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PubMed1991

User-friendly method for rapid brain and CSF volume calculation using transaxial MRI images.

A reliable computer method was developed for straightforward, rapid determination of whole brain and cerebrospinal fluid (CSF) volumes from a set of contiguous transaxial magnetic resonance images. The semiautomatic algorithm used a threshold-guided edge follower. Subtraction of proton-weighted from T2-weighted images was used to highlight CSF. Phantom studies were used for validity assessment. Interrater and intrarater reliability and correlation with manual measurement were excellent. Percent CSF and brain volumes were determined for small groups of Alzheimer's disease, HIV seropositive, obsessive-compulsive disorder, and schizophrenic patients as well as for young and elderly normal controls.

Algorithms↗
PubMed2026

Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.

Cellular pathways for experimental discovery provide a comprehensive overview of sirtuin biology and its critical involvement in HIV-associated neurocognitive disorders (HAND) and related neurodegenerative diseases, highlighting the translational potential of sirtuin-targeted therapeutic strategies. As NAD+-dependent deacetylases and ADP-ribosyl transferases, sirtuins regulate diverse cellular processes, including stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, autophagy, oxidative stress responses, and genomic stability, all of which contribute to neuronal dysfunction and disease progression. This chapter focuses on key mammalian sirtuins, including SIRT1 and SIRT2, which are primarily localized within the nucleus and cytosol; mitochondrial sirtuins SIRT3, SIRT4, and SIRT5; and nuclear/nucleolar sirtuins SIRT6 and SIRT7. Here, a method with a detailed protocol to isolate compartment-specific sirtuin expression and activity was used: subcellular fractionation was performed using a subcellular fractionation kit to obtain cytosolic and nuclear fractions, while mitochondrial isolation was carried out using Tom20 antibody-conjugated magnetic microbeads. These approaches were applied to brain tissues from HIV-positive individuals, as well as to HIV-Tat-treated human microglial (HMC3) cells and astrocytes. This experimental framework enables accurate assessment of compartment-resolved sirtuin regulation in disease-relevant models. Collectively, the chapter highlights the protective roles of sirtuins in mitigating key pathogenic mechanisms underlying HAND and related neurodegenerative diseases. These findings support the emerging concept that sirtuins represent promising pharmacological targets for the development of novel therapeutic interventions in neurodegeneration and HIV-associated brain disorders.

Humans↗
PubMed2005

Construct validity of Hopkins Verbal Learning Test-Revised component process measures in an HIV-1 sample.

Executive dyscontrol of episodic verbal learning and memory secondary to prefrontostriatal circuit neuropathophysiology is a common feature of HIV-1 infection. Prior research indicates that standard clinical learning and recall indexes from Hopkins Verbal Learning Test-Revised (HVLT-R) are among the most sensitive indicators of HIV-associated neurocognitive disorders. Emerging data support the validity of qualitative component process measures derived from the HVLT-R (e.g., Semantic Clustering); however, no prior studies have examined these particular indices of performance in an HIV-1-infected population. In the present study, we examined the construct validity of HVLT-R component process indices in a sample of 42 persons with HIV-1 infection and 29 demographically similar seronegative comparison participants. The HIV-1 sample performed significantly below the seronegative group on Total and Delayed Recall, Semantic Clustering, and the Retrieval Index. No between-group differences were observed on Serial Clustering, Pair Frequency, Learning, Repetitions, Semantic False Positive Recognition Errors, or the Recognition Discrimination Index. In addition, the HVLT-R component process measures demonstrated evidence of convergent and divergent validity with standard clinical tests in the HIV-1 sample. Findings support the construct validity of HVLT-R component process measures and are commensurate with prior literature indicating that HIV-1 disease is associated with deficient executive control of encoding and retrieval within verbal episodic memory.

Adult↗
PubMed2006

A new dimension of sensory dysfunction: stereopsis deficits in schizophrenia.

