Basis Of Cognitive Impairment Research Articles

Kallistatin leads to cognition impairment via downregulating glutamine synthetase

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

White Matter Characteristics of Cognitive Impairment in Tap-Test Positive Idiopathic Normal Pressure Hydrocephalus: A Diffusion Tensor Tract-Based Spatial Study.

The present study was designed to systemically evaluate changes in the diffusion tensor imaging (DTI)-derived parameters of iNPH (idiopathic normal pressure hydrocephalus) patients with different responses to the tap test (TT), and to correlate cognitive impairment with white matter (WM) degeneration. This study included 22 iNPH patients and 14 healthy controls with structural magnetic resonance imaging (MRI) and DTI scanning. DTI was used to explore the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for all participants. DTI parameters were evaluated using an ROI (region of interest)-based and tract-based spatial statistics (TBSS) approach. Neuropsychological assessments and the idiopathic normal pressure hydrocephalus grading scoring scale (iNPHGS) were performed. Compared to the TT non-responders, the TT responders group had significantly lower FA values in the corpus callosum, cingulum cingulate gyrus, superior longitudinal fasciculus, and lower AD values in the right cingulum cingulate gyrus and the left posterior thalamic radiation. Besides, the MD values were significantly increased in the corpus callosum, left anterior corona radiata, and the RD values in the corpus callosum and cingulum cingulate gyrus. In addition, the cognitive improvement was negatively correlated with FA of the corpus callosum, cingulum cingulate gyrus, and MD values of the genu of corpus callosum. While, the cognitive improvement was positively related to the AD of the cingulum cingulate gyrus, superior longitudinal, and RD values of the corpus callosum, cingulum cingulate gyrus and uncinate fasciculus. The ROI specific WM lesions in iNPH patients are the underlying basis for cognitive impairment.

Deficits in Early Sensory and Cognitive Processing Are Related to Phase and Nonphase EEG Activity in Multiple Sclerosis Patients.

Currently, there is scarce knowledge about the relation between spectral bands modulations and the basis of cognitive impairment in multiple sclerosis (MS). In this sense, analyzing the evoked or phase activity can confirm results from traditional event-related potential (ERP) studies. However, studying the induced or nonphase activity may be necessary to elucidate hidden compensatory or affected cognitive mechanisms. In this study, 30 remitting-relapsing multiple sclerosis patients and 30 healthy controls (HCs) matched in sociodemographic variables performed a visual oddball task. The main goal was to analyze phase and nonphase alpha and gamma bands by applying temporal spectral evolution (TSE) and its potential relation with cognitive impairment in these patients. The behavioural results showed slower reaction time and poorer accuracy in MS patients compared to controls. In contrast, the time-frequency analysis of electroencephalography (EEG) revealed a delay in latency and lower amplitude in MS patients in evoked and induced alpha compared to controls. With respect to the gamma band, there were no differences between the groups. In summary, MS patients showed deficits in early sensorial (evoked alpha activity) and cognitive processing (induced alpha activity in longer latencies), whereas the induced gamma band supported the hypothesis of its role in translation of attentional focus (induced activity) and did not show strong activity in this paradigm (visual oddball).

Altered phase and nonphase EEG activity expose impaired maintenance of a spatial-object attentional focus in multiple sclerosis patients

Some of the anatomical and functional basis of cognitive impairment in multiple sclerosis (MS) currently remains unknown. In particular, there is scarce knowledge about modulations in induced EEG (nonphase activity) for diverse frequency bands related to attentional deficits in this pathology. The present study analyzes phase and nonphase alpha and gamma modulations in 26 remitting-relapsing multiple sclerosis patients during their participation in the attention network test compared with twenty-six healthy controls (HCs) matched in sociodemographic variables. Behavioral results showed that the MS group exhibited general slowing, suggesting impairment in alerting and orienting networks, as has been previously described in other studies. Time–frequency analysis of EEG revealed that the gamma band was related to the spatial translation of the attentional focus, and the alpha band seemed to be related to the expectancy mechanisms and cognitive processing of the target. Moreover, phase and nonphase modulations differed in their psychophysiological roles and were affected differently in the MS and HC groups. In summary, nonphase modulations can unveil hidden cognitive mechanisms for phase analysis and complete our knowledge of the neural basis of cognitive impairment in multiple sclerosis pathology.

Disrupted Functional Network Connectivity Predicts Cognitive Impairment in Presbycusis Patients.

