Cognitive Pathology Research Articles

Abstract W P116: Cerebrovascular and Alzheimer’s Pathologies Combined in Mouse Models of Mixed Dementia Alter the Progression of Memory Impairment and Disease

Dementia is most often attributed to Alzheimer’s disease (~70%) or vascular dementia (~17%), yet 20-50% of dementia cases share aspects of both. Better understanding of dementias within this spectrum can improve diagnosis, inform interpretation of clinical data confounded by co-morbidity, and direct therapeutic approaches. We hypothesized that combined pathologies alter the time-course of memory impairment and the expression of primary disease pathology. We compared and combined aspects of cerebrovascular disease (chronic cerebral hypoperfusion) and Alzheimer’s disease (transgene-driven tau or amyloid pathology). We induced chronic cerebral hypoperfusion by wrapping each common carotid artery with a microcoil that remains in situ and reduces cerebral blood flow to approximately 80%; a procedure called bilateral carotid artery stenosis (BCAS). To create conditions of mixed dementia, we performed BCAS in two transgenic models of Alzheimer’s pathology; the rTg4510 which overexpresses mutant human tau, and APP/PS1 that develops ß-amyloid pathology. Transgenic mice and their wildtype littermates received BCAS or sham surgeries near the onset of pathology survived 1 or 6 months, or during advanced pathology and survived 1 month. This generated 12 experimental groups (n of 4-11 each). We evaluated spatial memory impairment, neuroimmune phenotype, white matter integrity, tau pathology and ß-amyloid pathology. The progression of memory impairment and disease pathology is altered in the mixed dementia models, and these changes are relative to the age of onset and duration of hypoperfusion. For example, hypoperfusion has a larger impact on spatial memory impairment in aged APP/PS1 mice. Additionally, BCAS reduced the expression of CD86, an immune marker associated with a de-activated immune state, only in rTg4510 mice. These findings highlight changes in the time-course of cognitive impairment and pathology that might be expected in the substantial clinical population with co-morbid vascular and Alzheimer’s dementias.

FUNCTIONAL PERFORMANCE IN THE COMPLEX ACTIVITIES OF DAILY LIVING: CHANGE AND LOSS PROFILE IN A HEALTHY AGED POPULATION

female and 78 male (age 72,31 Std 8,29 , instruction 8,6 Std 3.9) of which 104 have no cognitive pathology (control group); 49 subjects withMCI clinical diagnosis and 66 with mild/ moderate AD.The control group was evaluated with a General Cognitive Screening (Adas Cog) and MMSS. We established a cut point of 26 for the MMSS and normal performance in Adas Cog.An Anova analysis has been carried out considering the number of clusters, number of switching, number of exemplars and clusters size in the three groups.Results:The ANOVA analysis showed that: exemplars number, cluster and switching number are significant variables to identify the EA, MCI and Control groups. It was significant (Pr (>F) 1⁄4 .001) to distinguish between the means of the Control Group (8.23), MCI (5.18) and EA (3.64). It was also relevant the ANOVA of switchings (Pr (>F) 1⁄4 .001): Control Group (10.1), MCI (6.59) and EA (5.36). The cluster size distinguished the control group from MCI and EA , but not between them. Conclusions: The results obtained constitute a significant contribution to the knowledge of the normal and pathological lexical processing. The study of the clusters’organization in semantic fluency tasks might provide a new important marker in the clinical diagnosis profile of MCI patients.

