Acceleration of cortical thinning in familial Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the most common primary neurodegenerative dementia and an important, growing public health problem (Wimo et al., 2003). The familial, autosomal dominant form of AD (FAD) is associated with mutations in the amyloid precursor protein (APP), presenilin one (PSEN1) and presenilin two (PSEN2) genes and is rare, accounting for less than 1% of all cases (Campion et al., 1999). Mutations in PSEN1 and APP account for the majority of FAD in which a mutation is confirmed. FAD is a widely used paradigm for the sporadic, late onset form (SAD), with which it shares many neuropathological and clinical features (McKhann et al., 1984). It provides the opportunity to circumvent key research problems in AD such as the inability to predict in whom the disease will arise and antemortem diagnostic uncertainty.
In both FAD and SAD, AD pathology leads to neuronal degeneration and loss, producing profound regional cerebral atrophy which can be visualized in vivo using magnetic resonance imaging (MRI). MRI volumetry allows regional atrophy to be quantified. Very early changes have been demonstrated in the hippocampus and entorhinal cortex (ERC) in AD (Du et al., 2001, Fox et al., 1996), but the particular structure and/or technique which is most useful for early diagnosis remains unclear. Hippocampal and whole brain atrophy rates are significantly higher amongst carriers of pathogenic FAD mutations when compared to healthy controls, and the former difference pre-dates symptom onset by several years (Ridha et al., 2006). Detection and characterization of pathological change at such an early stage has important implications for diagnosis, prognosis and in evaluating treatment effects. However, almost all methods so far described involve time-consuming manual measurements which are subject to inter-rater variability and require expert anatomical knowledge.
Cortical thickness (CTh), is a potentially more stable marker than volume as the cytoarchitectural structure of the grey matter is less variable (Pakkenberg and Gundersen, 1997, Singh et al., 2006). Changes in the cortex are a well-established consequence of AD pathology with layer II of the ERC and layer III of the neocortex affected (Gomez-Isla et al., 1996, Pearson et al., 1985). Furthermore, fully automated cortical surface reconstruction is now possible, providing detailed information on the thickness of the cortical ribbon. This technique is complementary to existing radiological tools, and may provide meaningful statistical and clinical information even in small groups (Lerch and Evans, 2005). Regional CTh, including that of the medial temporal lobe (MTL), left anterior cingulate, frontal and parietal lobes, correlates well with the severity and nature of clinical deficits (Thompson et al., 2003, Du et al., 2007, Dickerson et al., 2009) and its measurement continues to show promise as a clinical and research tool (Lerch et al., 2008). However, the potential of CTh as a biomarker in confirmed FAD mutation carriers has not yet been fully defined. The objective of this study was to examine longitudinal patterns of CTh in a cohort of initially presymptomatic FAD mutation carriers (MC) in a period which included symptom onset and clinical diagnosis of AD.
Section snippets
Subjects
In a previously described MRI study of atrophy progression in FAD (Ridha et al., 2006), 9 carriers (4 men) of autosomal dominant mutations associated with early-onset FAD (MC) underwent longitudinal volumetric MRI assessment (see Table 1). Five had mutations in APP (2 V717G, 2 V717I and 1 V717L; mean 4.3 years before clinical diagnosis at baseline scan, range 1.2–7.6; mean age at onset 52.7, range 48.0–61.1) and 4 in PSEN1 (2 delta 4, 1 L250S and 1 M139V; mean 4.2 years before clinical
Results
The nature of the decline in CTh with age was characterized using a mixed model (1) in the control group. There was no evidence that the decline varied between individuals in any region and so the random effects (b2i) were omitted from the models. Table 2 shows the estimated age-related decline in CTh in controls. For example, in the posterior cingulate, the mean CTh for a 50-year old is 4.46 − (0.014 × (50 − 45)) = 4.39 mm, where the age-related decline is estimated to be 0.014 mm/year. There was strong
Discussion
Using a fully automated method, we have measured CTh from serial brain MRI of FAD mutation carriers and age/sex-matched controls. CTh change was investigated via longitudinal analysis of six regions in relation to age and time of clinical diagnosis of AD. ROI were selected on the basis of existing evidence that they are significant in early AD and may provide an early signal of disease. Histopathological and structural imaging studies indicate that limbic and heteromodal association areas fall
Conflict of interest
We have no scientific and financial conflicts of interest to declare.
Acknowledgements
The authors are extremely grateful to Ged Ridgway of the Centre for Medical Image Computing, University College London, UK for his assistance in illustrating results. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Dementia Research Centre is an Alzheimer's Research Trust Co-ordinating Centre. This work was also funded by the Medical Research Council UK. NCF holds an MRC Senior
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2018, Alzheimer's and DementiaCitation Excerpt :The “step change” model provides the most conservative estimate of when atrophy rates diverge. In contrast, the “gradual acceleration” model is probably more biologically plausible, based on previous results in ADAD [4,7,31,32] and by the well-characterized spatial spread of neurodegeneration [33] that typically begins in the medial temporal lobe and gradually spreads into neocortical regions. However, there are caveats to the gradual acceleration model used.
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2017, Biological PsychiatryCitation Excerpt :This is consistent with previous studies (39) that failed to find an effect of APOE on ERC thickness in a healthy middle-aged and older adult population. Conversely, the small increase in PCG thickness was unexpected because both manifest AD and genetic risk status have been associated with thinning of this area (59,60). Replication of this finding in future studies would be needed before strong conclusions can be drawn.
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