Purpose: Individuals with presbycusis often show deficits in cognitive function, however, the exact neurophysiological mechanisms are not well understood. This study explored the alterations in intra- and inter-network functional connectivity (FC) of multiple networks in presbycusis patients, and further correlated FC with cognitive assessment scores to assess their ability to predict cognitive impairment.Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) was performed in 40 presbycusis patients and 40 matched controls, and 12 resting-state networks (RSNs) were identified by independent component analysis (ICA) approach. A two-sample t-test was carried out to detect the intra-network FC differences, and functional network connectivity (FNC) was calculated to compare the inter-network FC differences. Pearson or Spearman correlation analysis was subsequently used to explore the correlation between altered FC and cognitive assessment scores.Results: Our study demonstrated that patients with presbycusis showed significantly decreased FC in the subcortical limbic network (scLN), default mode network (DMN), executive control network (ECN), and attention network (AN) compared with the control group. Moreover, the connectivity for scLN-AUN (auditory network) and VN (visual network)-DMN were found significantly increased while AN-DMN was found significantly decreased in presbycusis patients. Ultimately, this study revealed the intra- and inter-network alterations associated with some cognitive assessment scores.Conclusion: This study observed intra- and inter-network FC alterations in presbycusis patients, and investigated that presbycusis can lead to abnormal connectivity of RSNs and plasticity compensation mechanism, which may be the basis of cognitive impairment, suggesting that FNC can be used to predict potential cognitive impairment in their early stage.

The role of citicoline in the treatment of dyscirculatory encephalopathy and vascular cognitive impairment

Vascular cognitive impairment (VCI) is the main manifestation of dyscirculatory encephalopathy (DEP). According to the severity of cognitive impairment, Stage I DEP corresponds to mild (subjective) cognitive impairment; stage II DEP to moderate cognitive impairment; stage III DEP to severe cognitive impairment or vascular dementia. VCI is diagnosed on the basis of cognitive impairment, the clinical and neuroimaging findings confirming the presence of cerebrovascular disease, and the neuropsychological study results indicating a cognitive defect. Citicoline is one of the most widely used nootropic drugs for cerebrovascular pathology. The treatment of VCI involves the prevention of stroke and progressive chronic cerebrovascular disease (CCVD) and the use of drugs improving cognitive functions. Citicoline is one of the most widely used nootropic drugs for cerebrovascular disease. This drug was synthesized in Japan to treat stroke, then it became widely used in different countries in patients with CCVD and VCI. The data of clinical trials and a Cochrane systematic review prove the efficacy and safety of citicoline in the elderly and senile patients.

Analysis of influencing factors of visual working memory in young adult patients with schizophrenia

BackgroundPatients with schizophrenia have general cognitive impairments, and the impairment of working memory is considered to be the basis of cognitive impairments. The research on visual working memory, one of...

Wavelet based features of EEG power spectra analysis in children with borderline intellectual functioning

Objective To investigate the features of absolute electroencephalogram (EEG) power spectra in children with borderline intellectual functioning (BIF) as well as their correlation with cognitive function and behavioral problems. Methods 30 children with borderline intellectual functioning and 42 typical developing children (TDC) were recruited in this study. All of them underwent the Chinese Revised Wechsler Intelligence Scale for Children (C-WISC) and their behavioral problems were assessed according to the Conners’ Parent Symptom Questionnaire (PSQ). Resting EEG of 128 electrodes were recorded when the participants closed their eyes and analyzed using wavelet transform to assess the absolute power of alpha, beta, theta, gamma and theta/beta ratio (TBR). Results (1)PSQ scores of BIF (conduct problems(0.78±0.16), learning problems(1.53±0.14), psychosomatic disorder(0.17±0.04), impulsivity-hyperactivit(1.13±0.14), anxious(0.52±0.08), hyperactivity inde(1.04±0.10))were higher than TDC(conduct problems(0.21±0.03), learning problems(0.35±0.05), psychosomatic disorder(0.07±0.02), impulsivity-hyperactivit(0.27±0.05), anxious(0.26±0.03), hyperactivity index(0.25±0.04)), and the difference was statistically significant(P<0.05). (2)alpha band: the main effects of the two groups on the left and right hemisphere (F=14.44, P<0.01)and the anterior and posterior hemispheres (F=29.54, P<0.01) were significant.The interaction effect between the left and right hemisphere and the anterior and posteriorm hemispheres was significant(F=8.55, P<0.01). The activity of the alpha wave was significant in the right posterior hemisphere.(3)The main effects of the two groups on the left and right hemispheres (F=6.49, P=0.01)and the anterior and posterior hemispheres(F=8.01, P=0.01) were significant.The two groups had significant interaction effects between the left and right hemisphere and the type(F=5.84, P=0.02). The interaction between the left and right hemisphere and anterior and posterior hemispheres was significant(F=10.51, P<0.01). The activity of the right anterior and right posterior parts was more significant.(4)delta band: the main effects of the two groups were significant in the anterior and posterior hemispheres(F=11.15, P<0.01), and the activities in the anterior hemisphere were larger than those in the posterior hemisphere.(5)TBR: the main effects of the two groups were significant in the anterior and posterior hemispheres(F=4.80, P=0.03). The TBR of the two groups was statistically significant in the right hemisphere(t=2.61, P=0.01). Conclusion The TBR activity of BIF on the right was higher than TDC.The increased TBR activity in the right hemisphere of BIF may be a neurobiological basis for cognitive impairment such as adaptive behavior disorder and executive function. Key words: Borderline intellectual functioning; EEG power spectra; Wavelet transform; Children

