Progression Of Cognitive Dysfunction Research Articles

Exendin-4 Protected against Cognitive Dysfunction in Hyperglycemic Mice Receiving an Intrahippocampal Lipopolysaccharide Injection

BackgroundChronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer’s disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study.Methodology/Principal FindingsTen days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 µg/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-κB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection.Conclusions/SignificanceThese findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-κB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases.

Long-term Outcome of Cognitive Functions, Emotional Behavior, and Quality of Life in a Family With Familial Hemiplegic Migraine

To investigate long-term cognitive outcome, mood, and quality of life in a family with genetically proven familial hemiplegic migraine (FHM). FHM is a rare autosomal-dominant subtype of migraine with aura, characterized by some degree of hemiparesis during the aura. In a previous study, we showed preserved and impaired cognitive functions in patients with FHM. Until now, the progression of cognitive dysfunctions has not been known. However, the ability to predict progression is important for counseling patients about education, career, and family life. Seven years after extensive baseline neuropsychological testing, we retested 6 members of a family with FHM, including questionnaires about mood and quality of life. The follow-up assessment revealed no global cognitive decline. All the patients' linguistic abilities and verbal memory remained intact; however, their figural memory, attention, and some aspects of executive function were impaired. Half the patients had a slight deterioration in their visuoconstructional functions. Half had higher scores on the trait and state anxiety measures. Cognitive deficits in a family with FHM persisted, but without marked progression. Worsening of visuoconstructional abilities may be related to executive dysfunction, confirming a disturbance of cerebrocerebellar circuits.

112 Is cognition stable in progressive supranuclear palsy after diagnosis, or are we testing the wrong thing?

IntroductionProgressive supranuclear palsy (PSP) is an akinetic rigid syndrome, used by Albert in 1974 as a model of subcortical dementia. Despite this, there has been insufficient information regarding progression of...

Progression of Cognitive Dysfunction in Elderly Chronic Kidney Disease Patients in a Veteran's Institution in Central Taiwan: a 3-Year Longitudinal Study

A strong positive correlation between estimated glomerular filtration rate (eGFR) multiplied by follow-up time and memory function has been demonstrated previously. The purpose of this study was to investigate the factors affecting progression of cognitive dysfunction in the elderly with different levels of kidney function. In April 2002, a prospective study on progression of cognitive function was conducted on 356 elderly people. All participants received a comprehensive geriatric assessment, serum biochemical test, homeostasis model assessment (HOMA), and a genetic polymorphism study, including polymorphism of apolipoprotein E (APOE), Cystatin, C-reactive protein (CRP) and tumor necrosis factor (TNF). Lean body mass-adjusted eGFR was used to evaluate severity of chronic kidney disease (CKD), and a clinical dementia rating scale was used to assess cognitive dysfunction. Patients were stratified according to eGFR (≥49 mL/min and <49 mL/min). Using multivariate logistic regression models, older age (OR=1.27, 95% CI=1.00-1.61) was associated with a high risk for progression of cognitive function in patients with a relatively low eGFR. In patients with lower eGFR, higher mini-mental state examination (MMSE) scores (OR=0.23, 95% CI=0.10-0.54) were correlated with a low risk for progression of cognition, while in patients with higher eGFR, higher MMSE scores (OR=0.39, 95% CI=0.23-0.65) were less correlated with cognitive dysfunction. However, elevated serum plasminogen activator inhibitor-1 (PA1-1) was associated with a high risk for cognitive dysfunction (OR=1.06, 95% CI=1.01-1.11) in patients with a better eGFR. Age, MMSE score and serum PAI-1 were found to be factors that predicted cognitive dysfunction at different functional levels of CKD.

S14G-Humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aβ) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aβ-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aβ accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aβ-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aβ plaque deposition, insoluble Aβ levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.

