Identification of candidate genes for developmental colour agnosia in a single unique family.

Colour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was performed, and linkage analysis was carried out using DominantMapper, resulting in the identification of 19 cosegregating chromosomal regions. Whole exome sequencing resulted in 11 rare coding variants present in all affected family members with developmental colour agnosia and absent in unaffected members. These variants affected genes that have been implicated in neural processes and functions (CACNA2D4, DDX25, GRINA, MYO15A) or that have an indirect link to brain function, development or disease (MAML2, STAU1, TMED3, RABEPK), and a remaining group lacking brain expression or involved in non-neural traits (DEPDC7, OR1J1, OR8D4). Although this is an explorative study, the small set of candidate genes that could serve as a starting point for unravelling mechanisms of higher level cognitive functions and cortical specialization, and disorders therein such as developmental colour agnosia.

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease.

Importance: Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. Objective: To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. Design, Setting, and Participants: This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Main Outcomes and Measures: Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. Results: This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed. Conclusions and Relevance: In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline.

Late-onset Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Presenting With Auditory Agnosia.

INTRODUCTION: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder that usually presents in childhood. Patients can have a wide array of neurological symptoms when presenting with stroke-like episodes, and imaging characteristics during the episodes can overlap with different neurological disorders. CASE REPORT: A 61-year-old woman presented with communication difficulties consistent with auditory agnosia and was found to have bitemporal abnormalities on imaging that first raised the concern for herpes simplex virus encephalitis. Further work-up, in conjunction with the patient's past medical and family history, suggested a mitochondrial disorder. Mitochondrial full genome analysis revealed m.3243A>G variant in the MT-TL1 gene, with 6% heteroplasmy in blood leading to a diagnosis of MELAS. CONCLUSIONS: MELAS is a disorder with clinical variability. Neuroimaging studies during stroke-like episodes in MELAS can provide significant clues to the underlying disorder. Although patients typically present in childhood, the first stroke-like episode can occur later in life in some patients, potentially related to a lower heteroplasmy level.

The mitochondrial DNA 10197 G > A mutation causes MELAS/Leigh overlap syndrome presenting with acute auditory agnosia.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes/Leigh (MELAS/LS) overlap syndrome is a mitochondrial disorder subtype with clinical and magnetic resonance imaging (MRI) features that are characteristic of both MELAS and Leigh syndrome (LS). Here, we report an MELAS/LS case presenting with cortical deafness and seizures. Cranial MRI revealed multiple lesions involving bilateral temporal lobes, the basal ganglia and the brainstem, which conformed to neuroimaging features of both MELAS and LS. Whole mitochondrial DNA (mtDNA) sequencing and PCR-RFLP revealed a de novo heteroplasmic m.10197 G > A mutation in the NADH dehydrogenase subunit 3 gene (ND3), which was predicted to cause an alanine to threonine substitution at amino acid 47. Although the mtDNA m.10197 G > A mutation has been reported in association with LS, Leber hereditary optic neuropathy and dystonia, it has never been linked with MELAS/LS overlap syndrome. Our patient therefore expands the phenotypic spectrum of the mtDNA m.10197 G > A mutation.

Two cases of selective developmental voice-recognition impairments.

Recognizing other individuals is an essential skill in humans and in other species. Over the last decade, it has become increasingly clear that person-identity recognition abilities are highly variable. Roughly 2% of the population has developmental prosopagnosia, a congenital deficit in recognizing others by their faces. It is currently unclear whether developmental phonagnosia, a deficit in recognizing others by their voices, is equally prevalent, or even whether it actually exists. Here, we aimed to identify cases of developmental phonagnosia. We collected more than 1,000 data sets from self-selected German individuals by using a web-based screening test that was designed to assess their voice-recognition abilities. We then examined potentially phonagnosic individuals by using a comprehensive laboratory test battery. We found two novel cases of phonagnosia: AS, a 32-year-old female, and SP, a 32-year-old male; both are otherwise healthy academics, have normal hearing, and show no pathological abnormalities in brain structure. The two cases have comparable patterns of impairments: both performed at least 2 SDs below the level of matched controls on tests that required learning new voices, judging the familiarity of famous voices, and discriminating pitch differences between voices. In both cases, only voice-identity processing per se was affected: face recognition, speech intelligibility, emotion recognition, and musical ability were all comparable to controls. The findings confirm the existence of developmental phonagnosia as a modality-specific impairment and allow a first rough prevalence estimate.

