Genetic underpinnings in Alzheimer's disease - a review.

In this review, we discuss the genetic etiologies of Alzheimer's disease (AD). Furthermore, we review genetic links to protein signaling pathways as novel pharmacological targets to treat AD. Moreover, we also discuss the clumps of AD-m ediated genes according to their single nucleotide polymorphism mutations. Rigorous data mining approaches justified the significant role of genes in AD prevalence. Pedigree analysis and twin studies suggest that genetic components are part of the etiology, rather than only being risk factors for AD. The first autosomal dominant mutation in the amyloid precursor protein (APP) gene was described in 1991. Later, AD was also associated with mutated early-onset (presenilin 1/2, PSEN1/2 and APP) and late-onset (apolipoprotein E, ApoE) genes. Genome-wide association and linkage analysis studies with identified multiple genomic areas have implications for the treatment of AD. We conclude this review with future directions and clinical implications of genetic research in AD.

Mathematics, anxiety, and the brain.

Given that achievement in learning mathematics at school correlates with work and social achievements, it is important to understand the cognitive processes underlying abilities to learn mathematics efficiently as well as reasons underlying the occurrence of mathematics anxiety (i.e. feelings of tension and fear upon facing mathematical problems or numbers) among certain individuals. Over the last two decades, many studies have shown that learning mathematical and numerical concepts relies on many cognitive processes, including working memory, spatial skills, and linguistic abilities. In this review, we discuss the relationship between mathematical learning and cognitive processes as well as the neural substrates underlying successful mathematical learning and problem solving. More importantly, we also discuss the relationship between these cognitive processes, mathematics anxiety, and mathematics learning disabilities (dyscalculia). Our review shows that mathematical cognition relies on a complex brain network, and dysfunction to different segments of this network leads to varying manifestations of mathematical learning disabilities.

The thalamus as a relay station and gatekeeper: relevance to brain disorders.

Here, we provide a review of behavioural, cognitive, and neural studies of the thalamus, including its role in attention, consciousness, sleep, and motor processes. We further discuss neuropsychological and brain disorders associated with thalamus function, including Parkinson's disease, Alzheimer's disease, Korsakoff's syndrome, and sleep disorders. Importantly, we highlight how thalamus-related processes and disorders can be explained by the role of the thalamus as a relay station.

Neural substrates and potential treatments for levodopa-induced dyskinesias in Parkinson's disease.

Parkinson's disease (PD) is primarily a motor disorder that involves the gradual loss of motor function. Symptoms are observed initially in the extremities, such as hands and arms, while advanced stages of the disease can effect blinking, swallowing, speaking, and breathing. PD is a neurodegenerative disease, with dopaminergic neuronal loss occurring in the substantia nigra pars compacta, thus disrupting basal ganglia functions. This leads to downstream effects on other neurotransmitter systems such as glutamate, γ-aminobutyric acid, and serotonin. To date, one of the main treatments for PD is levodopa. While it is generally very effective, prolonged treatments lead to levodopa-induced dyskinesia (LID). LID encompasses a family of symptoms ranging from uncontrolled repetitive movements to sustained muscle contractions. In many cases, the symptoms of LID can cause more grief than PD itself. The purpose of this review is to discuss the possible clinical features, cognitive correlates, neural substrates, as well as potential psychopharmacological and surgical (including nondopaminergic and deep brain stimulation) treatments of LID.

The cerebellum and psychiatric disorders.

The cerebellum has been considered for a long time to play a role solely in motor coordination. However, studies over the past two decades have shown that the cerebellum also plays a key role in many motor, cognitive, and emotional processes. In addition, studies have also shown that the cerebellum is implicated in many psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorders, schizophrenia, bipolar disorder, major depressive disorder, and anxiety disorders. In this review, we discuss existing studies reporting cerebellar dysfunction in various psychiatric disorders. We will also discuss future directions for studies linking the cerebellum to psychiatric disorders.

Corrigendum: Homocysteine levels in schizophrenia and affective disorders-focus on cognition.

[This corrects the article on p. 343 in vol. 8, PMID: 25339876.].

Impairments of working memory in schizophrenia and bipolar disorder: the effect of history of psychotic symptoms and different aspects of cognitive task demands.