Association of ApoE and LRP mRNA levels with dementia and AD neuropathology

Inheritance of the ε4 allele of apolipoprotein E (ApoE) is the only confirmed and consistently replicated risk factor for late onset Alzheimer's disease (AD). ApoE is also a key ligand for low-density lipoprotein (LDL) receptor-related protein (LRP), a major neuronal low-density lipoprotein receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indexes of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared with those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in amyloid beta (Aβ) and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.

Cognitive reserve moderates decline in information processing speed in multiple sclerosis patients

Cognitive reserve is widely recognized as a moderator of cognitive decline in patients with senile dementias such as Alzheimer's disease. The same effect may occur in multiple sclerosis (MS), an immunologic disorder affecting the central nervous system. While MS is traditionally considered an inflammatory, white matter disease, degeneration of gray matter is increasingly recognized as the primary contributor to progressive cognitive decline. Our aim was to determine if individual differences in estimated cognitive reserve protect against the progression of cognitive dysfunction in MS. Ninety-one patients assessed twice roughly 5 years apart were identified retrospectively. Cognitive testing emphasized mental processing speed. Cognitive reserve was estimated by years of education and by performance on the North American Adult Reading Test (NAART). After controlling for baseline characteristics, both years of education (p = .013) and NAART scores (p = .049) significantly improved regression models predicting cognitive decline. Symbol Digit Modalities Test (SDMT) performance showed no significant change in patients with > 14 years of education, whereas it declined significantly in patients with ≤ 14 years of education. We conclude that greater cognitive reserve as indexed by either higher premorbid intelligence or more years of education protects against the progression of cognitive dysfunction in MS.

Is there progressive cognitive dysfunction in Sjögren Syndrome? A preliminary study

The aim of this study was to determine the progression of cognitive dysfunction in primary Sjögren Syndrome (SS). Twelve subjects with SS were compared with ten subjects with migraine and ten healthy controls on neuropsychological, mood and fatigue tests at baseline and 8 years later. At follow-up, SS subjects performed below subjects with migraine on the Continuous Performance Test (CPT) but did not differ on other tasks. Compared with controls, both clinical groups obtained lower scores on simple reaction time, patients with SS obtained lower scores on the Wisconsin Card Sorting Test (WCST) and patients with migraine performed below controls on the Benton's Judgment of Line Orientation Test (JOLO). Clinical groups did not differ on cognitive changes over time, except that migraine subjects improved on verbal fluency. Compared with baseline, both SS and migraine patients were more impaired on simple reaction time, Trail Making Test part B, Stroop and JOLO. However, they showed higher scores on verbal and visual memory, WCST and CPT reaction time. SS also showed higher levels of depression and fatigue than migraine and controls, with no significant changes over time. Preliminary evidence indicates some cognitive deficits in both SS and migraine following a pattern of fronto-subcortical dysfunction without a significant cognitive decline over time.

Carotid Artery Ultrasound and Echocardiography Testing to Lower the Prevalence of Alzheimer's Disease

The use of two clinic office techniques, carotid artery ultrasound and echocardiography (CAUSE), to detect deficient brain blood flow delivery in the healthy, cognitively normal, older individual is proposed. Evidence indicates that persistent heart-to-brain blood flow deficit involving low cardiac output or low ejection fraction and carotid artery narrowing can promote cognitive impairment and that such impairment may lead to Alzheimer's disease (AD) or vascular dementia (VaD). A number of independent epidemiologic studies reported cardiovascular and cerebrovascular disease to be risk factors to AD and VaD. The clinical rationale for CAUSE is to detect and prevent progression of cognitive dysfunction in elderly persons and is based on the general understanding that mild cognitive impairment is a preclinical threshold to AD or VaD with high conversion rates to either dementia. The use of CAUSE is anticipated to prevent or attenuate, by appropriate clinical management, mild cognitive impairment arising from persistent brain hypoperfusion, a condition implicated in the promotion of cognitive impairment in the elderly and a common preclinical feature seen in AD and VaD. As detection of lowered cerebral perfusion from cardiac and carotid artery pathology is achieved using these cost-effective, noninvasive, and relatively accurate ultrasound procedures, a significant reduction in the number of new AD and VaD cases would be anticipated after appropriate patient treatment. In this context, a brief summary is presented outlining recent medical and surgical treatments that may improve cerebral blood flow insufficiency. The merit of CAUSE in screening and treating mentally healthy elderly persons who are identified as being at risk of cognitive decline is that it could blunt the soaring socioeconomic impact that will hammer the health care system of many nations by the mounting dementia prevalence rate expected in the next 25 years. A 5- year delay in the onset of AD could reduce the prevalence of AD by 50%. We are making preparations to test the merit of CAUSE in a clinical study of a cognitively healthy elderly population.