Cortical basis of cognitive impairment in idiopathic REM sleep behavior disorder

Cortical basis of cognitive impairment in idiopathic REM sleep behavior disorder

Association Between Montreal Cognitive Assessment Scores and Measures of Functional Mobility in Lower Extremity Amputees After Inpatient Rehabilitation

ObjectiveTo determine whether scores on a cognitive measure are associated with walking endurance and functional mobility of individuals with transfemoral or transtibial amputations at discharge from inpatient prosthetic rehabilitation. DesignRetrospective cohort study. SettingRehabilitation hospital. ParticipantsConsecutive admissions (N=176; mean age ± SD, 64.27±13.23y) with transfemoral or transtibial amputation that had data at admission and discharge from an inpatient prosthetic rehabilitation program. InterventionsNot applicable. Main Outcome MeasuresCognitive status was assessed using the Montreal Cognitive Assessment (MoCA). The L Test and the 2-minute walk test (2MWT) were used to estimate functional mobility and walking endurance. ResultsThe mean ± SD MoCA score was 24.05±4.09 (range, 6–30), and 56.3% of patients had scores <26. MoCA scores had a small positive correlation with the 2MWT (r=.29, P<.01), and a small negative correlation to the L Test (r=−.24, P<.01). In multivariable linear regression, compared with people with the highest MoCA score quartile, there was no difference on the 2MWT, but people in the lowest 2 quartiles took longer to complete the L Test. ConclusionsCognitive impairment was very prevalent. The association between MoCA and functional mobility was statistically significant. These results highlight the potential for differences on complex motor tasks for individuals with cognitive impairment but does not indicate a need to exclude them from rehabilitation on the basis of cognitive impairment alone.

Exposure to the mold Stachybotrys alters microglial morphology differentially in CA1 and CA2-3 of the dorsomedial hippocampus

Our labs have developed a mouse model to study the neural basis of cognitive impairments following exposure to mold. Here, we compared the effects of mold exposure on individual microglial parameters across subregions of the dorsomedial hippocampus. Adult male C57Bl/6 mice were exposed to either intact spores (IN), extracted spores (EX), or saline vehicle (VEH). Extracted spores had their toxins removed and proteins denatured leaving the spore casing, thereby simulating spore components remaining after commercial mold abatement. Iba1 + cells were visualized using immunohistochemistry. Cell body contours in CA1 and CA2-3 (combined) were traced using Neurolucida (Microbrightfield). Standard Neurolucida contour parameters were compared across treatments and between hippocampal regions. In CA1, 2, 3 combined, cells were rounder and more compact in the IN group than in EX. EX cells had a more complex perimeter (form factor) than VEH or IN. Within the VEH group, cell bodies in CA1 were larger and more round than in CA2-3. There were no differences in any of the measured parameters between CA1 and CA2-3 in IN mice, and a different pattern of differences in parameters between CA1 and CA2-3 in EX mice. No differences in microglial density were found across hippocampal regions or treatments. In sum, both IN and EX mold treatment gives rise to characteristically different phenotype profiles of microglia in the hippocampus, specific to CA1 and CA2-3 subregions.

Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer's disease.

