Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer’s Disease

Abstract

The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer’s disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study–Cognition Study (mean age = 79.2±3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p < 0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5 × 10−8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person’s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

“…The113 participants with dementia met the criteria for dementia based on standard diagnostic criteria (see Methods section) and had both cognitive changes from baseline and disability related to their cognitive changes. They also differed from the normals on brain MRI, especially hippocampal volume and ventricular size [49]. …”

“…Lower hippocampal volume and higher ventricular grade, a marker of brain ‘atrophy’, were determinants of dementia in the CHS-CS [49]. We have previously reported that specific volumetric brain loss evaluated by Voxel-based morphometry was associated with time to both MCI and dementia in the CHS-CS [50].…”

“…We have previously reported that specific volumetric brain loss evaluated by Voxel-based morphometry was associated with time to both MCI and dementia in the CHS-CS [50]. …”

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

“…The latter is one of the first and most severely affected areas (Braak and Braak, 1997) and the memory loss characteristic of AD is generally thought to be due to neuronal degeneration in the hippocampus (Carli et al, 1997). Although there are some morphological changes that occur in the hippocampus as a result of normal aging, numerous studies have demonstrated particular pathological alterations associated specifically with AD (Ohnishi et al, 2001;Salat et al, 2001;Zeifman et al, 2014). Degradation in the cortices and hippocampus is characterized by a gradual decline in volume of gray matter (Irish et al, 2013;Möller et al, 2013;Ohnishi et al, 2001;Salat et al, 2011).…”

Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment

“…However, other brain regions may also be valuable for the prediction of progression, as indicated by voxel-based morphometry studies [ 13 – 15 ]. Two previous studies have used hypothesis-free voxel-level survival analyses to show that decreased gray matter in the medial temporal lobe and posterior cingulate cortex can predict time to conversion to AD-type dementia in nondemented subjects [ 16 , 17 ]. However, it is still unclear whether such predictive atrophy patterns are specific for amyloid pathology.…”