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease. We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated. The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials. The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Background: Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease. Methods: We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated. Results: The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials. Conclusions: The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.

Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus

Memory impairment is outstanding within the spectrum of cognitive deficits in multiple sclerosis (MS) patients. Demyelination has been reported in the hippocampus formation of MS patients. The degree of hippocampus lesions in MS strongly correlates with progression of cognitive dysfunction. Because no appropriate animal model for the study of hippocampus demyelination has been established, we used the cuprizone mouse model to investigated demyelination in young adult and aged mice. The myelin status was analyzed by classical histological staining, immunocytochemistry for proteolipoprotein, and electron microscopy. Oligodendrocyte, astroglial, and microglia markers were studied. Cuprizone intoxication induced an almost complete demyelination of distinct hippocampus subregions to a similar extent in young adult and aged male mice. Demyelination was pronounced in a subset of white and gray matter areas, i.e., the stratum lacunosum moleculare containing the perforant path, medial alveus, stratum pyramidale in the cornu ammonis 2/3 region, and hilus region. Besides demyelination, affected areas displayed hypertrophic and hyperplastic astrocytosis. No significant effect on microglia invasion was detected at any investigated time point (0, 3, 5, and 7 weeks). We conclude that cuprizone-induced demyelination provides an adequate animal model to investigate appropriate therapy strategies for the prevention of hippocampus demyelination.

Cognitive Dysfunctions Associated With PTSD: Evidence from World War II Prisoners of War

The authors aim to delineate cognitive dysfunction associated with posttraumatic stress disorder (PTSD) by evaluating a well-defined cohort of former World War II prisoners of war (POWs) with documented trauma and minimal comorbidities. The authors studied a cross-sectional assessment of neuropsychological performance in former POWs with PTSD, PTSD with other psychiatric comorbidities, and those with no PTSD or psychiatric diagnoses. Participants who developed PTSD had average IQ, while those who did not develop PTSD after similar traumatic experiences had higher IQs than average (approximately 116). Those with PTSD performed significantly less well in tests of selective frontal lobe functions and psychomotor speed. In addition, PTSD patients with co-occurring psychiatric conditions experienced impairment in recognition memory for faces. Higher IQ appears to protect individuals who undergo a traumatic experience from developing long-term PTSD, while cognitive dysfunctions appear to develop with or subsequent to PTSD. These distinctions were supported by the negative and positive correlations of these cognitive dysfunctions with quantitative markers of trauma, respectively. There is a suggestion that some cognitive decrements occur in PTSD patients only when they have comorbid psychiatric diagnoses.