Comparisons of cognitive impairments between schizophrenia (SZ) and bipolar disorder (BPD) have produced mixed results. We applied different working memory (WM) measures (Digit Span Forward and Backward, Short-delay and Long-delay CPT-AX, N-back) to patients with SZ (n = 23), psychotic BPD (n = 19) and non-psychotic BPD (n = 24), as well as to healthy controls (HC) (n = 18) in order to compare the level of WM impairments across the groups. With respect to the less demanding WM measures (Digit Span Forward and Backward, Short-delay CPT-AX), there were no between group differences in cognitive performance; however, with respect to the more demanding WM measures (Long-delay CPT-AX, N-back), we observed that the groups with psychosis (SZ, psychotic BPD) did not differ from one another, but performed poorer than the group without a history of psychosis (non-psychotic BPD). A history of psychotic symptoms may influence cognitive performance with respect to WM delay and load effects as measured by Long-delay CPT-AX and N-back tests, respectively. We observed a positive correlation of WM performance with antipsychotic treatment and a negative correlation with depressive symptoms in BPD and with negative symptoms in SZ subgroup. Our study suggests that WM dysfunctions are more closely related to a history of psychosis than to the diagnostic categories of SZ and BPD described by psychiatric classification systems.

Homocysteine levels in schizophrenia and affective disorders-focus on cognition.

Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.

Impulse control disorders in Parkinson's disease are associated with dysfunction in stimulus valuation but not action valuation.

A substantial subset of Parkinson's disease (PD) patients suffers from impulse control disorders (ICDs), which are side effects of dopaminergic medication. Dopamine plays a key role in reinforcement learning processes. One class of reinforcement learning models, known as the actor-critic model, suggests that two components are involved in these reinforcement learning processes: a critic, which estimates values of stimuli and calculates prediction errors, and an actor, which estimates values of potential actions. To understand the information processing mechanism underlying impulsive behavior, we investigated stimulus and action value learning from reward and punishment in four groups of participants: on-medication PD patients with ICD, on-medication PD patients without ICD, off-medication PD patients without ICD, and healthy controls. Analysis of responses suggested that participants used an actor-critic learning strategy and computed prediction errors based on stimulus values rather than action values. Quantitative model fits also revealed that an actor-critic model of the basal ganglia with different learning rates for positive and negative prediction errors best matched the choice data. Moreover, whereas ICDs were associated with model parameters related to stimulus valuation (critic), PD was associated with parameters related to action valuation (actor). Specifically, PD patients with ICD exhibited lower learning from negative prediction errors in the critic, resulting in an underestimation of adverse consequences associated with stimuli. These findings offer a specific neurocomputational account of the nature of compulsive behaviors induced by dopaminergic drugs.

Cognitive correlates of psychosis in patients with Parkinson's disease.

INTRODUCTION: Psychosis and hallucinations occur in 20-30% of patients with Parkinson's disease (PD). In the current study, we investigate cognitive functions in relation to the occurrence of psychosis in PD patients. METHODS: We tested three groups of subjects - PD with psychosis, PD without psychosis and healthy controls - on working memory, learning and transitive inference tasks, which are known to assess prefrontal, basal ganglia and hippocampal functions. RESULTS: In the working memory task, results show that patients with and without psychosis were more impaired than the healthy control group. In the transitive inference task, we did not find any difference among the groups in the learning phase performance. Importantly, PD patients with psychosis were more impaired than both PD patients without psychosis and controls at transitive inference. We also found that the severity of psychotic symptoms in PD patients [as measured by the Unified Parkinson Disease Rating Scale Thought Disorder (UPDRS TD) item] is directly associated with the severity of cognitive impairment [as measured by the mini-mental status exam (MMSE)], sleep disturbance [as measured by the Scales for Outcome in Parkinson Disease (SCOPA) sleep scale] and transitive inference (although the latter did not reach significance). CONCLUSIONS: Although hypothetical, our data may suggest that the hippocampus is a neural substrate underlying the occurrence of psychosis, sleep disturbance and cognitive impairment in PD patients.

Iodine deficiency in Egyptian autistic children and their mothers: relation to disease severity.

