Tracking atrophy progression in familial Alzheimer's disease: A serial MRI study
Dementia Research Centre, University College London, Institute of Neurology, London, UK. The Lancet Neurology
(Impact Factor: 21.9).
11/2006; 5(10):828-34. DOI: 10.1016/S1474-4422(06)70550-6
Serial MRI scanning of autosomal dominant mutation carriers for Alzheimer's disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimer's disease progresses from the presymptomatic stage through to diagnosis.
Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimer's disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed.
Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimer's disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis.
Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimer's disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.
Available from: Abigail Andrews
- "This suggests that acceleration of atrophy starts both some time after the build-up of significant amyloid load, and at least 18 months before symptom onset, in keeping with the current model of biomarker progression (Jack et al., 2013 ). Several longitudinal studies have demonstrated acceleration of brain atrophy in symptomatic familial Alzheimer's disease (Chan et al., 2003; Ridha et al., 2006), and sporadic MCI or Alzheimer's disease (Jack et al., 2008b; Leung et al., 2013; Schuff et al., 2009 ). Carlson and colleagues reported that rates of ventricular enlargement in healthy controls increased more than 2 years before the emergence of clinical cognitive impairment (Carlson et al., 2008). "
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ABSTRACT: Increased rates of brain atrophy measured from serial magnetic resonance imaging precede symptom onset in Alzheimer's disease and may be useful outcome measures for prodromal clinical trials. Appropriate trial design requires a detailed understanding of the relationships between β-amyloid load and accumulation, and rate of brain change at this stage of the disease. Fifty-two healthy individuals (72.3 ± 6.9 years) from Australian Imaging, Biomarkers and Lifestyle Study of Aging had serial (0, 18 m, 36 m) magnetic resonance imaging, (0, 18 m) Pittsburgh compound B positron emission tomography, and clinical assessments. We calculated rates of whole brain and hippocampal atrophy, ventricular enlargement, amyloid accumulation, and cognitive decline. Over 3 years, rates of whole brain atrophy (p < 0.001), left and right hippocampal atrophy (p = 0.001, p = 0.023), and ventricular expansion (p < 0.001) were associated with baseline β-amyloid load. Whole brain atrophy rates were also independently associated with β-amyloid accumulation over the first 18 months (p = 0.003). Acceleration of left hippocampal atrophy rate was associated with baseline β-amyloid load across the cohort (p < 0.02). We provide evidence that rates of atrophy are associated with both baseline β-amyloid load and accumulation, and that there is presymptomatic, amyloid-mediated acceleration of hippocampal atrophy. Clinical trials using rate of hippocampal atrophy as an outcome measure should not assume linear decline in the presymptomatic phase.
Available from: Chelcie Heaney
- "Mounting evidence suggests that there is considerable overlap of many key features between T2DM and the two leading types of dementia, including the aggregation of Ab proteins, increased tau phosphorylation, altered glycogen synthase kinase-3b activity (GSK-3b), increased oxidative stress, altered insulin signaling, and vascular abnormalities (Li and Holscher, 2007). The vast majority of transgenic AD models are based on a number of mutations that exist in three genes, the APP (amyloid precursor protein), presenilin-1 and presenilin-2, that lead to earlyonset (<60 years) AD, however, these mutations only account for 1% of AD cases (Ridha et al., 2006). The vast majority of AD cases are sporadic in origin (sporadic AD) and are less clearly influenced by a single mutation but rather some combination of many potential genetic and environmental risk factors (Pedersen et al., 2004 ), which includes T2DM and insulin perturbations. "
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ABSTRACT: Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 μL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABAB1, kalirin-9, and β-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.
Copyright © 2015. Published by Elsevier Ltd.
Available from: Pieter Jelle Visser
- "immediately preceding diagnosis). Our results further correspond with the observation that the earliest pathological changes in AD usually occur in the medial temporal lobe regions, which are known to be critical for episodic memory functioning (Ridha et al. 2006; Sluimer et al. 2009). Moreover, our established multi-domain decline in pre-demented subjects also matches findings of spread pathology before AD diagnosis, indicating that multiple brains structures, like the parietal (Jacobs et al. 2011), and frontal cortex (Burgmans et al. 2009) are affected. "
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ABSTRACT: We investigated the course of decline in multiple cognitive domains in non-demented subjects from a memory clinic setting, and compared pattern, onset and magnitude of decline between subjects who progressed to Alzheimer's disease (AD) dementia at follow-up and subjects who did not progress.
In this retrospective cohort study 819 consecutive non-demented patients who visited the memory clinics in Maastricht or Amsterdam between 1987 and 2010 were followed until they became demented or for a maximum of 10 years (range 0.5-10 years). Differences in trajectories of episodic memory, executive functioning, verbal fluency, and information processing speed/attention between converters to AD dementia and subjects remaining non-demented were compared by means of random effects modelling.
The cognitive performance of converters and non-converters could already be differentiated seven (episodic memory) to three (verbal fluency and executive functioning) years prior to dementia diagnosis. Converters declined in these three domains, while non-converters remained stable on episodic memory and executive functioning and showed modest decline in verbal fluency. There was no evidence of decline in information processing speed/attention in either group.
Differences in cognitive performance between converters to AD dementia and subjects remaining non-demented could be established 7 years prior to diagnosis for episodic memory, with verbal fluency and executive functioning following several years later. Therefore, in addition to early episodic memory decline, decline in executive functions may also flag incident AD dementia. By contrast, change in information processing speed/attention seems less informative.
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