Аутоімунна реакція проти нейроспецифічних білків та якість життя пацієнтів з уродженою вадою серця

The results of experimental investigation of autoimmune reaction targeted against neirospecific protein antigens in patients with congenital heart failure are presented. It is shown that titer for autoanibodies to these patients’ brain proteins is significantly higher compared with healthy persons. Elevation of titer of these autoantibodies is correlated with the ability to solve tasks for revealing complex analogies and decrease of life quality. Therefore, worsening of life quality and development of cognitive deficit in patients with cardiovascular diseases might be associated with autoimmune reaction against specific proteins of nervous tissue cells. The results obtained demonstrate that generation of autoantibodies in patients with congenital heart failure is linked with the cognitive deficit. One of the most important causes of cognitive decline could be hypoxia state due to surgery intervention. Consequences of hypoxia, in their turn, are accompanied by chronic oxidative stress. Molecular and cell injuries induced by free radicals are known to be the widely spread cause of various pathologies. Further investigations for validation of diagnostic hallmarks for estimation of the origin of progression of the cognitive deficit in patients with congenital heart failure are needed. These studies will allow clarifying mechanisms of influence of hypoxia-induced injuries associated with the aggravation of oxidative stress in nervous tissue cells. Understanding of relationship between decline of cognitive function and pathologies of cardiovascular system is necessary for more precise clinical diagnostics of the early prevention of possible complications and proper treatment of patients.

Williams Syndrome As a Model for Elucidation of the Pathway Genes - the Brain - Cognitive Functions: Genetics and Epigenetics

Genomic diseases or syndromes with multiple manifestations arise spontaneously and unpredictably as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture. The Williams syndrome is believed to be one of the most attractive models for linking genes, the brain, behavior and cognitive functions. It is a neurogenetic disorder resulting from a 1.5 Mb deletion at 7q11.23 which covers more than 20 genes; the hemizigosity of these genes leads to multiple manifestations, with the behavioral ones comprising three distinct domains: 1) visuo-spatial orientation; 2) verbal and linguistic defect; and 3) hypersocialisation. The shortest observed deletion leads to hemizigosity in only two genes: eln and limk1. Therefore, the first gene is supposed to be responsible for cardiovascular pathology; and the second one, for cognitive pathology. Since cognitive pathology diminishes with a patient's age, the original idea of the crucial role of genes straightforwardly determining the brain's morphology and behavior was substituted by ideas of the brain's plasticity and the necessity of finding epigenetic factors that affect brain development and the functions manifested as behavioral changes. Recently, non-coding microRNAs (miRs) began to be considered as the main players in these epigenetic events. This review tackles the following problems: is it possible to develop relatively simple model systems to analyze the contribution of both a single gene and the consequences of its epigenetic regulation in the formation of the Williams syndrome's cognitive phenotype? Is it possible to use Drosophila as a simple model system?

Celebrating the Work of William T. Carpenter Jr

Celebrating the Work of William T. Carpenter Jr

INTER-SPECIES GLIA DIFFERENCES: IMPLICATIONS FOR SUCCESSFUL TRANSLATION OF TRANSGENIC RODENT ALZHEIMER’S DISEASE MODEL TREATMENT USING BEXAROTENE

Despite a multitude of efficacious treatments for the cognitive symptoms and pathology in transgenic mouse models of Alzheimer's disease (AD), success in human trials has been elusive. Rodent-human brain dissimilarities may help explain failures of past human trials and improve outcomes of future ones. This review highlights the essential role of the human brain's exceptional myelination in achieving and maintaining optimal brain functions, as well as underlying its vulnerability to age-related myelin breakdown and the degenerative brain diseases that process can trigger. This alternative myelin-centered perspective is used herein to help explain key disconnects in the existing treatment literature by focusing on recent reports on brain effects of bexarotene, the only marketed retinoid X receptor (RXR) agonist. The myelin perspective exposes significant yet underexplored opportunities for novel treatment and prevention interventions that have the potential to considerably reduce the tremendous burden of degenerative brain diseases.

