal aged individuals (Aizenstein et al, 2008; Andrews et al, 2013). This cognitive resilience in the face of pathological lesions could be due to a “reserve” of connectivity with many extra synapses perhaps resulting from a highly enriched lifestyle.…”

Ushering in the study and treatment of preclinical Alzheimer disease

“…In preclinical AD populations, high Aβ levels on PET imaging correlates with decreased performance on episodic memory and language assessments 148 and increased hippocampal atrophy rate 175 over 18 months. Additional follow-up is needed to assess the predictive value of high abnormal amyloid levels on PET imaging in cognitively healthy individuals for progression to MCI or AD dementia.…”