BACKGROUND: Schizophrenia is a neurocognitive disorder with a wide range of cognitive and sensory impairments. Early visual processing has been shown to be especially impaired. This article investigates the integrity of binocular depth perception (stereopsis) in schizophrenia. METHODS: Seventeen schizophrenia patients and 19 healthy control subjects were compared on the Graded Circles Stereo Test. Results of stereoacuity were compared between patients and control subjects using t test. RESULTS: Schizophrenia patients demonstrated significantly (p = .006) reduced stereoacuity (mean = 142 arcseconds) versus control subjects (mean = 55 arcseconds). At the normative level for adults, patients performed below chance. CONCLUSIONS: These findings demonstrate an impairment of binocular depth perception and further confirm deficits of early visual processing in schizophrenia. Findings are discussed in context of magnocellular/dorsal stream processing with implications for visual processing and cognitive deficits.

Adult↗
PubMed2005

"Frontal variant Alzheimer's disease": a reappraisal.

Two cases of clinically diagnosed sporadic Alzheimer's disease with early and prominent behavioural features (social disinhibition, emotional blunting, stereotyped verbal utterances) sufficient to prompt an initial diagnosis of frontotemporal dementia are presented. It is suggested that the term "frontal variant AD" be used for this clinically defined phenotype, which has also been described in cases of inherited AD associated with certain presenilin-1 gene mutations. This differs from previous usage of the term "frontal variant AD" to describe AD with predominant frontal lobe neuropathological change (although the clinical phenotype may reflect regional distribution of pathology), but parallels the clinical definition of visual agnosic, aphasic and apraxic presentations of AD. The proposed usage would also emphasise differential diagnosis.

Alzheimer Disease↗
PubMed2005

Neuropsychological abnormalities in cirrhosis include learning impairment.

BACKGROUND/AIMS: Minimal hepatic encephalopathy is a neurocognitive disorder secondary to liver failure that is characterized by a pattern of subcortical impairment. The most conspicuous neuropsychological abnormalities are on attention and psychomotor tests; memory has been inconsistently implicated. We designed a study to assess the presence of memory abnormalities in cirrhotic patients and the effects of liver transplantation. METHODS: Ninety-seven cirrhotics without overt hepatic encephalopathy underwent neuropsychological assessment, including the Auditory Verbal Learning Memory Test. The results were compared to those of healthy controls (n=75) and the assessment was repeated at one year of follow-up (n=33) or after liver transplantation (n=23). RESULTS: Cirrhotic patients exhibited multiple neuropsychological abnormalities, including several disturbances of the Auditory Verbal Learning memory test: learning, long-term memory and recognition. Abnormalities of long-term memory and recognition were corrected after adjusting for learning impairment. Memory abnormalities correlated to attention impairment and to parameters of liver function. Neuropsychological indexes following liver transplantation did not differ from controls. Repeated testing did not have a major effect on neuropsychological tests in healthy subjects and in non-transplanted cirrhotics. CONCLUSIONS: Learning impairment is present in cirrhotic patients with neuropsychological abnormalities. This abnormality is consistent with attention deficit secondary to minimal hepatic encephalopathy.

Female↗
PubMed2026

In vivo genome editing of central nervous system SIV reservoirs in ART-suppressed rhesus macaques.

Latent human immunodeficiency virus type 1 (HIV-1) reservoirs in the central nervous system (CNS) may sustain viral persistence and neuroinflammation contributing to HIV-associated neurocognitive disorders (HAND) despite suppressive ART. AAV9-delivered CRISPR has successfully edited SIV proviral DNA in peripheral tissues with acceptable safety profiles, but the extent of in vivo genome editing in the brain remains unclear. Using SIV-infected rhesus macaques, we mapped intact proviral DNA across CNS regions and tested systemic AAV9-CRISPR-Cas9 targeting conserved sites within Ψ packaging signal and Gag region. Ten adult rhesus macaques were infected with genetically barcoded SIVmac239, suppressed with ART, then randomized to receive intravenous AAV9-SaCas9 with dual gRNAs (Ψ + Gag) or a Cas9-only control. At necropsy after viral rebound, SIV genomes were detected in multiple brain regions as well as lymphoid tissues, confirming the CNS as a persistent reservoir during ART. Barcode analysis revealed region-specific patterns consistent with compartmentalized CNS persistence. In CRISPR-treated animals, proviral editing was measurable across anatomically distinct CNS sites. These findings demonstrate that intact and potentially replication-competent virus persists in the primate brain under ART and that systemic AAV9-CRISPR can reach and edit proviral DNA in this sanctuary, supporting genome editing as a strategy toward durable remission of CNS reservoirs.