Brain metabolic dysfunction is known to influence brain activity in several neurological disorders, including Alzheimer’s disease (AD). In fact, deregulation of neuronal metabolism has been postulated to play a key role leading to the clinical outcomes observed in AD. Besides deficits in glucose utilization in AD patients, recent evidence has implicated neuroinflammation and endoplasmic reticulum (ER) stress as components of a novel form of brain metabolic stress that develop in AD and other neurological disorders. Here we review findings supporting this novel paradigm and further discuss how these mechanisms seem to participate in synapse and cognitive impairments that are germane to AD. These deleterious processes resemble pathways that act in peripheral tissues leading to insulin resistance and glucose intolerance, in an intriguing molecular connection linking AD to diabetes. The discovery of detailed mechanisms leading to neuronal metabolic stress may be a key step that will allow the understanding how cognitive impairment develops in AD, thereby offering new avenues for effective disease prevention and therapeutic targeting.

OP87 Psychological distress following facial injury: a prospective study

<h3>Background</h3> People who suffer facial injury, whether from accidents or interpersonal violence, face a range of psychosocial issues as a result. Though standards of oral and maxillofacial surgery (OMFS) to restore function and appearance continue to improve, psychological problems may be overlooked in busy wards and clinics. Major trauma patients are known to be at risk of high levels of acute stress disorder (ASD), as well as depression and anxiety and, in the longer term, may develop post-traumatic stress disorder (PTSD); however, there has been limited exploration of the experience of OMFS trauma patients. Changes to appearance can be distressing and can impede the return to normal life; they can also exacerbate problems by reminding patients of traumatic events. This study aims to establish the prevalence of psychological distress (ASD, depression, anxiety, appearance concerns) in facial injury patients. <h3>Methods</h3> This prospective study recruited injury patients being treated at the Royal London Hospital by OMFS, and discussed at bi-weekly multidisciplinary meetings. Participants completed standardised self-completion questionnaires within two weeks of injury: these assessed symptoms of ASD (ASDS: Acute Stress Disorder Scale), psychological distress (HADS: Hospital Anxiety and Depression Scale) and appearance concerns (DAS24: Derriford Appearance Scale). Patients were excluded on the basis of cognitive impairment; self-harm leading to admission; and insufficient understanding of English. <h3>Results</h3> Data from 106 patients show that a high proportion of patients experienced clinically significant symptoms of distress. Twenty nine (29) percent of patients experienced symptoms indicative of ASD on the ASDS, which is associated with subsequent PTSD. Twenty nine (29) percent and 48 percent respectively experienced symptoms of depression and anxiety, using the HADS to assess clinically significant symptoms. Those experiencing clinically significant levels of distress on the ASDS or HADS had higher levels of appearance concern on the DAS24 (mean=40, SD=13.6), compared with those without significant distress (mean=26, SD=7.6). Refusal rates were low (&gt;10%), however in this diverse East London population, English language requirements excluded many otherwise eligible patients (22%). <h3>Discussion</h3> There are high levels of psychological distress and unmet needs in this cohort. Rehabilitation involves a return to normal psychosocial functioning as well as physical function and appearance, and there is a need for a simple, practical means of assessing distress. These psychological conditions are treatable, however, and the ability to identify those at risk would enable healthcare practitioners to provide important interventions.

P-174 - Comparison of cognitive function in bipolar depressionversus major depressive disorder

Introduction Major depressive episodes are characteristic of both Unipolar Depression (UPD) and Bipolar Disorder (BD). Cognitive impairment is a well documented finding in such episodes. Wide-ranging cognitive deficits have been reported in UPD patients, including psychomotor, attention, memory and executive functions. BD patients were found impaired in attention capacity, memory and learning deficits. Distinguishing BD from UPD patients on the basis of cognitive impairment requires additional research. Objectives Our objective was to clarify differences in cognitive functioning between UPD and BD patients during an acute depressive episode. Aims A better understanding of the cognitive impairments in each disorder, may significantly improve early diagnosis in acute depressed patients, in cases where it is unclear whether the patient presents UPD or BD. Methods Participants were 128 acute depressive outpatients, 87 had UPD and 41 had BD. Patients were assessed using Hamilton depression rating scale; Clinical Global Impression severity scale; Hamilton Anxiety Depression Survey; Beck Depression Inventory and Cambridge Neuropsychological Test Automated Battery (CANTAB). We used statistical modeling via logistic regression, to differentiate between UPD vs. BD, by means of their cognitive functions. Results Significant differences between the two groups were found in several domains: visual memory, working memory and sustained attention. The predictive model that was constructed has a discriminatory power as measured by the area under the ROC curve of 0.76. Conclusions UPD and BD patients present different cognitive impairments during acute depression. Our model may help to predict the underlying mental disorder, and thus facilitate earlier initiation of proper treatment.

