Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models.

It is well established that epilepsy is associated with numerous neurobehavioral comorbidities, with a bidirectional relationship; people with epilepsy have an increased incidence of depression, anxiety, learning and memory difficulties, and numerous other psychosocial challenges, and the occurrence of epilepsy is higher in individuals with those comorbidities. Although the cause-and-effect relationship is uncertain, a fuller understanding of the mechanisms of comorbidities within the epilepsies could lead to improved therapeutics. Here, we review recent data on epilepsy and its neurobehavioral comorbidities, discussing mainly rodent models, which have been studied most extensively, and emphasize that clinically relevant information can be gained from preclinical models. Furthermore, we explore the numerous potential factors that may confound the interpretation of emerging data from animal models, such as the specific seizure induction method (e.g., chemical, electrical, traumatic, genetic), the role of species and strain, environmental factors (e.g., laboratory environment, handling, epigenetics), and the behavioral assays that are chosen to evaluate the various aspects of neural behavior and cognition. Overall, the interplay between epilepsy and its neurobehavioral comorbidities is undoubtedly multifactorial, involving brain structural changes, network-level differences, molecular signaling abnormalities, and other factors. Animal models are well poised to help dissect the shared pathophysiological mechanisms, neurological sequelae, and biomarkers of epilepsy and its comorbidities.

Evidence of risky driving in Korean older adults: A longitudinal cohort.

OBJECTIVES: The aim of this study was to determine the differences in the risk factors for dangerous driving between older adults with normal cognition and those with cognitive impairment. DESIGN: The driving risk questionnaire (DRQ) that was applied to a community-dwelling older adult cohort and 2 years of accident/violation records from the National Police Agency were analyzed. We conducted regression analyses with the presence or absence of risky driving based on records (accidents + violations) 2 years before and after evaluation as a dependent variable and dichotomized scores of each risky driving factor as independent variables. RESULTS: According to four identified factors-crash history, safety concern, reduced mileage, and aggressive driving-significant associations were found between risky driving over the past 2 years and crash history and for aggressive driving in the normal cognition group. In the cognitive impairment group, only crash history was significantly associated, although safety concerns showed a trend toward significance. CONCLUSIONS: In this study, it was suggested that the factors of DRQ have a significant association with actual risky driving. Our results are expected to contribute to establishing the evidence for evaluating and predicting risky driving and advising whether to continue driving in clinics.

Why Are Perivascular Spaces Important?

Perivascular spaces (PVS) and their enlargement (EPVS) have been gaining interest as EPVS can be visualized non-invasively by magnetic resonance imaging (MRI) when viewing T-2-weighted images. EPVS are most commonly observed in the regions of the basal ganglia and the centrum semiovale; however, they have also been identified in the frontal cortex and hippocampal regions. EPVS are known to be increased in aging and hypertension, and are considered to be a biomarker of cerebral small vessel disease (SVD). Interest in EPVS has been significantly increased because these PVS are now considered to be an essential conduit necessary for the glymphatic pathway to provide the necessary efflux of metabolic waste. Metabolic waste includes misfolded proteins of amyloid beta and tau that are known to accumulate in late-onset Alzheimer's disease (LOAD) within the interstitial fluid that is delivered to the subarachnoid space and eventually the cerebral spinal fluid (CSF). The CSF acts as a sink for accumulating neurotoxicities and allows clinical screening to potentially detect if LOAD may be developing early on in its clinical progression via spinal fluid examination. EPVS are thought to occur by obstruction of the PVS that associates with excessive neuroinflammation, oxidative stress, and vascular stiffening that impairs flow due to a dampening of the arterial and arteriolar pulsatility that aids in the convective flow of the metabolic debris within the glymphatic effluxing system. Additionally, increased EPVS has also been associated with Parkinson's disease and non-age-related multiple sclerosis (MS).

Reduced thalamic resting-state functional connectivity and impaired cognition in acute abstinent heroin users.

