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Background The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. Objective To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. Design Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging–derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. Setting Multiple sclerosis center, University of Navarra, Pamplona, Spain. Patients Sixty-one patients with multiple sclerosis. Main Outcome Measure Mapping of WM regions contributing to GM atrophy in the optic pathway. Results Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. Conclusions Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

Background Gray matter (GM) atrophy has been reported in multiple sclerosis (MS). However, little is known about its regional distribution. Objective To investigate the regional distribution of GM atrophy in clinically early primary progressive MS (PPMS). Design and Patients Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied. All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only. Magnetic resonance images underwent an optimized voxel-based morphometric analysis that segments magnetic resonance data volumes in a normalized space and quantifies tissue atrophy on a voxel-by-voxel basis. A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions. A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study. Results At baseline, patients with PPMS displayed bilateral thalamic atrophy compared with controls. In addition, a significant association between lesion load and decreased GM volume was found for the thalami. Loss of GM in the putamen, caudate, thalami, and cortical and infratentorial areas was observed in patients after 1 year of follow-up. Conclusions Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to neurodegeneration. Cortical and infratentorial atrophy developed as the disease evolved.

Objective To characterize rates of regional Alzheimer disease (AD)–specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages. Design Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer’s Disease Neuroimaging Initiative. Setting Research centers across the United States and Canada. Patients We examined a total of 317 participants with baseline cerebrospinal fluid biomarker measurements and 3 T1-weighted magnetic resonance images obtained within 1 year. Main Outcome Measures We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile. Results In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants. Conclusions Alzheimer disease–specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers.