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Perminder Sachdev

Publications and source records attributed to Perminder Sachdev.

At least 37 records · Page 2Linked to original sources
PubMed2004

[Homocysteine and neuropsychiatric disorders].

The author presents an overview of the current literature on homocysteine as a risk factor for neuropsychiatric disorders. The databases MEDLINE, Current Contents and EMBASE were searched (between 1966 and 2002) for English language publications with the key words 'Homocysteine' and 'Stroke'; 'Alzheimer Disease'; 'Cognitive Impairment'; 'Epilepsy'; 'Depression'; or 'Parkinson's disease'. Individual articles were hand searched for relevant cross-references. It is biologically plausible that high homocysteine levels may cause brain injury and neuropsychiatric disorders. Homocysteine is proatherogenic and prothrombotic, thereby increasing the risk of cerebrovascular disease, and may have a direct neurotoxic effect. Evidence for homocysteine as a risk factor for cerebral microvascular disease is conflicting but warrants further study. Cross-sectional and some longitudinal studies support increased prevalence of stroke and vascular dementia in hyperhomocysteinemic individuals. The evidence of increased neurodegeneration is accumulating. The relationship with depression is still tentative, as it is with epilepsy. Currently, treatment studies are necessary to place the evidence on a stronger footing, and maybe high-risk patients should be screened for hyperhomocysteinemia and this should be treated with folic acid. More research evidence is necessary before population screening can be recommended.

Alzheimer Disease↗
PubMed2004

Quantification of hemorphins in Alzheimer's disease brains.

The hemorphins are a family of opioid receptor-binding peptides originating from the beta-chain of hemoglobin and have been found at high levels within the central and peripheral nervous systems. In addition to opioid receptor binding, hemorphins have been shown to have a number of effects on the renin-angiotensin system, including inhibition of angiotensin-converting enzyme and angiotensin IV receptor binding. However, relatively few studies have examined the role of hemorphins in neurological diseases. Here we report the first study of hemorphins in Alzheimer's disease (AD) brains. Quantitative MALDI-TOF mass spectrometry was employed to assess levels of LVV and VV hemorphin-6 and -7 in 10 control and 10 AD brain tissue samples. LVV hemorphin-6 and total hemorphin levels were elevated in AD temporal neocortex but not in hippocampus, occipital lobe, or frontal lobe. The elevation of hemorphins is probably indicative of a vascular abnormality resulting from cerebral amyloid angiopathy associated with both neurodegenerative disease and aging.

Aged↗
PubMed2004

Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men.

BACKGROUND: High serum homocysteine (HCY) levels have been associated with thromboembolic cerebrovascular disease, but their relationship to microvascular disease is uncertain. Homocysteine also has a direct neurotoxic effect and has been linked to brain atrophy and an increased risk of Alzheimer disease. OBJECTIVE: To examine the relationship of HCY levels to brain and cognitive measures in a healthy community sample. DESIGN: Cross-sectional study. SETTING: Individuals residing in Canberra and Queanbeyan, Australia, who were participating in the longitudinal PATH Through Life Project. PARTICIPANTS: Individuals aged 60 to 64 years selected randomly from the community, 196 men and 189 women. MAIN OUTCOME MEASURES: Regression coefficients with HCY level as the putative determinant and various magnetic resonance imaging measures (brain atrophy index, ventricle-brain ratios, volume of periventricular and deep white matter hyperintensities) and cognitive measures (information processing speed, verbal memory, fine motor speed) as dependent measures. RESULTS: Homocysteine levels did not have a significant relationship with brain atrophy index or ventricle-brain ratios. High HCY levels were related to increased deep white matter hyperintensities but not periventricular white matter hyperintensities, after correcting for levels of folate, vitamin B(12), creatinine, and thyrotropin; hypertension; smoking; and diabetes, the relationship being significant only in men. Homocysteine levels were related to impairment in verbal memory and fine motor speed but not after the previously mentioned correction. CONCLUSIONS: Total HCY level is independently related to leukoaraiosis in middle-aged men, and this may be functionally relevant in the form of mild cognitive impairment. The remediation of hyperhomocysteinemia should begin early in life if its deleterious effects on the brain are to be prevented.

Brain↗
PubMed2004

Effect of white matter hyperintensities on cortical cerebral blood volume using perfusion MRI.

White matter hyperintensities (WMHs) are commonly seen on brain magnetic resonance imaging (MRI) scans of elderly individuals, but their functional significance remains controversial. We used perfusion-weighted MRI to determine the impact of WMHs on cortical regional cerebral blood volume (rCBV). We studied 24 elderly stroke patients and 27 control subjects with conventional MRI which included T2-weighted FLAIR coronal slices through whole brain and gadolinium-DTPA (0.2 mmol/kg)-based perfusion MRI (pMRI) with echo planar imaging. Volumes of WMHs, including deep WMHs and periventricular hyperintensities (PVHs), were computed by an automated method after excluding regions of infarction. Partial correlations between WMH and corresponding cortical rCBV were determined after correction for age and atrophy. The relative rCBV of gray matter was higher in control subjects and there was no significant hemispheric asymmetry. When both stroke and control groups were included, there were significant correlations among frontal cortical rCBV and frontal WMHs, temporal cortical rCBV with temporal WMHs, and cortical rCBV with both total deep WMHs and PVHs. Although the trends of correlation still existed when the two groups were analyzed separately, they were not significant. The correlations between cortical rCBV and WMHs in the same lobe were significant for subjects with more severe hyperintensities irrespective of the group. In conclusion, T2-weighted WMHs are associated with reduced rCBV in the cerebral cortex, particularly in individuals with extensive hyperintensities.

Age Factors↗
PubMed2004

The topography of white matter hyperintensities on brain MRI in healthy 60- to 64-year-old individuals.

We report the topography of brain white matter hyperintensities (WMHs) on T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging in 477 healthy subjects aged 60-64 years selected randomly from the community. WMHs were delineated by using a computer algorithm. We found that all subjects had periventricular WMHs and 96.6% subjects also had deep WMHs. The mean volume of WMHs was 4.9 ml, comprising 0.83% of the white matter, of which 1.2 ml was severe in intensity. The deep WMHs were distributed throughout the cerebral hemispheres, with the occipital and frontal white matter bearing the greatest burden. The territory of the lenticulostriate arteries had the greatest WMHs. A white matter region of 4 mm adjacent to the cortex was not affected by hyperintensities. The mean (SD) number of discrete WMHs was 19.6 (7.1) per subject, of which 6.1 (4.4) were severe in intensity. Nearly half (48.6%) of the subjects had at least one large WMH (>12 mm diameter) and one eighth (12.5%) of the subjects had at least one large WMH that appeared to be severe in MRI. The overall load of WMHs was similar in men and women, but the latter had a higher proportion of their white matter so affected. This study provides the first detailed topographic analysis of WMHs in a large representative middle-aged sample, emphasizes their high prevalence in mid-adult life and raises issues about their etiology and significance.

Aging↗
PubMed2004

Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study.

OBJECTIVE: To determine whether acute neuroleptic-induced parkinsonism and akathisia were risk factors for the later development of tardive dyskinesia (TD) in patients on typical neuroleptics. METHOD: Of 100 subjects examined for parkinsonism and akathisia after the initiation of typical neuroleptic medication, 78 were followed up for TD after a mean 41.2 months. RESULTS: Nine (11.5%) subjects were diagnosed with TD, predominantly manifesting as oro-facial dyskinesia. They had greater severity of parkinsonism and akathisia at baseline, and a larger neuroleptic load, than those who did not develop TD. On regression analyses, parkinsonism at baseline was a significant predictor of later TD. Examined independently of parkinsonism, akathisia severity at 2 weeks was also a significant predictor of later TD. CONCLUSIONS: Acute drug-induced parkinsonism and akathisia are both predictors of TD, with parkinsonism having greater predictive value. Acute and tardive extrapyramidal syndromes may share vulnerability factors.

Adult↗
PubMed2004

Cognitive generation of affect in bipolar depression: an fMRI study.

Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age-matched and sex-matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state-related or trait-related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance.

Adult↗
PubMed2004

Cognitive generation of affect in hypomania: an fMRI study.

OBJECTIVE: To identify the brain regions associated with the cognitive generation of affect in hypomanic bipolar patients. METHODS: The study examined 10 hypomanic female subjects with bipolar affective disorder, and 10 age- and sex-matched comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned-pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (a) negative and reference, (b) positive and reference and (c) positive and negative captioned-pictures. RESULTS: The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal cortex. Activation in patients involved additional subcortical regions namely the caudate and thalamus. CONCLUSIONS: This preliminary study suggests that hypomanic patients recruit additional subcortical limbic systems for emotional evaluation when advanced prefrontal cortical processing is no longer sufficient. The differential patterns of activation inform us about bipolar disorder and may have potential diagnostic and therapeutic significance.

Adult↗
PubMed2004

Cerebral blood volume in T2-weighted white matter hyperintensities using exogenous contrast based perfusion MRI.