As a critical component of cortico-striato-thalamo-cortical loop in addiction, our understanding of the thalamus in impaired cognition of heroin users (HU) has been limited. Due to the complex thalamic connection with cortical and subcortical regions, thalamus was divided into prefrontal (PFC), occipital (OC), premotor, primary motor, sensory, temporal, and posterior parietal association subregions according to white matter tractography. We adopted seven subregions of bilateral thalamus as regions of interest to systematically study the implications of distinct thalamic nuclei in acute abstinent HU. The volume and resting-state functional connectivity (RSFC) differences of the thalamus were investigated between age-, gender-, and alcohol-matched 37 HU and 33 healthy controls (HCs). Trail making test-A (TMT-A) was adopted to assess cognitive function deficits, which were then correlated with neuroimaging findings. Although no significant different volumes were found, HU group showed decreased RSFC between left PFC_thalamus and middle temporal gyrus as well as between left OC_thalamus and inferior frontal gyrus and supplementary motor area relative to HCs. Meanwhile, the higher TMT-A scores in HU were negatively correlated with PFC_thalamic RSFC with inferior temporal gyrus, fusiform, and precuneus. Craving scores were negatively correlated with OC_thalamic RSFC with accumbens, hippocampus, and insula. Opiate Withdrawal Scale scores were negatively correlated with left PFC/OC_thalamic RSFC with orbitofrontal cortex and medial PFC. We indicated two thalamus subregions separately involvement in cognitive control and craving to reveal the implications of thalamic subnucleus in pathology of acute abstinent HU.

Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates.

INTRODUCTION: The etiology of sporadic Alzheimer's disease (AD) requires non-genetically modified animal models. METHODS: The relationship of tau phosphorylation to calcium-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno-electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques. RESULTS: Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808-RyR2). Calcium also regulated early tau phosphorylation in vitro. Age-related reductions in the calcium-binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques. DISCUSSION: Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.

Disrupted Intrinsic Networks Link Amyloid-ß Pathology and Impaired Cognition in Prodromal Alzheimer's Disease.

Amyloid-ß pathology (Aß) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aß-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aß-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest- and cognitive task-states, might link Aß-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aß-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aß-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aß-pathology with cognitive impairment in early AD.

Pain in Dementia: An Empirical Test of a Common Assumption.

Numerous, and often largely overlapping, observational pain assessment tools have been developed specifically to assess pain in older adults with dementia under the assumption that a specialized approach is necessary to evaluate pain in this population. However, this assumption has never been tested empirically. As an empirical test of this implicit assumption, our goal was to compare existing tools for people living with dementia (with respect to psychometric properties), not only against each other, but also against a tool developed for a different population with cognitive impairments. Videos of older adults with severe dementia recorded in long-term care settings were coded for pain behaviors in the laboratory. Trained coders coded pain behaviors in video segments of older adults with dementia during a quiet baseline condition as well as during a physical examination (designed to identify painful areas), using various observational pain assessment tools. An observational measure of agitation was employed to facilitate the assessment of discriminant validity. Consistent with our expectations, all pain tools (including the tool developed for younger people with cognitive impairments) successfully differentiated between painful and nonpainful states, with large effect sizes. This was the first study to compare tools specifically developed to assess pain in people living with dementia to a tool developed for a different population. Given that all tools under study showed satisfactory psychometric properties when tested on persons with dementia, this study suggests that the assumption that different tools are necessary for different populations with cognitive impairments cannot be taken for granted. PERSPECTIVE: This article challenges an implicitly held assumption that specialized tools are needed to assess pain in different populations with cognitive impairments. Given commonalities in pain expression across populations, further research is needed to determine whether population-specific tools are needed.

Reliability and validity of the Brief Assessment of Impaired Cognition (Chinese version) for stroke patients.

Objective and accurate cognitive assessment scales are essential for guiding cognitive rehabilitation following stroke. The aim of this study was to evaluate the validity and reliability of the Mandarin Chinese version of the Brief Assessment of Impaired Cognition (BASIC) in stroke patients. The English version of the BASIC scale was translated into Mandarin Chinese, and 56 stroke patients at a stroke treatment center were enrolled in the study. The Mini-Mental State Examination (MMSE) and BASIC scale were used to evaluate the patients' cognitive function, and content validity, structural validity, concurrent validity, internal consistency, interrater consistency and reliability and test-retest reliability were used to evaluate the test results. The correlation coefficients between each item of the BASIC scale and the total score were between 0.416 and 0.804 (p < 0.05). The total score on the BASIC scale was correlated with the total score on the MMSE (r = 0.479, p < 0.05). Four factors were extracted by exploratory factor analysis, and the cumulative variance contribution rate was 74.932%. The factor loading of each item on the corresponding factor was > 0.5, indicating that the scale has good structural validity. Internal consistency was good (Cronbach's α = 0.821), as were interrater (ICC > 0.95) and test-retest reliability (ICC = 0.815-0.941). Therefore, the Chinese version of the BASIC scale has good reliability and validity and can assist in screening for cognitive dysfunction or dementia in stroke patients.