Olfactory functions scale with circuit restoration in a rapidly reversible Alzheimer's disease model.

Neural circuits maintain a precise organization that is vital for normal brain functions and behaviors, but become disrupted during neurological disease. Understanding the connection between wiring accuracy and function to measure disease progression or recovery has been difficult because of the complexity of behavioral circuits. The olfactory system maintains well-defined neural connections that regenerate throughout life. We previously established a reversible in vivo model of Alzheimer's disease by overexpressing a humanized mutated amyloid precursor protein (hAPP) in olfactory sensory neurons (OSNs). Using this model, we currently show that hAPP is present in the OSN axons of mutant mice, which exhibit strong caspase3 signal and reduced synaptic protein expression by 3 weeks of age. In the olfactory bulb, we show that glomerular structure is distorted and OSN axonal convergence is lost. In vivo functional imaging experiments further demonstrate disruption of the glomerular circuitry, and behavioral assays reveal that olfactory function is significantly impaired. Because OSNs regenerate, we also tested if the system could recover from hAPP-induced disruption. We found that after 1 or 3 weeks of shutting-off hAPP expression, the glomerular circuit was partially restored both anatomically and functionally, with behavioral deficits similarly reversed. Interestingly, the degree of functional recovery tracked directly with circuit restoration. Together, these data demonstrate that hAPP-induced circuit disruption and subsequent recovery can occur rapidly and that behavior can provide a measure of circuit organization. Thus, olfaction may serve as a useful biomarker to both follow disease progression and gauge potential recovery.

Critical evaluation of mouse models used to study pain and loss of pain perception in diabetic neuropathy.

A number of studies have addressed diabetic neuropathy (DN) in transgenic and knock out mouse models to unravel the molecular mechanisms underlying metabolic pain and loss of pain perception. However, it is difficult to compare these studies with each other or even with human DN due to experimental differences including the type of diabetes, the background strain of the respective mouse model, the methods of diabetes induction and the duration of diabetes, animal age and gender. To receive useful information for DN from genetically modified mice, it is therefore mandatory to first define the appropriate model and - if necessary - to backcross transgenic strains into the respective background to allow a reliable (and at least in part translatable to human DN) interpretation of the results.

Curiouser and curiouser: genetic disorders of cortical specialization.

The processes by which cortical areas become specialized for high-level cognitive functions may be revealed by the study of familial developmental disorders such as dyslexia, dyscalculia, prosopagnosia, color agnosia and amusia. These disorders are characterised by the inability to integrate information across multiple areas and the consequent failure to develop representations of the knowledge of some category based on its associated attributes. In contrast, synesthesia may be seen as a hyper-associative condition, possibly due to a failure to properly segregate areas into distinct networks. Here, I consider recent advances in our understanding of the genetic and neurobiological bases of these conditions and the developmental mechanisms underlying the specialization of cortical areas and networks.

Reversible loss of neuronal marker protein expression in a transgenic mouse model for sinusitis-associated olfactory dysfunction.