Interplay of Cognitive Efficiency, Cognitive Ability and Motivation

The current body of research often focuses on the problem of cognitive decline through ageing. People adapt to these changes of cognitive resources by using brain reserve. An overview of results of different studies on how cognitive abilities of older adults decline highlights high variability of conclusions and sometimes contradiction but it has been shown older adults can be as good as or even better than younger participants in specific domains. Among others, personal meaningfulness of a situation and closeness to the researcher can be strong factors when assessing cognitive abilities and the aim of this paper was to research how these effect cognitive efficiency. In the pilot study we eliminated the factor of laboratory setting and checked how cognitive efficiency and abilities change in relation to motivation. Forty-eight participants, divided into two age groups, were asked to pass a proverb interpretation test. The results showed that participant's subjective view on the researcher, perceived closeness, correlated with the adequacy in proverb interpretation. Both groups scored higher on adequacy of interpretation when they perceived to be close to the researcher. The younger adults outperformed the older but those in the older adults' group, who felt to be close to the researcher scored as well as younger adults who didn't perceived to be close to the researcher. This motivational reserve might play a role in assessing cognitive abilities and pathologies that affect the outcome of neuropsychological tests.

Pathophysiology of epileptic encephalopathies

The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.

Cognitive Reserve and Cortical Plasticity

The term “cognitive reserve” describes resistance to the deterioration of cognitive functions in the dementia and other brain degradation of brain substance. Cognitive resistance is measured behaviorally, while neuropathological damage is assessed histologically and by imagistic methods or based on markers.The study of cognitive reserve suggests that innate intelligence or life experiences (such as educational and professional achievements) may increase this reserve in the form of sets of behavioral skills that allow subjects to manage better than others cognitive pathology of a certain kind (e.g., Alzheimer disease). In these circumstances the psychological intervention for cognitive practice since the beginning of the pathology could contribute substantially to establishing or increasing the cognitive reserve.

Schizophrenia and frontotemporal dementia: Shared causation?

The relationship between specific genes and particular diseases in neuropsychiatry is unclear, and newer studies focus on shared domains of neurobiological and cognitive pathology across different disorders. This paper reviews the evidence for an association between schizophrenia and frontotemporal dementia, including symptom similarity, familial co-morbidity, and neuroanatomical changes. Genetic as well as epigenetic findings from both schizophrenia and frontotemporal dementia are also discussed. As a result, we introduce the hypothesis of a shared susceptibility for certain subgroups of schizophrenia and frontotemporal dementia. This common causation may involve the same gene(s) at different stages of life: early in schizophrenia and late in frontotemporal dementia. Additionally, we provide a rationale for future research that should emphasize both genetic and cognitive parallels between certain forms of schizophrenia and frontotemporal dementia in a synergistic, coordinated way, placing both in the context of aberrant lateralization patterns.

The Function of Metabotropic Glutamate Receptors in Thalamus and Cortex

Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies.

Can Neurostimulation Prevent the Risk of Alzheimer's Disease in Elderly Individuals with Schizophrenia?

As patients with schizophrenia live longer, because of better medical management, suicide prevention, and appropriate nutrition, we are beginning to face a new phenomenon: elderly patients with chronic schizophrenia developing Alzheimer's disease. In the past two decades several neurostimulation methods have been introduced in psychiatry. These include transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and transcranial direct current stimulation (tDCS). To date only TMS and tDCS have been used in the treatment of positive, negative, and cognitive symptoms of schizophrenia (1). These treatment modalities show promise to decrease the risk of Alzheimer's disease in elderly individuals with schizophrenia, but in order to optimize their benefits it is essential to recognize the differences in the cognitive pathology involved. Since it is possible that specific neurostimulatory modalities or sites of stimulation affect different regions of the brain or domains of neurocognitive pathology in a different manner, it is necessary to have a better understanding of the cognitive deficits in each condition.

Neurocognitive functioning in young high-risk offspring having a parent with bipolar I disorder

To investigate attention, memory, verbal-linguistic ability, and executive functions in symptom-free young offspring having a parent with bipolar I disorder (BD1O) in comparison with healthy controls (CO). Materials and methods: Thirty symptom-free BD1O and 37 CO were recruited. The groups (both all participants and those >=11 years of age) were well-matched for age, sex, IQ, and years of education. The neurocognitive battery included the Rey Auditory Verbal Learning and Memory Test, Controlled Word Association Test, Digit Span Test, Trail Making Test, Auditory Consonant Trigram Test, Wisconsin Card Sorting Test, Stroop Test, and Test of Variables of Attention. Results: The BD1O group demonstrated impairments in psychomotor speed, focused attention, verbal attention, phonemic verbal fluency, short-term memory, and learning functions and performed marginally worse in divided attention, information processing, and working memory. No group difference was found in sustained attention, executive functions, or alternating attention. Conclusion: Divided attention, information processing, and working memory seem to be important in evaluating the cognitive pathology before the onset of affective psychopathology.