The Relationship Between Brain Fog and Medication Adherence for Individuals With Hypothyroidism.

Individuals with hypothyroidism suffer from symptoms including impairments to cognition (i.e., "brain fog"). Medication can help reduce symptoms of hypothyroidism; however, brain fog may hinder adherence. The aim of this study was to determine if memory impairment and cognitive failures are related to treatment nonadherence in 441 individuals with hypothyroidism. Participants with a diagnosis of hypothyroidism and currently prescribed a thyroid hormone replacement medication were placed in two groups according to adherence level and compared on validated scales assessing impairments to memory and cognition. Results indicated a significant association between treatment nonadherence and self-reported brain fog, represented by greater cognitive and memory impairments. Nonadherent individuals indicated impairments with prospective, retrospective, and short- and long-term memory; and more cognitive failures, compared to adherent individuals. Findings suggest the importance of interventions to enhance adherence for individuals with brain fog, such as encouraging the use of reminders.

Pain in Older Adults With Dementia: A Survey in Spain.

The risk of suffering pain increases significantly throughout life, reaching the highest levels in its latest years. Prevalence of pain in nursing homes is estimated to range from 40 to 80% of residents, most of them old adults affected with dementia. It is already known that pain is under-diagnosed and under-treated in patients with severe cognitive impairment and poor/absent verbal communication, resulting in a serious impact on their quality of life, psychosocial, and physical functioning. Under-treated pain is commonly the cause of behavioral symptoms, which can lead to misuse of antipsychotic treatments. Here, we present two Regional and National Surveys in Spain (2015-2017) on the current practices, use of observational tools for pain assessment, guidelines, and policies. Results, discussed as compared to the survey across central/north Europe, confirm the professional concerns on pain in severe dementia, due to poor standardization and lack of guidelines/recommendations. In Spain, observational tools are scarcely used because of their difficulty and low reliability in severe dementia, since the poor/absent verbal communication and comprehension are considered limiting factors. Behavioral observation tools should be used while attending the patients, in a situation including rest and movement, should be short (3-5 min) and scored using a numeric scale. Among the pain items to score, "Facial expression" and "Verbalization" were considered essential and very useful, respectively. This was in contrast to "Body movements" and "Vocalizations," respectively, according to the survey in central/north Europe. Scarce time availability for pain assessment and monitoring, together with low feasible and time-consuming tools, can make pain assessment a challenge. The presence of confounding factors, the low awareness and poor knowledge/education of specific tools for this population are worrisome. These complaints draw future directions to improve pain assessment. More time available, awareness, and involvement of the teams would also benefit pain assessment and management in cognitive impairment. The experiences and opinions recorded in these surveys in Spain and other E.U. countries were considered sources of knowledge for designing the "PAIC-15 scale," a new internationally agreed-on meta-tool for Pain Assessment in Impaired Cognition and the "Observational pain assessment" in older persons with dementia.

The Relationship Between Enlarged Perivascular Spaces and Cognitive Function: A Meta-Analysis of Observational Studies.

Enlarged perivascular spaces (ePVS), visible on magnetic resonance imaging (MRI), are associated with aortic pulse wave changes produced by arterial stiffening. However, the relationship between ePVS and cognition is still unclear. We aimed to benchmark current knowledge of associations between ePVS and cognitive function using a meta-analysis of all available published data. We searched three databases for studies examining ePVS and cognition, identified seven studies involving 7,816 participants, plotted multivariate-adjusted odds ratio (OR) and 95% CI and generated summary OR with a fixed effects model. EPVS were related to the risk of impaired cognition (OR = 1.387, 95% CI = 1.198-1.606, z=4.38, P<0.001) with low heterogeneity. There was publication bias, which could be corrected by trimming and supplementation (OR=1.297, 95% CI= 1.130-1.490). EPVS were associated with impaired cognition and may be a sign of cognitive impairment rather than particular diseases. More studies are required to validate ePVS as a measurable risk marker for cognition using consistent methods to determinea characteristic appearance of ePVS.

High prevalence of cognitive impairment among students near mount Merapi: a case study.

