Objective Age-related cognitive decline trajectories were compared in apolipoprotein E (APOE) e4 homozygotes (HMZ), heterozygotes (HTZ), and noncarriers (NC) in the absence of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). Background At how young an age memory decline diverges from that of noncarriers in healthy people with elevated genetic risk for late-onset AD due to APOE e4 is unknown. Methods Cognitively normal participants age 21-97 years were recruited with local ads, grouped using an APOE e4 enrichment paradigm, and had longitudinal neuropsychological testing. Anyone who developed MCI or dementia during followup was excluded. Acceleration of the rates of decline for predetermined cognitive measures were compared between APOE e4/4 HMZ, e3/4 HTZ, and e4 NC using a mixed model for longitudinal change with age. Results 79 e4 HMZ, 238 HTZ and 498 NC were included. APOE e4 carriers were younger (mean 58.0 vs 61.4 years, p<0.001) and had more years of followup (5.3 v 4.7 years, p=0.01), with equivalent education (15.4 years) and gender (69% women). With accelerating declines beginning prior to age 60 in e4 carriers, longitudinal decline in memory in e4 carriers accelerated more than in NC (p=0.0253) with a possible e4 gene-dose effect (p=0.0231) in which longitudinal decline in e4 HMZ accelerated more than in NC (p=0.0087). Weaker similar effects were also found on a visuospatial and general mental status measure. Conclusions Age-related memory decline in APOE e4 carriers diverges from NC prior to age 60 and appears most severe in HMZ despite ongoing normal clinical status.

To examine the validity of different theoretical assumptions about the neuropsychological mechanisms and lesion correlates of phonological dyslexia and dysgraphia, we studied written and spoken language performance in a large cohort of patients with focal damage to perisylvian cortical regions implicated in phonological processing. Despite considerable variation in accuracy for both words and non-words, the majority of participants demonstrated the increased lexicality effects in reading and spelling that are considered the hallmark features of phonological dyslexia and dysgraphia. Increased lexicality effects were also documented in spoken language tasks such as oral repetition, and patients performed poorly on a battery of phonological tests that did not involve an orthographic component. Furthermore, a composite measure of general phonological ability was strongly predictive of both reading and spelling accuracy, and we obtained evidence that the continuum of severity that characterized the written language disorder of our patients was attributable to an underlying continuum of phonological impairment. Although patients demonstrated qualitatively similar deficits across measures of written and spoken language processing, there were quantitative differences in levels of performance reflecting task difficulty effects. Spelling was more severely affected than reading by the reduction in phonological capacity and this differential vulnerability accounted for occasional disparities between patterns of impairment on the two written language tasks. Our findings suggest that phonological dyslexia and dysgraphia in patients with perisylvian lesions are manifestations of a central or modality-independent phonological deficit rather than the result of damage to cognitive components dedicated to reading or spelling. Our results also provide empirical support for shared-components models of written language processing, according to which the same central cognitive systems support both reading and spelling. Lesiondeficit correlations indicated that phonological dyslexia and dysgraphia may be produced by damage to a variety of perisylvian cortical regions, consistent with distributed network models of phonological processing.

Although normalization of brain images is critical to the analysis of structural damage across individuals, loss of tissue due to focal lesions presents challenges to the available normalization algorithms. Until recently, cost function masking, as advocated by Brett and colleagues (2001), was the accepted method to overcome difficulties encountered when normalizing damaged brains; however, development of the unified segmentation approach for normalization in SPM5 (Ashburner & Friston, 2005) offered an alternative. Crinion et al. (2007) demonstrated this approach produced normalization results without cost function masking that appeared to be robust to lesion effects when tested using the same simulated lesions studied by Brett et al. (2001). The present study sought to confirm the validity of this approach in brains with focal damage due to vascular events. To do so, we examined outcomes of normalization using unified segmentation with and without cost function masking in 49 brain images with chronic stroke. Lesion masks were created using two approaches (precise and rough drawings of lesion boundaries), and normalization was implemented with both smoothed and unsmoothed versions of the masks. We found that failure to employ cost function masking produced less accurate results in real and simulated lesions, compared to masked normalization, both in terms of deformation field displacement and voxelwise intensity differences. Additionally, unmasked normalization led to significant underestimation of lesion volume relative to all four masking conditions, especially in patients with large lesions. Taken together, these findings suggest cost function masking is still necessary when normalizing brain images with chronic infarcts.