Executive attention deficits in schizophrenia: Putative mandatory and differential cognitive pathology domains in medicated schizophrenia patients

Executive attention (EA) is a core-construct of working memory (WM) capacity. EA performance is directly related to dorsolateral prefrontal cortex (DLPFC) activation, a neural mechanism that is dysfunctional in schizophrenia. We examined the differences in particular types of EA failure in schizophrenia patients and healthy controls. We evaluated executive attention in 60 medicated schizophrenia patients and 60 matched healthy individuals. We used a standard WM task, a verbal n-Back task, to measure executive attention (WM accuracy). Our standard-version WM task (control block, 10min long) was designed to examine baseline executive attention function and was followed by one out of three different experimental blocks (revised n-Back tasks). Baseline executive attention performance was significantly related to psychosis severity and functional capacity in the psychiatric group. In both healthy and psychiatric groups, experimental-block conditions revealed that domain-general recall had a differential effect on WM scores, and was related to the patient's clinical condition. Only in the psychiatric group domain-specific recall impairments were mandatory, most severe, and independent of baseline WM scores. The results revealed the importance of domain-general recall WM scores in the evaluation of executive attention deficits in patients and controls. Disruption in domain-specific recall may represent a specifier of cognitive impairment in schizophrenia spectrum disorders.

Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 mice

Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1ppm) but also levels previously considered to be low (<100ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic.

Local effects and global impact in neurotoxicity and neurodegeneration: The Xi’an International Neurotoxicology Conference

Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1 ppm) but also levels previously considered to be low (<100 ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50 ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50 ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic.

Don’t Leave Sleep in the Dark: A Call for Integrative Cognitive Models

This special issue includes empirical research on the relationship between sleep and cognition, focusing on a variety of populations: Young, middle-aged, and older adults with insomnia, and patients with chronic pain. The editors of this special issue note the overlap between the dysfunctional cognitions observed in people with sleep problems with the cognitions observed in a variety of psychological and medial disorders. The editors call for researchers to integrate sleep into our models of cognitive dysfunction, medical and psychological pathology and well being, paying particular attention to how sleep disturbances may maintain or exacerbate said pathologies.

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.

Reducing Prefrontal Gamma-Aminobutyric Acid Activity Induces Cognitive, Behavioral, and Dopaminergic Abnormalities That Resemble Schizophrenia

Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming. We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons. Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity. These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed in schizophrenia.

Neurocognitive sequelae in African American and Caucasian children with multiple sclerosis.

To examine domain-specific neurocognitive differences between African American (AA) and Caucasian (CA) patients with pediatric-onset multiple sclerosis (POMS). An extensive battery of neuropsychological tests was given to each subject, including tests in all major domains of cognitive function. Point-biserial correlations between ethnicity and test performance were computed. Significant correlations were followed up with hierarchical multiple regression analysis, accounting for clinical and demographic variables before examining ethnic differences. Forty-two patients with POMS including 20 AA and 22 CA subjects were assessed. The cohorts did not differ in age, gender, socioeconomic status, disease duration, disability score, immunoglobulin G index, or number of relapses in the first 2 years of disease. Retaining some of these variables as covariates in the hierarchical regression analysis, the AA cohort performed worse on measures of language (p < 0.001) and complex attention (p < 0.01) than their CA peers. AA patients with POMS may be at higher risk for adverse cognitive impact in the areas of language and complex attention. Longitudinal characterization of cognitive pathology is critical for the development of effective intervention strategies to prolong cognitive functioning in POMS cohorts.