Visual and social differences in dyslexia: deep phenotyping of four cases with spared phonology

Diagnostic criteria for dyslexia describe specific reading difficulties, and single-deficit models, including the phonological deficit theory, have prevailed. Children seeking diagnosis, however, do not always show phonological deficits, and may present with strengths and challenges beyond reading. Through extensive neurological, neuropsychological, and academic evaluation, we describe four children with visuospatial, socio-emotional, and attention impairments and spared phonology, alongside long-standing reading difficulties. Diffusion tensor imaging revealed white matter alterations in inferior longitudinal, uncinate, and superior longitudinal fasciculi versus neurotypical children. Findings emphasize that difficulties may extend beyond reading in dyslexia and underscore the value of deep phenotyping in learning disabilities.</p

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

<div><p>Background</p><p>Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.</p><p>Methods and findings</p><p>Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (<i>n</i> = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02~DRB1*15</i>:<i>01~DQA1*01</i>:<i>02~DQB1*06</i>:<i>02</i> (<i>p</i> = 9.6 x 10⁻⁴, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E <i>(APOE</i>) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02</i> (<i>p</i> = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype <i>DRB1*15</i>:<i>01- DQA1*01</i>:<i>02- DQB1*06</i>:<i>02</i> (<i>DR15</i>) (<i>p</i> = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying <i>A*03</i>:<i>01~B*07</i>:<i>02</i> was associated with higher CSF amyloid levels (<i>p</i> = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the <i>DR15</i> haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [<i>p</i> = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [<i>p</i> = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of <i>DR15</i> was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (<i>p</i> = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes.</p><p>Conclusions</p><p>We provide evidence that variation in the HLA locus—including risk haplotype <i>DR15</i>—contributes to AD risk. <i>DR15</i> has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that <i>DR15</i>-associated mechanisms may contribute to pan-neuronal disease vulnerability.</p></div

Genes associated with frontotemporal dementia (FTD) and immune-mediated disease differentially altered in patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTD-U) versus controls.

<p>Genes associated with frontotemporal dementia (FTD) and immune-mediated disease differentially altered in patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTD-U) versus controls.</p