Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database

Abstract

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…MRS biomarkers that reflect the metabolic status of the brain may be better suited to demonstrate target engagement and follow response to treatment compared to biomarkers reflecting amyloid and Tau pathologies in AD. In the classification analyses between older CN and AD groups within this study, Glc outperformed all other MRS metabolites, and was comparable in performance to the whole brain CSF fraction representative of the atrophy and ventricular enlargement found in AD 38, 39, 40. Moreover, it is mechanistically relevant to a promising line of AD experimental therapeutics targeting glucose metabolism.…”

“…Aside from demonstrating the ability of J‐PRESS to replicate previous findings of lower NAA in AD, this study revealed substantial elevations in Glc, Lac, and Asc in the disease. The inclusion of Glc into classification models improved their accuracy beyond that of anatomical measurement of brain atrophy 38, 39, 40. Myo‐Inositol, while not differing between groups, was nevertheless reflective of several important clinical and laboratory measures of AD severity.…”

Patch-based segmentation using expert priors: Application to hippocampus and ventricle segmentation

“…In such patients, structural variability is increased as a result of the pathology, and this variability represents a challenge for segmentation techniques such as atlas warping. Ventricular volume has been shown to provide a useful marker of neuronal degeneration and thus could be used as an indicator of AD (Nestor et al, 2008). However, despite the high contrast between tissue and cerebrospinal fluid (CSF), various factors render ventricle segmentation difficult.…”

A novel MRI‐compatible brain ventricle phantom for validation of segmentation and volumetry methods

“…In particular, enlargement of the lateral ventricles (cerebrospinal fluid-filled cavities in the interior of the cerebral hemispheres) has been consistently demonstrated and may be among the most sensitive of imaging biomarkers of AD progression (2). This enlargement is a consequence of the disease process; as surrounding healthy brain tissues atrophy, there is a corresponding increase in cerebrospinal fluid (CSF) within the ventricles.…”