This descriptive, cross-sectional study illustrates the high prevalence of intellectual impairment among students at the Kanisius Prontakan primary school near Mt. Merapi, one of the most active volcanic mountains in Indonesia. To determine the possible cause of these abnormal cognitive impairments, we considered and investigated the threats to society and the environment of the frequent volcanic eruptions, as well as the effects of malnutrition due to extreme poverty, in that area. The results showed that intellectual impairment and stunting were remarkably common among the students, with 10.7% of the students showing sigma of intellectual impairment and 96.4% showing signs of stunting. No noticeable chemical problems due to the volcanic activity were found in the drinking water, and no causes of such disorders other than poor nutrition due to poverty were found. Nevertheless, our results provide information on the high prevalence of health problems being experienced by children living in one of the most isolated and underdeveloped volcano mountain areas in Indonesia and draws attention to the severe effects of malnutrition on the development of those children.

Self-assembling nanofibers alter the processing of amyloid precursor protein in a transgenic mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most common dementia, which is not effectively cured to date. Amyloid-beta (Abeta) deposition cascade and disintegrity of brain extracellular matrix (ECM) scaffold attribute to the progress of AD. Thus, it maybe an effective way to treat AD by altering the processing of amyloid precursor protein (APP) and regaining the integrity of ECM. The peptide amphiphile (PA) with a laminin epitope isoleucine-lysine-valine-alanine-valine (IKVAV) (IKVAV-PA) can be trigged into ECM in vivo. In addition, IKVAV-PA could significantly improve cognitive impairment with remarkable increase of endoneurogensis in the hippocampus, as well as reduction of burden of amyloid plaque in the brain. METHODS: We used heterozygous AbetaPPswe/PS1dE9 double transgenic mice as the animal model of AD. After 1 week of initial stereotaxic administration into bilateral hippocampus, the mice were subjected to the Morris Water Maze (MWM) test. At the end of MWM test, immunohistochemical staining, Western blot and real-time polymerase chain reaction (PCR) were performed in mice. RESULTS: Here we showed that IKVAV-PA significantly improved cognitive impairment accompanying with reducing the burden of Abeta plaques, as well as the levels of soluble Abeta1-40 and Abeta1-42 in the cortex and hippocampus after 2 weeks of initial administration into bilateral hippocampus. Further examination demonstrated that IKVAV-PA also altered the processing of APP via inhibiting the gene expression of beta-secretase (BACE1), as well as improving the gene expression of insulin-degrading enzyme (IDE) and neprilysin (NEP). CONCLUSION: Our data suggest that IKVAV-PA may serve as an alternative therapeutic intervention for treating the learning and memory losses in AD.

A retrospective study of cognitive function in doctors and dentists with suspected performance problems: an unsuspected but significant concern.

OBJECTIVE: To examine the performance assessments and cognitive function of practitioners referred to the National Clinical Assessment Service (NCAS). DESIGN: Retrospective observational study. SETTING: Practitioners referred to NCAS for performance assessment due to suspected performance problems. PARTICIPANTS: One hundred and nine practitioners over the age of 45 years referred to NCAS between 1 September 2008 and 30 June 2012. MAIN OUTCOME MEASURES: Reasons for referral of practitioners and their characteristics; details of their assessments including screening for cognition using Addenbrooke's Cognitive Examination Revised (ACE-R); outcome of the process. RESULTS: Reasons for referral included 'clinical difficulties' and 'governance or safety issues'. Eighty-seven practitioners scored above 88 on ACE-R. Twenty-two were found to have an ACE-R score of ≤88. On further assessment, 14 of these 22 practitioners were found to have cognitive impairment. The majority of all practitioners were found to be performing below the expected level of practice for someone at their grade and specialty. Of those scoring ≤88 on the screening, only seven continued in clinical practice. CONCLUSIONS: A high proportion of practitioners scoring poorly on ACE-R were found to have cognitive impairment following detailed neuropsychological testing, the youngest aged 46 years. Many were working in isolation. Nearly all practitioners scoring poorly on ACE-R were international medical graduates; reasons for this are unclear. Performance assessment results showed persisting failings in the practitioners' record keeping and in their assessment of patients. Our findings highlight the need for increased vigilance and training of responsible officers to recognise performance problems and emphasise the importance of comprehensive assessment.

When Should Brain Imaging be Performed?: A Case Report of Caudate Nucleus Infarct.

A 21-year-old man presented in a state of delirium with compulsive, pathologic laughter and no focal neurologic findings. Brain imaging revealed a lenticulostriate artery infarct of the caudate nucleus. The absence of neurological signs made the diagnosis difficult, but the presence of delirium was a clue to the existence of structural brain disease.