BACKGROUND AND AIMS: Because autism may be a disease of early fetal brain development, maternal hypothyroxinemia (HT) in early pregnancy secondary to iodine deficiency (ID) may be related to etiology of autism. The aim of the study was to assess the iodine nutritional status in Egyptian autistic children and their mothers and its relationship with disease characteristics. METHODS: Fifty autistic children and their mothers were studied in comparison to 50 controls. All subjects were subjected to clinical evaluation, measurement of urinary iodine (UI), free triiodothyronine (fT3), free tetraiodothyronine (fT4) and thyroid-stimulating hormone (TSH) along with measurement of thyroid volume (TV). In addition, electroencephalography (EEG) and intelligence quotient (IQ) assessment were done for all autistic children. RESULTS: Of autistic children and their mothers, 54% and 58%, respectively, were iodine deficient. None of the control children or their mothers was iodine deficient. UI was lower among autistic patients (p <0.001) and their mothers (p <0.001). Childhood Autism Rating Scale (CARS) score correlated negatively with UI (r = -0.94, p <0.001). Positive correlations were detected between autistic patients and their mothers regarding UI (r = 0.88, p <0.001), fT3 (r = 0.79, p = 0.03), fT4 (r = 0.91, p <0.001) and TSH (r = 0.69, p = 0.04). Autism had a significant risk for association with each of low UI (OR: 9.5, 95% CI: 2.15-33.8, p = 0.02) and intake of noniodized salt (OR: 6.82, 95% CI = 1.36-34.27, p = 0.031). CONCLUSIONS: ID is prevalent in Egyptian autistic children and their mothers and was inversely related to disease severity and could be related to its etiology.

Factors underlying probabilistic and deterministic stimulus-response learning performance in medicated and unmedicated patients with Parkinson's disease.

OBJECTIVE: Prior studies have not tested individual differences or effects of medication dosage on stimulus-response learning in patients with Parkinson's disease (PD). In the current study, we investigated the effects of motor variables (including tremor, akinesia, and disease duration) as well as dopaminergic medication dosage on learning in unmedicated PD patients, medicated PD patients, and healthy controls. METHOD: We tested all subjects on probabilistic and deterministic learning tasks, and also collected awareness measures data using postexperimental questionnaires. Importantly, we tested learning performance in tremor-dominant and akinesia-dominant PD patients, and further correlated learning performance with disease duration and medication dosage. RESULTS: Results show that akinesia-dominant patients were more impaired than tremor-dominant patients at probabilistic reward- but not punishment-based learning, which is in agreement with prior studies of the relationship between akinesia and basal ganglia dysfunction. We also found no difference between medicated and unmedicated PD patients in reward- or punishment-based deterministic learning, but medicated patients were better than unmedicated patients at reward-based probabilistic learning. Our results show that awareness measures explain differences among probabilistic and deterministic learning performance. Moreover, we found that disease duration and motor severity are inversely correlated, and medication dosage is positively correlated, with reward-based probabilistic learning. CONCLUSION: Our results suggest that stimulus-response learning performance in patients with PD depends on the type of learning (probabilistic vs. deterministic), medication status (on vs. off medication, dopaminergic medication dosage), disease duration as well as motor severity and subtype in PD patients (tremor- vs. akinesia-dominant).

The effects of clinical motor variables and medication dosage on working memory in Parkinson's disease.

In this study, we investigate the interrelationship between clinical variables and working memory (WM) in Parkinson's disease (PD). Specifically, the aim of the study was to investigate the relationship between disease duration, dopaminergic medication dosage, and motor disability (UPDRS score) with WM in individuals with PD. Accordingly, we recruited three groups of subjects: unmedicated PD patients, medicated PD patients, and healthy controls. All subjects were tested on three WM tasks: short-delay WM, long-delay WM, and the n-back task. Further, PD encompasses a spectrum that can be classified either into akinesia/rigidity or resting tremor as the predominant motor presentation of the disease. In addition to studying medication effects, we tested WM performance in tremor-dominant and akinesia-dominant patients. We further correlated WM performance with disease duration and medication dosage. We found no difference between medicated and unmedicated patients in the short-delay WM task, but medicated patients outperformed unmedicated patients in the long-delay WM and n-back tasks. Interestingly, we also found that akinesia-dominant patients were more impaired than tremor-dominant patients at various WM measures, which is in agreement with prior studies of the relationship between akinesia symptom and basal ganglia dysfunction. Moreover, the results show that disease duration inversely correlates with more demanding WM tasks (long-delay WM and n-back tasks), but medication dosage positively correlates with demanding WM performance. In sum, our results show that WM impairment in PD patients depend on cognitive domain (simple vs. demanding WM task), subtype of PD patients (tremor- vs. akinesia-dominant), as well as disease duration and medication dosage. Our results have implications for the interrelationship between motor and cognitive processes in PD, and for understanding the role of cognitive training in treating motor symptoms in PD.