Comprehensive studies of cognitive impairment of the elderly with type 2 diabetes

Type 2 diabetes mellitus is associated with cognitive dysfunction and increases the risk of dementia for the elderly. The aim of the study presented here was to provide a brief review of how disturbance of glucose and metabolic homeostasis may be implicated in the cognitive decline of patients with type 2 diabetes. Several risk factors such as nutrition, cerebrovascular disorders and the neurotoxic effects of hyperglycemia may combine for the formation of mechanisms of cognitive decline in the diabetic elderly. It should be noted that cognitive deficits of diabetes are accompanied by neuroradiological changes in the brain, so that cognitive dysfunction both with and without brain structural changes may overlap during cognitive decline of the diabetic elderly. Recently, we conducted two studies to explore, by means of brain imaging, hierarchical relationships among clinical profiles of diabetes, cognitive function, white matter hyperintensity and brain atrophy. The results suggested that subcortical brain atrophy and hyperintensity constitute predictors of the rate of progression of cognitive dysfunction in the diabetic elderly, while cortical atrophy is associated with high diastolic blood pressure and lower HbA1c. These hypotheses may explain in part the underlying mechanisms of cognitive impairment in the diabetic elderly. Prospective intervention studies are needed, however, to clarify the mechanism of cognitive dysfunction of the diabetic elderly and what the targets are for preventive measures.

Are there protective treatments for cognitive decline in MS?

Despite its frequency and high functional impact, very little is known about effective strategies for managing cognitive impairment in multiple sclerosis (MS). Disease-modifying drugs, such as beta-interferons and glatiramer acetate, may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial. Moreover, pilot studies have tested symptomatic therapies for fatigue, a frequent symptom in MS, which may share a common physiopathological substrate with cognitive dysfunction. Small trials with amantadine, pemoline, 4-aminopyridine and 3–4 aminopyridine have provided mainly negative results. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer's disease (AD)–such as donepezil, rivastigmine, and galantamine–have recently been tested in other cognitive disorders, including MS. The majority of pilot trials with AchEI in MS have provided promising results, and the donepezil study recently published by Krupp et al. represents a major development in this field. As for non-pharmacological interventions based on cognitive rehabilitation, few studies have used an experimental approach and, in general, results have been disappointingly negative. Further research is clearly needed in this area.

Assessing Neurocognitive Dysfunction in Cranial Radiotherapy: Can Cognitive Event-related Potentials Help?

Cognitive changes are common sequelae of cancer and cancer treatment, particularly in patients receiving cranial radiotherapy (RT). These effects are typically assessed by subjective clinical examination or using objective neuropsychological tests. Biologically based neurophysiological methods have been increasingly applied to the study of cognitive processing in neuropsychiatric and neurological disorders and as objective measures of cognitive status for patients with dementia. These methods detect the activation of neural circuits that directly mediate cognitive function in the human brain and include metabolic and electrophysiology based techniques. Neuroimaging procedures such as 18FDG PET and more recently fMRI, which detect metabolic activation associated with cognitive processing, provide excellent spatial resolution and can be directly correlated with neuroradiological findings associated with cranial RT neurotoxicity. Clinical electrophysiology procedures such as cognitive event-related potentials (ERP), which detect the neuronal electrical activity associated with cognitive processing, offer excellent temporal resolution at low cost. Cognitive ERP techniques are already being used to assess severity and progression of cognitive dysfunction in patients with vascular and degenerative dementias, but have been largely overlooked in studies of radiation-related cognitive impairments. We review these various electrophysiological methods in the context of their relevance to assessing cranial RT effects on cognitive function, and provide recommendations for a neurophysiological approach to supplement current neuropsychological tests for RT cognitive impairments. This technology is well suited for clinical assessment of neurocognitive sequelae of cancer and should provide new insights into the mechanism of RT-related cognitive dysfunction.

The Amyloid-β Peptide Suppresses Transforming Growth Factor-β1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells