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers

Cognitive impairment is a recognized effect of drug misuse, including the use of opiates. The pathological basis for this is unknown but the temporal and frontal cortices have been implicated. We have shown previously that deposits of hyperphosphorylated tau in drug user brains exceed those seen in age-matched controls. The present quantitative study of hyperphosphorylated tau and beta amyloid in drug user brains allows comparison with the related pathology in Alzheimer's disease. Brains were obtained from the Edinburgh Medical Research Council Brain Banks, comprising 39 human immunodeficiency virus negative drug users, five subjects with Alzheimer's disease and 37 age-matched, cognitively normal controls, all legally and ethically approved for research. Hyperphosphorylated tau positive (AT8, AT100) neuropil threads were significantly increased in the frontal and temporal cortex, and in the locus coeruleus, of drug users aged > 30 years (all P = 0.04). Under the age of 30 years, drug users showed a similar increase in neuropil threads compared with controls, but this reached significance only in the frontal cortex (P = 0.03). Immunopositivity for both three- and four-repeat tau was present in drug user brains. There was a direct relationship between the numbers of neuropil threads and of neurofibrillary tangles: neurofibrillary tangles were sparse in brains that had neuropil thread counts below 200 cm(2). Hyperphosphorylated tau positive neuropil threads increased at a faster rate in drug users than in controls and the levels of the phosphorylating enzyme, GSK-3, was raised in drug user brains. Beta amyloid (AB4, AB42 and 4G8) was raised in drug user brains (mainly as shadow plaques) but not significantly different from controls and there was no correlation between high beta amyloid and hyperphosphorylated tau in individual cases. Hyperphosphorylated tau levels correlated significantly (P = 0.038) with microglial activation in drug users but not in controls. The levels of hyperphosphorylated tau in drug users fell far short of those seen in Alzheimer's disease but overlapped with those in elderly controls. We conclude that drug users show early Alzheimer's disease-related brain pathology that may be the basis for cognitive impairment and that neuroinflammation is an early accompanying feature. This provides an opportunity to study the pathogenesis of tau pathology in the human brain.

O038 Biomechanical differences in transtibial amputee fallers vs. non-fallers during level walking

To determine whether scores on a cognitive measure are associated with walking endurance and functional mobility of individuals with transfemoral or transtibial amputations at discharge from inpatient prosthetic rehabilitation.Retrospective cohort study.Rehabilitation hospital.Consecutive admissions (N=176; mean age ± SD, 64.27±13.23y) with transfemoral or transtibial amputation that had data at admission and discharge from an inpatient prosthetic rehabilitation program.Not applicable.Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA). The L Test and the 2-minute walk test (2MWT) were used to estimate functional mobility and walking endurance.The mean ± SD MoCA score was 24.05±4.09 (range, 6–30), and 56.3% of patients had scores <26. MoCA scores had a small positive correlation with the 2MWT (r=.29, P<.01), and a small negative correlation to the L Test (r=−.24, P<.01). In multivariable linear regression, compared with people with the highest MoCA score quartile, there was no difference on the 2MWT, but people in the lowest 2 quartiles took longer to complete the L Test.Cognitive impairment was very prevalent. The association between MoCA and functional mobility was statistically significant. These results highlight the potential for differences on complex motor tasks for individuals with cognitive impairment but does not indicate a need to exclude them from rehabilitation on the basis of cognitive impairment alone.

Multiple cognitive deficits during the transition to Alzheimer's disease.