BACKGROUND: Chronic rhinosinusitis (CRS) is among the most common causes of olfactory loss. The loss of the sense of smell is thought to result from structural and functional changes occurring in the olfactory epithelium caused by inflammation. However, the cellular mechanisms underlying CRS-associated olfactory loss remain incompletely understood. METHODS: Transgenic mice expressing TNF-alpha specifically within the olfactory epithelium were used as a model for CRS-associated olfactory loss. TNF-alpha expression was induced over different time intervals, and olfactory epithelial tissue was assessed for the expression of neuronal markers by laser scanning confocal microscopy and Western blot. RESULTS: TNF-alpha expression results in an inflammatory infiltrate in the olfactory epithelium, thinning of the olfactory neuron layer, and a progressive loss of olfactory function. Reduced expression of markers for neurons and mature olfactory neurons (neural cell adhesion molecule [NCAM] and olfactory marker protein [OMP], respectively) was observed in the neuroepithelium and in the subepithelial axon bundles. Expression of growth-associated protein (GAP) 43, a marker for immature neurons, was also reduced. These alterations were reversed when TNF-alpha expression was discontinued. CONCLUSION: TNF-alpha expression in a transgenic model of CRS-associated olfactory loss results in progressive loss of olfactory neurons. Decreased GAP-43 expression suggests that TNF-alpha-associated inflammation inhibits differentiation of progenitor cells into immature olfactory neurons. Therefore, reduced regeneration of olfactory neurons may be an important mechanism underlying olfactory loss in CRS, in addition to neuronal loss or apoptosis. This mouse model represents a potential tool in the development of novel therapeutic strategies for the prevention of olfactory neuron loss in CRS.

Prefrontal cortex function in nonpsychotic siblings of individuals with schizophrenia.

BACKGROUND: Cognitive dysfunction is a hallmark feature of schizophrenia. In recent years, it has been proposed that impairments in attention, working memory and executive function may all reflect an underlying deficit in context processing. In individuals with schizophrenia, deficits in context processing have been associated with functional impairments of the dorsolateral prefrontal cortex (DLPFC). METHODS: We used a variation of the continuous performance task, the AX-CPT, to test the hypothesis that genetic high-risk individuals (full siblings of individuals with schizophrenia) have deficits in context processing and abnormal activation of the DLPFC as compared to community controls. RESULTS: Siblings of individuals with schizophrenia made significantly more B-X errors on the AX-CPT, indicative of a deficit in context processing. They also showed task-related hyper-activation in a number of brain regions, including the DLPFC. CONCLUSIONS: Inefficient hyper-activation of the DLPFC may underlie deficits in context processing and contribute to the genetic vulnerability for developing schizophrenia.

Early visual processing deficits in dysbindin-associated schizophrenia.

BACKGROUND: Variation at the dysbindin gene (DTNBP1) has been associated with increased risk for schizophrenia in numerous independent samples and recently with deficits in general and domain-specific cognitive processing. The relationship between dysbindin risk variants and sensory-level deficits in schizophrenia remains to be explored. We investigated P1 performance, a component of early visual processing on which both patients and their relatives show deficits, in carriers and noncarriers of a known dysbindin risk haplotype. METHODS: Event-related potential responses to simple visual isolated-check stimuli were measured using high-density electrical scalp recordings in 26 individuals meeting DSM-IV criteria for schizophrenia, comprising 14 patients who were carriers of the dysbindin risk haplotype and 12 patients who were nonrisk haplotype carriers. RESULTS: Carriers of the dysbindin risk haplotype demonstrated significantly reduced P1 amplitudes compared with noncarriers. A large effect size of d = .89 was calculated for the difference in P1 amplitude over scalp sites where the deficit was maximal. CONCLUSIONS: The P1 deficits associated with a dysbindin risk haplotype previously identified in our sample presents functional confirmation of its deleterious effect on brain activity. Building on evidence of dysbindin's role in higher cognitive function, these early visual processing deficits suggest a generalized role for dysbindin in brain function and is likely to be part of the mechanism by which illness susceptibility is mediated.

Nonverbal delayed recognition in the relatives of schizophrenia patients with or without schizophrenia spectrum.