ART↗
PubMed2005

Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia?

Schizophrenia is widely regarded to be a neurocognitive disorder, i.e. a dysfunction of the neural and cognitive systems subserving thinking and reasoning, memory, language, attention and perception. However, although cognitive dysfunction is certainly a cardinal feature of schizophrenia, we argue that dysfunction of emotional brain systems may be even more important in understanding the disorder. Indeed, in recent years research on the emotional aspects of schizophrenia is accumulating at a high rate. Here, we review the available evidence regarding behavioral and neural manifestations of abnormal emotional systems in schizophrenia. This evidence comes from patient studies using tasks of emotion recognition, emotional expression and emotional experience. Furthermore, studies of schizophrenia patients using structural MRI have demonstrated volume reductions of the amygdala, a key structure of the emotional brain. Finally, functional fMRI studies have revealed an attenuated response of the amygdala to emotional stimuli as compared to neutral stimuli. Beyond demonstrating that dysfunction of the emotional brain is a hallmark of schizophrenia, we propose a model that integrates previous neural accounts of emotional abnormalities in schizophrenia, and specifies a neural basis for differential emotional correlates of positive and negative symptoms. Specifically, a lesion to the amygdala in combination with reduced interconnectivity with the prefrontal cortex is hypothesized to give rise to reduced emotional expression (affective flattening) and emotion recognition deficits. In contrast, an imbalance in dopamine systems may underlie increased anxiety and autonomic arousal, and the assignment of emotional salience to insignificant stimuli, associated with psychosis. We also hypothesize that the central and basolateral nuclei of the amygdala may contribute differentially to these abnormalities.

Affective Symptoms↗
PubMed2004

Cobalamin: a critical vitamin in the elderly.

Vitamin B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol/L (300-350 pg/mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced vitamin B(12) level is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B(12) status is assumed to be involved in the development and progression of dementia (e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of elderly persons (>/=60 years) should be regularly controlled and a general supplementation with vitamin B(12) (>50 microg/day) should be considered.

Aged↗
PubMedDate not supplied

Psychopathology in 90 consecutive human immunodeficiency virus-seropositive and acquired immune deficiency syndrome patients with mostly intravenous drug use history.

This report presents systematic clinical data regarding psychiatric diagnoses, personal and family psychiatric histories, and symptomatologic aspects of 90 consecutive human immunodeficiency virus (HIV)-seropositive and acquired immune deficiency syndrome (AIDS) patients, of whom slightly less than two thirds were at risk due to intravenous drug abuse. In addition, a comparison was made between the distribution patterns of these variables at various stages of HIV illness and related at-risk behaviors. Eighty-four percent of the patients met criteria for a spectrum of DSM-III-R diagnoses (mostly affective) that were associated with high rates of affective and alcohol abuse disorders among first-degree relatives. Mood disorders did not differ significantly between the two main groups at risk (intravenous drug users [IVDUs] v others) by gender, age, or stage of illness. The overall data from the rating scales show high levels of psychic and somatic anxiety in the early stages of illness, whereas cognitive symptoms, retardation, and disorientation are dominant in later stages. A noteworthy finding in this study is that many depressed patients demonstrated current and/or past hypomanic, hyperthymic, or cyclothymic features with no evidence of brain damage detectable by computed axial tomography (CAT). These temperamental attributes, which preceded HIV infection, may have served as risk factors for both drug abuse and impulsive sexual behavior in all types of at-risk groups.

Adjustment Disorders↗
PubMedDate not supplied

[Leponex, 10 years after -- a clinical review].