The relationship between associative learning, transfer generalization, and homocysteine levels in mild cognitive impairment.

Previous studies have shown that high total homocysteine levels are associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). In this study, we test the relationship between cognitive function and total homocysteine levels in healthy subjects (Global Dementia Rating, CDR = 0) and individuals with MCI (CDR = 0.5). We have used a cognitive task that tests learning and generalization of rules, processes that have been previously shown to rely on the integrity of the striatal and hippocampal regions, respectively. We found that total homocysteine levels are higher in MCI individuals than in healthy controls. Unlike what we expected, we found no difference between MCI subjects and healthy controls in learning and generalization. We conducted further analysis after diving MCI subjects in two groups, depending on their Global Deterioration Scale (GDS) scores: individuals with very mild cognitive decline (vMCD, GDS = 2) and mild cognitive decline (MCD, GDS = 3). There was no difference among the two MCI and healthy control groups in learning performance. However, we found that individuals with MCD make more generalization errors than healthy controls and individuals with vMCD. We found no difference in the number of generalization errors between healthy controls and MCI individuals with vMCD. In addition, interestingly, we found that total homocysteine levels correlate positively with generalization errors, but not with learning errors. Our results are in agreement with prior results showing a link between hippocampal function, generalization performance, and total homocysteine levels. Importantly, our study is perhaps among the first to test the relationship between learning (and generalization) of rules and homocysteine levels in healthy controls and individuals with MCI.

Basal and adrenocorticotropic hormone stimulated plasma cortisol levels among Egyptian autistic children: relation to disease severity.

BACKGROUND: Autism is a disorder of early childhood characterized by social impairment, communication abnormalities and stereotyped behaviors. The hypothalamic-pituitary-adrenocortical (HPA) axis deserves special attention, since it is the basis for emotions and social interactions that are affected in autism. AIM: To assess basal and stimulated plasma cortisol, and adrenocorticotropic hormone (ACTH) levels in autistic children and their relationship to disease characteristics. METHODS: Fifty autistic children were studied in comparison to 50 healthy age-, sex- and pubertal stage- matched children. All subjects were subjected to clinical evaluation and measurement of plasma cortisol (basal and stimulated) and ACTH. In addition, electroencephalography (EEG) and intelligence quotient (IQ) assessment were done for all autistic children. RESULTS: Sixteen% of autistic patients had high ACTH, 10% had low basal cortisol and 10% did not show adequate cortisol response to ACTH stimulation. Autistic patients had lower basal (p = 0.032) and stimulated cortisol (p = 0.04) and higher ACTH (p = 0.01) than controls. Childhood Autism Rating Scale (CARS) score correlated positively with ACTH (r = 0.71, p = 0.02) and negatively with each of basal (r = -0.64, p = 0.04) and stimulated cortisol (r = -0.88, p < 0.001). Hormonal profile did not differ in relation to EEG abnormalities, IQ and self- aggressive symptoms. CONCLUSIONS: The observed hormonal changes may be due to a dysfunction in the HPA axis in autistic individuals. Further studies are warranted regarding the role of HPA axis dysfunction in the pathogenesis of autism.

Oxidative stress in Egyptian children with autism: relation to autoimmunity.

UNLABELLED: We are the first to study the relationship between oxidative stress (by measuring plasma F2-isoprostane, as a marker of lipid peroxidation, and glutathione peroxidase, as an antioxidant enzyme) and autoimmunity (as indicated by serum antineuronal antibodies) in a group of 44 Egyptian autistic children and 44 healthy matched-children. Our results showed that oxidative stress was found in 88.64% of autistic children. Oxidative stress, resulting from elevated plasma F2-isoprostane and/or reduced glutathione peroxidase, had significant risk for antineuronal positivity, which was found in 54.5% of autistic children, (odds ratio: 12.38 and 6.43, respectively, confidence interval: 1.37-112.10 and 1.21-34.19, respectively). CONCLUSIONS: the strong association between oxidative stress and autoimmunity in autistic children may indicate the possible role of oxidative stress, through induction of autoimmunity, in some autistic patients. Therefore, studies considering the role of antioxidants and immunotherapy in amelioration of autistic manifestations are recommended.