BACKGROUND: There is increased interest in the study of cognitive deficits as possible endophenotypic markers for schizophrenia. The main goal of this study was to determine how familiality and schizophrenia spectrum personality symptomatology are related to performance of auditory and visuospatial delayed recognition memory tasks. METHODS: The study sample consisted of 162 subjects divided into five groups. The groups included 39 patients with a DSM-IV diagnosis of schizophrenia or schizophreniform disorder; first-degree relatives of schizophrenia patients, 22 with and 31 without schizophrenia spectrum personality traits; and healthy control subjects with no family history of psychosis, 22 with and 48 without schizophrenia spectrum traits. Auditory and visuospatial delayed recognition memory performance was assessed. RESULTS: Significant differences were observed between patients and healthy control subjects in both auditory [F(1,79) = 7.358 p = .008] and visual [F(1,47) = 34.67, p < .001] delayed recognition tasks. When comparing the four non-patient groups, auditory and visuospatial discriminability decreased as a function of familiality of schizophrenia (p < .05). Deficits were more pronounced in relatives with schizophrenia spectrum traits [auditory d = .7114; visual d = 1.0199]. CONCLUSIONS: A biological relationship to schizophrenia increases the likelihood of impaired delayed recognition memory. Likewise, poorer performance is associated with schizophrenia spectrum phenotype only when combined with familiality.

Neural substrates of olfactory processing in schizophrenia patients and their healthy relatives.

Odorants represent powerful stimuli capable of eliciting various emotional responses. In schizophrenia patients and their non-affected relatives, olfactory and emotional functions are impaired, revealing a familial influence on these deficits. We aimed at determining the neural basis of emotional olfactory dysfunctions using odors of different emotional valence for mood induction and functional magnetic resonance imaging (fMRI) by comparing 13 schizophrenia patients, their non-affected brothers and 26 matched healthy controls. Blood-oxygen-level-dependent (BOLD) effects and subjective mood changes were assessed during negative (rotten yeast), positive (vanilla) and neutral (ambient air) olfactory stimulation. Group comparisons of brain activation were performed in regions of interest. Subjective ratings were comparable between groups and indicated successful mood induction. However, during stimulation with the negative odor, hypofunctional activity emerged in regions of the right frontal and temporal cortex in the patients. A familial influence in the neural substrates of negative olfactory dysfunction was indicated by a similar reduced frontal brain activity in relatives. Dysfunctions therefore appeared to be located in regions involved in higher cognitive processes associated with olfaction. No familial influences were indicated for cerebral dysfunctions during positive olfactory stimulation. Results point to a differentiation between trait and state components in cerebral dysfunctions during emotional olfactory processing in schizophrenia.

Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease.

Alzheimer's disease is associated with progressively dysfunctional gene expression in the limbic system of the brain. The thalamus and primary visual cortex are thought to be initially spared of Alzheimer-type changes that ravage the association neocortex. In this study, using DNA arrays and Western immunoassay, gene expression patterns were examined in the thalamus and primary visual cortex of moderate-stage and late-stage Alzheimer's disease and age-matched controls using a set of proinflammatory genes known to be upregulated in the temporal lobe neocortex and hippocampus of moderate-stage Alzheimer's disease. The data indicate that, in late-stage Alzheimer's disease, proinflammatory and proapoptotic gene expression spreads into the primary visual sensory cortex. This upregulation of pathological gene expression could be, in part, responsible for the visual disturbances associated with end-stages of the Alzheimer process.

Family resemblance: ten family members with prosopagnosia and within-class object agnosia.

We report on neuropsychological testing done with a family in which many members reported severe face recognition impairments. These 10 individuals were high functioning in everyday life and performed normally on tests of low-level vision and high-level cognition. In contrast, they showed clear deficits with tests requiring face memory and judgements of facial similarity. They did not show deficits with all aspects of higher level visual processing as all tested performed normally on a challenging facial emotion recognition task and on a global-local letter identification task. On object memory tasks requiring recognition of particular cars and guns, they showed significant deficits so their recognition impairments were not restricted to facial identity. These results strongly suggest the existence of a genetic condition leading to a selective deficit of visual recognition.

An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism.

BACKGROUND: During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay. METHODS: Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. RESULTS: The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion. CONCLUSION: Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.

Sanfilippo type D presenting with acquired language disorder but without features of mucopolysaccharidosis.

A 7-year-old girl presented with a language disorder reminiscent of verbal auditory agnosia. Later, she proved to have defective N-acetylglucosamine-6-sulfate sulfatase, the enzyme deficient in Sanfilippo D syndrome. She did not show clinical features of mucopolysaccharidosis. The language disorder had a fluctuating course, which eventually evolved into a progressive dementing encephalopathy.