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

Modelling Huntington’s disease

Huntington’s disease (HD) is one of a group of inherited neurodegenerative disorders caused by a polyglutamine (CAG)-repeat expansion. The pathology of these disorders is associated with the presence of neuronal intranuclear inclusions, which contain the polyglutamine- repeat-containing protein that is specific to the disease, along with ubiquitin. Sathasivam et al.1xFormation of polyglutamine inclusions in non-CNS tissue. Sathasivam, K. et al. Hum. Mol. Genet. 1999; 8: 813–822Crossref | PubMedSee all References1 report the formation of nuclear inclusions (NIs) in non-neuronal tissue in previously described transgenic mice that express exon 1 of the human HD gene that contains a highly expanded CAG repeat. In this model, NIs were found in several tissues, including cardiac and skeletal muscle, liver, kidney, adrenal gland and pancreas. They report a correlation between the presence of NIs and a progressive decrease in organ size. It is not known whether similar non-neuronal NIs occur in human HD patients, and as such the relevance of this aspect of the model is unclear. Despite this, the presence of NIs in tissues such as skeletal muscle provides a good system to study NIs and to investigate ways to prevent their formation.Although the association of NIs with HD is well documented, their role in the pathology of the disease remains unproven, and an unknown property of the expanded polyglutamine repeat that is independent of NI formation might underlie certain aspects of the disease. A new mouse model, described by Shelbourne et al.2xA Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Shelbourne, P.F. et al. Hum. Mol. Genet. 1999; 8: 763–774Crossref | PubMedSee all References2, provides a valuable tool to study this possibility. This mouse has a stretch of 72–80 CAG repeats inserted into the endogenous Hdh gene. This ‘knockin’ mutation is similar to the human HD mutation as the mice express full-length mutant huntingtin in a wild-type genomic context. From a genetic viewpoint, this model appears to closely mirror the human HD mutation. As in humans, the expanded CAG repeat is unstable and a parent-of-origin effect on the repeat length is observed, with expansions tending to be associated with paternal transmission and contractions being associated with maternal transmission. The brains of the mutant mice are histologically normal with no evidence of NI formation. However, a reduction in brain size is seen in the mutant strains. The mutant mice also displayed chronic aggressive behaviour; human HD patients often exhibit symptoms such as irritability and aggression and ∼50% of patients present with psychiatric symptoms. These mice might therefore provide a model for the psychiatric disorder in HD.The knockin model was used to study the possible basis of cognitive impairment in HD (Ref. 3xImpaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Usdin, M.T. et al. Hum. Mol. Genet. 1999; 8: 839–846Crossref | PubMedSee all ReferencesRef. 3). Long-term potentiation (LTP) is the sustained increase in synaptic strength following a high-frequency conditioning stimulus. LTP provides a model for a mechanism that underlies some forms of learning and memory. LTP was significantly reduced in the stratum radiatum of area CA1 of hippocampal slices from the mutant mice. Post-tetanic potentiation and paired-pulse facilitation were also shown to be impaired, suggesting that the presynaptic terminals might be less able to sustain neurotransmitter release with repetitive stimulation. This was tested by monitoring the opening of N-methyl-d-aspartate (NMDA) channels by glutamate release. Glutamatergic synapses in area CA1 were shown to transmit normally in response to single stimuli but were impaired in their ability to release neurotransmitter at moderate levels of stimulation. The authors propose that the polyglutamine expansion might interfere with neurotransmitter release at the presynaptic terminals. This hypothesis is consistent with previous reports of wild-type HD protein being associated with microtubules and synaptic vesicles.This new mouse model provides evidence that some of the symptoms of HD might be independent of NI formation and might precede neurodegeneration. The two mouse models provide insights into distinct aspects of HD; taken together they should complement each other to facilitate research into the molecular basis and treatment of this disease.

No increased incidence of Alzheimer's disease in elderly schizophrenics.

There is currently controversy as to the morphological basis of cognitive impairment in elderly schizophrenics. In contrast to previous findings, recent studies have found no increased frequency of Alzheimer's disease (AD) pathology in elderly schizophrenics. We examined 99 consecutive autopsy cases of patients over the age of 55 years from a psychiatric hospital who met the DSM-III-R and ICD.10 criteria for schizophrenia (mean age 69.5 +/- 8.25 years; mean duration of illness 35.15 +/- 10.1 years), 56% showing moderate to severe dementia. All brains were blindly reviewed for evidence of AD using CERAD criteria and Braak staging of neuritic AD lesions. "Definite" AD (CERAD C, Braak stage V) was seen in 2 cases aged 56 and 67 years, respectively [2% of total or 1/68 (1.4%) of those over age 65]. "Probable" AD (CERAD B, Braak stages IV-V) were seen in 5 cases aged 71-89 years (mean 79 years; 5% of total or 7.3% of those over age 65), and 1 case each with multiple cerebral infarcts and with Parkinson's disease pathology. In addition, 2 females aged 82 and 89 years, respectively, revealed senile dementia with tangles (NIA, CERAD negative; Braak stage IV), 1 with hippocampal sclerosis. The total incidence of definite and probable AD in this cohort was 7.1% or 8.7% for those over age 65. This is in line with other recent studies showing that the frequency of AD in elderly schizophrenics may be equal or even less than in the general population. The reasons for this negative association and the basis of cognitive deficits in elderly schizophrenics--those with dementia usually showing significantly lower brain weight--await further elucidation.