Clozapine was one of the major advances in the treatment of schizophrenia since the introduction of the classic antipsychotic agent chlorpromazine in the 1950s. Over the past 10 years, clozapine has become the reference compound for the development of new antipsychotics, and new drugs have been developed which have also claimed atypical status. The indications of clozapine were recently extended to Psychosis in Parkinson's disease and harmonized in the European Union. This provides the opportunity to update the data on clozapine in the treatment of schizophrenia. In this article we review current clinical evidence in schizophrenia to address the following issues: 1) Efficacy in refractory/positive symptoms: a systematic and critical analysis of 14 double-blind clinical trials in comparison with both standard and novel antipsychotics show consistent findings in favour of clozapine, with all but three of the reports demonstrating superiority. The review of studies allow us to say little about the predictors of treatment response, time to clozapine response and about the impact of clozapine on the quality of patients'life and longer-term outcome. Treatment options for clozapine non-responders are reviewed. 2) Risk of EPS: clozapine is considered to have a minimal risk of EPS and in all studies where a valid methodology was used, a clear superiority over the other neuroleptics is demonstrated. It is pointed out that, if the prevalence and incidence of EPS with clozapine is low, it is not zero. All the studies assessing clozapine treatment for TD have major methodological limitations, so no final conclusion can be drawn. 3) Efficacy for primary and secondary negative symptoms and neurocognitive effects: the data of clinical studies where negative symptoms scales were used favour clozapine in terms of improvement. However most of the studies were carried out in populations with predominantly positive symptoms. With regard to the need to distinguish primary and secondary symptoms, data are conflicting regarding the benefit of clozapine. Due to the lack of studies with a valid methodology, no definitive conclusion can be drawn about the efficacy on clozapine on the deficit syndrome and on neurocognitive disorders. 4) Impact on suicide risk: 4 out of 6 retrospective studies provide evidence for the ability of clozapine therapy to reduce suicidal behaviour. The results of a recent randomized, parallel-group study designed to compare clozapine versus olanzapine in preventing suicide attempts seems to confirm this hypothesis. We also address the tolerability and safety data, especially haematologic, comitial, cardiovascular and metabolic side-effects. The effectiveness of blood monitoring for the management of neutropenia and agranulocytosis demands that the recommendations are strictly followed. The use of clozapine at doses higher than 600 mg daily should follow published recommendations, in order to minimize the risk of seizures; these include anticonvulsant regimens based on blood levels. With regard to the cardiovascular mortality, if clozapine therapy has negligible effects on QT interval, its association with potential fatal myocarditis cannot be excluded in young patients who should be investigated if they develop cardiac symptoms in the first weeks of treatment. Available data support the notion that the frequency of bodyweight gain is high with several new antipsychotics, including clozapine. Potential long term effects of bodyweight gain on mortality and morbidity have to be taken into consideration. The pharmacological mechanisms underlying the "unique clozapine profile" is discussed. Clozapine remains the only antipsychotic with efficacy at relatively low D2 receptor occupancy. The pharmacogenetic and pharmacokinetic aspects are also reviewed. Finally, the place of clozapine in the current treatment of schizophrenia is highlighted to inform the development of guidelines for clinical management.

Antipsychotic Agents↗
PubMed1992

Prevalence of mental disorders in newly admitted medical inpatients with AIDS.

The authors evaluated 42 newly admitted medical inpatients with acquired immune deficiency syndrome (AIDS) using DSM-III-R criteria and obtained quantitative ratings of psychiatric morbidity using standard instruments. A current Axis I disorder was present in 61.9% of the patients. Organic mental disorders predominated (47.6% of all patients) and were more common in the most severely ill patients. Major depressive syndrome was rarer than expected (9.5%). Recent physical disability was correlated with repeated hospitalizations, and trends were found suggesting correlation of recent physical disability with increased anxiety and cognitive impairment. This study, using actual patient evaluations, suggests predictors of psychiatric morbidity in this setting and argues for routine psychiatric screening of medical inpatients with AIDS.

AIDS Dementia Complex↗