The effect of surface dyslexia genes in semantic dementia
Abstract
People with surface dyslexia have difficulty reading exception words and are unable to recall the meaning and pronunciation of words. Recent research has found three genes, KIAA0319, CNTNAP2, and DCDC2, that play an important role in dyslexia. Several studies already have looked into the relation between these dyslexia genes and types of primary progressive aphasia (PPA) and forms of dementia. Although the neural basis of surface dyslexia in semantic dementia (SD), gradual loss of semantic memory, has been studied, the dyslexia genes were not taken into account. That is why it is proposed to study the effect of surface dyslexia genes in semantic dementia. 8 SD patients, 8 patients with surface dyslexia, and 8 healthy controls shall be included in this study. With the use of gene study, within the genes of interest there should be searched for single nucleotide polymorphisms (SNP’s). With the use of MRI the brain regions of interest (mainly the temporal regions) should be examined for atrophy. Finally with the use of language tasks it should be determined whether the patients perform worse than the healthy control. It is expected that the patients have similar SNP’s, atrophy locations, and language impairments.
Introduction
Surface dyslexia
Surface dyslexia is a form of dyslexia or reading disorder. Patients who suffer from this type of dyslexia have difficulty reading exception words, these are words that do not follow the pronunciation rules. Also, individuals with surface dyslexia are unable to recall a word’s pronunciation from memory and they cannot read a word as a whole. These patients rely heavily on the pronunciation rules in language, this way they can read regular words (e.g., move) and non-words (e.g., yatchet) without any trouble. However, irregular words (exception words) such as dove (pronounced as “doove”), pint (pronounced as mint), or chaos (“ch” pronounced as in church) are quite difficult for these individuals to pronounce.
The dual-route model of reading can give some insight on this disfunction. This model consists of a route for lexical-semantic conversion (used for irregular words) and grapheme-phoneme conversion (used for regular and nonsense words). In patients suffering from surface dyslexia, the grapheme-phoneme route is preserved which enables these patients to read and pronounce regular and nonsense words, while the lexical-semantic route is impaired which leads to these individuals reading irregular words as regular ones.
Recent research has found several genes that are involved in dyslexia, mainly the KIAA0319 gene, CNTNAP2 gene, and the DCDC2 gene. The KIAA0319 gene, which is associated to reading, causes grey matter (GM) and white matter (WM) atrophy in the left middle and inferior temporal gyri, which correspond to language areas.1 These polymorphisms were mostly found in patients with primary progressive aphasia (PPA) and with frontotemporal dementia (FTD). It has been found that the CNTNAP2 gene, associated with autism and schizophrenia, causes reduced cortical thickness in the left insula and left temporal regions.2,3 Lastly the DCDC2 gene has been found to affect WM volume in the pathways connecting the middle temporal gyrus with the inferior parietal lobe.4 Extensive research has been done on the relation between these dyslexia susceptibility genes and several PPA and forms of dementia. Also, the presence of symptoms of dyslexia in PPA and dementia patients has been studied in various papers. However, this has not been studied in every PPA or subform of dementia, such as semantic dementia.
Semantic dementia
Dementia is a broad term for a gradual loss of memory, of which semantic dementia (SD) is a subtype, a far less frequently occurring subtype that is. Patients with SD lose information from semantic memory, which stores knowledge about the world, places, people and meaning of words and objects. Lesion studies and voxel-based morphometry have shown GM and WM atrophy in the left anterior temporal lobe, lateral and medial temporal regions, and fusiform gyri.5 SD has been less researched compared to Alzheimer’s disease (AD) and is seen as the temporal-lobe variant of frontotemporal lobar degeneration, or as the fluent variant of PPA.5 In SD in these areas it is typically the WM that degenerates, especially in the left frontotemporal lobe.6
Surface dyslexia has been described as one of the side effects of SD. Patients with SD show semantic impairment and are having difficulty in reading words with an irregular spelling. Patients with SD and surface dyslexia read these irregular words as they are spelled, however, there is no impairment in reading regular words and non-words. Furthermore speech fluency, syntax, and phonology are spared.7 Also in the case of both SD and surface dyslexia, atrophy is present in the temporal regions, and language areas.
As stated before, extensive research has been done on the role of dyslexia in PPA and several forms of dementia, with the dyslexia susceptibility genes kept in mind.2 But not in the case of SD, while the neural basis of surface dyslexia has been researched in SD,7 these dyslexia genes were not taken into account. Therefore it is proposed to research what the impact is of (surface) dyslexia susceptibility genes in semantic dementia. The hypothesis is that variants in the dyslexia genes (KIAA0319, CNTNAP2, DCDC2) are present in SD and cause atrophy in the same brain regions as in SD, namely in the temporal regions and language regions.
Methods and expected results
Participants
8 SD patients, 8 patients with surface dyslexia, and 8 healthy participants shall be included in this study. The patients and participants must be evaluated somatically and neurologically, and should be able to give their informed consent.
Genetic analysis
DNA should be isolated from tissue samples, such as oral mucosa or blood, following standard procedures. Within the genes of interest (KIAA0319, CNTNAP2, DCDC2) there should be searched for single nucleotide polymorphisms (SNP’s) that are located on these genes. This should be done for both SD patients and patients with surface dyslexia to determine whether the same variant or mutation is present on these genes in both SD and surface dyslexia, and for the healthy control group to determine that they have not these SNP’s.
MRI
With the use of MRI it should be determined in which brain areas atrophy is present. This should be the case for the temporal gyri, fusiform gyri, left anterior temporal lobe, lateral and medial temporal regions, and left frontotemporal lobe. MRI is a good structural imaging technique for this because it can distinguish between GM and WM, which is important for the left frontotemporal lobe because there is only WM atrophy present there. Furthermore, MRI has a good spatial resolution and is able to image the gyri which is necessary for the temporal and fusiform gyri.
Verb-generation task and reading task
The patients will perform two tasks, the verb-generation task where they need to respond to a word with a verb (e.g. cake – eat), and the reading task where they need to read out loud. With the use of fMRI the BOLD in the temporal and fusiform gyri, the two regions that are involved in semantic memory, can be examined during these tasks. Also the tasks themselves will indicate whether the patients have trouble naming a verb in the verb-generation task and whether it is difficult for them to read the word out loud during the reading task.
Expected results
It is expected that SD patients and patients with surface dyslexia have similar SNP’s on the KIAA0319, CNTNAP2, and DCDC2 gene and that the control group of healthy participants does not have these SNP’s. MRI is expected to show atrophy in the same brain areas of SD patients and patients with surface dyslexia, namely the temporal gyri, fusiform gyri, left anterior temporal lobe, lateral and medial temporal regions, and left frontotemporal lobe. No atrophy is expected in the healthy control group. Finally from the verb-generation task and reading task the same language impairment is expected to show up in both patients, that is, having difficulty generating a verb in the verb-generation task and having trouble reading words out loud compared to the healthy control group.