Accumulation of the amyloid-beta (Abeta) peptide in the brain is a crucial factor in the development of Alzheimer disease. Expression of transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, has been associated in vivo with Abeta accumulation in transgenic mice and recently with Abeta clearance by activated microglia, suggesting its deleterious and beneficial effects in neuronal cells. In this study, we demonstrated that TGF-beta1 stimulated the production of matrix metalloproteinase-2 (MMP-2) in a time- and dose-dependent manner in a human monocytic THP-1 cell line. Notably, we found that Abeta1-42 consistently inhibited the TGF-beta1-induced production of MMP-2, the endogenous gene containing Smad response elements, whereas the reverse peptide, Abeta42-1, evidenced little effect. Additionally, Abeta1-42 reduced TGF-beta1-induced increase in plasminogen activator inhibitor-1 (PAI-1). This inhibitory effect of Abeta1-42 was also seen in human astroglial T98G cell line. Furthermore, Abeta1-42 significantly induced the expression of Smad7, which appears in turn to mediate the Abeta suppression of the TGF-beta1-induced MMP-2 production. Indeed, Smad7 overexpression mimicked the inhibitory effect of Abeta1-42 on TGF-beta1-induced MMP-2 production. Importantly, Abeta1-42 markedly suppressed the transactivation of the transfected reporter construct, p3TP-Lux, which contains TGF-beta1-inducible Smad response elements. This was concomitant with a decreased MMP-2 production in TGF-beta1-treated cells. Inhibition of cellular Smad7 levels via the small interference RNA method significantly ameliorated the Abeta1-42-mediated suppression of TGF-beta1-inducible transcription reporter activity, thereby restoring MMP-2 induction, whereas Smad7 transfection down-regulated TGF-beta1-inducible transcription reporter activity. Collectively, these data suggest that Abeta1-42 may play an important role in the negative regulation of TGF-beta1-induced MMP-2 production via Smad7 expression.

Remarkable increase in the concentration of 8-hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer's disease.

To investigate the possible role of oxidative RNA damage in the pathogenesis of Alzheimer's disease (AD), the concentrations of the oxidative stress marker 8-hydroxyguanosine (8-OHG) were measured in the cerebrospinal fluid (CSF) and the serum of patients with AD and control subjects. The concentration of 8-OHG in CSF in AD patients was approximately fivefold that in controls (P < 0.001). The concentration of 8-OHG in CSF decreased significantly with the duration of illness (r(s) = -0.48, P < 0.05) and the progression of cognitive dysfunctions (r(s) = 0.67, P < 0.01). However, the concentration of 8-OHG in CSF showed no correlation with that in serum in both the controls and AD patients. In addition, the concentration of 8-OHG in serum was not significantly altered in AD patients compared to that in controls, suggesting that the 8-OHG concentrations in the CSF do not reflect those in serum and may be probably reflect those in brain tissue. These in vivo findings suggest a possible role of 8-OHG and increased oxidative RNA damage in the early stage of the development of AD.

Cognitive functions and psychopathological dimensions in schizophrenia

Adolescence and early adulthood are periods of particular vulnerability to the neurotoxic effects of alcohol. Young people with alcohol-use disorders display deficits in working memory (WM). This function is supported by the prefrontal cortex, a late-maturing brain region. However, little is known about the progression of cognitive dysfunctions associated with a binge-drinking (BD) pattern of alcohol consumption among non-clinical adolescents. The objective of this study was to analyze the relationship between BD trajectory and WM in university students. An initial sample of 155 male and female first-year university students was followed prospectively over 6 years. The participants were classified as stable non-BDs, stable BDs, and ex-BDs, according to the third item of the Alcohol Use Disorders Identification Test (AUDIT). WM was assessed using the Self-Ordered Pointing Task. Generalized linear mixed models were applied. The results showed that stable BDs committed more total perseverative errors and showed a lower WM span in the difficult blocks than stable non-BDs. Difficulties in WM span showed some improvement, whereas perseveration errors remained constant throughout the follow-ups in the stable BDs. There were no significant differences between ex-BDs and non-BDs. In conclusion, stable BD is associated with WM deficits, particularly perseverations and low WM span in demanding trials, when compensatory mechanisms may no longer be successful. The partial improvement in WM span may support the notion of a neuromaturational delay, whereas the temporal stability of perseveration deficits may reflect either neurotoxic effects of alcohol or premorbid characteristics. Abandoning the BD pattern of alcohol consumption may lead to partial recovery.