We used perfusion weighted magnetic resonance imaging (MRI) to determine relative regional cerebral blood volume (rCBV) in regions of white matter hyperintensity (WMH) in 28 elderly stroke patients and 27 healthy comparison subjects, using T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence MRI for anatomical localization and bolus gadolinium-DTPA tracking for perfusion weighted imaging. We found that WMHs had significantly lower rCBV than contralateral normal WMH, irrespective of size or group membership, and rCBV was significantly related to the size of the WMH. For the larger WMHs, there was a significant increase in rCBV from inner core to outer ring. The findings suggest hemodynamic perturbation in the microvasculature of hyperintense regions, which becomes greater as the size of the WMH increases. This is equally applicable to stroke patients and healthy older individuals.

Aged↗
PubMed2003

Memory training alters hippocampal neurochemistry in healthy elderly.

Accumulating epidemiological evidence supports the notion of brain reserve, but there has been no investigation of neurobiological change associated with brief mental activation training in humans. Healthy older individuals were therefore investigated with magnetic resonance spectroscopy (MRS) in different brain regions before and after 5 weeks of focused memory training. Recall of a test-word list of > 23 items was achieved accompanied by elevation of creatine and choline signals in the hippocampus. Those at risk for neural dysfunction, as indicated by lower neurometabolites at baseline, demonstrated the largest MRS increases after training. Biochemical changes related to cellular energy and cell-membrane turnover were found to increase after structured memory exercises and were limited to the medial temporal lobe.

Aged↗
PubMed2003

ECNI GC-MS analysis of picolinic and quinolinic acids and their amides in human plasma, CSF, and brain tissue.

To study the complex inter-relationships between inflammatory and apoptotic responses and the kynurenine pathway, we have utilized electron-capture negative ion mass spectrometry to develop trace analyses to concurrently quantify nicotinic acid (NIC), picolinic acid (PIC) and quinolinic acid (QUIN) in biological samples. We have shown that NIC and its amide nicotinamide (NAM) can be separately quantified by analyzing samples pre- and post-acid hydrolysis. We have now examined human plasma, CSF and brain tissue samples for the presence of putative picolinamide (PAM) and quinolinamide (QAM) by comparing PIC and QUIN concentrations pre- and post- gas phase hydrolysis. We report for the first time that, with respect to the free acids, relatively high concentrations of the amides (or, at least, hydrolysable precursors of the acids) are present in plasma and brain with marked relative increases in CSF. In normal control subjects (n=22) pre-hydrolysis plasma levels (+/- sem) of PIC and QUIN were 0.299 +/- 0.034 and 0.47 +/- 0.047 micromol/L respectively. Following hydrolysis the concentrations rose more than 4-fold to 1.33 +/- 0.115 and 2.2 +/- 0.27 micromol/L respectively. In CSF samples from patients with no sign of brain injury or pathology (n=10) pre-hydrolysis concentrations of PIC and QUIN were 0.017 +/- 0.005 and 0.018 +/- 0.006 micromol/L, respectively, which rose to 0.30 +/- 0.06 and 0.06 +/- 0.008 micromol/L respectively, after hydrolysis. In CSF samples from patients with a range of brain oedema or injury (eg subdural haemorrage, motor vehicle accident) (n=6) pre-hydrolysis concentrations of PIC and QUIN were 0.053 +/- 0.03 and 0.29 +/- 0.12 micromol/L, respectively. Following hydrolysis the concentrations were markedly increased to 6.06 +/- 1.5 and 0.94 +/- 0.63 micromol/L, respectively. The present investigation has shown for the first time that PAM and QAM are present endogenously with PAM being relatively higher than QAM, especially in CSF samples from patients with presumed brain inflammation. The site and mechanism of amidation of PIC and QUIN needs investigation.

Adult↗
PubMed2003

Savant-like skills exposed in normal people by suppressing the left fronto-temporal lobe.

The astonishing skills of savants have been suggested to be latent in everyone, but are not normally accessible without a rare form of brain impairment. We attempted to simulate such brain impairment in healthy people by directing low-frequency magnetic pulses into the left fronto-temporal lobe. Significant stylistic changes in drawing were facilitated by the magnetic pulses in four of our 11 participants. Some of these "facilitated" participants also displayed enhanced proofreading ability. Our conclusions are derived from 11 right-handed male university students, eight of whom underwent placebo stimulation. We examined performance before, during and after exposure to the stimulation.

Adult↗
PubMed2003

Neuropsychiatry.

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Biological Psychiatry↗
PubMed2003

Long-term outcome of late-onset schizophrenia: 5-year follow-up study.

BACKGROUND: There is controversy about whether late-onset schizophrenia is a precursor of cognitive decline. AIMS: To examine the long-term outcome of a group of patients with late-onset schizophrenia. METHOD: Patients with onset of DSM-III-R schizophrenia at age 50 years or over, but without dementia, and a healthy control group were assessed at baseline (n=27 and n=34, respectively), after 1 year and after 5 years (n=19 and n=24, respectively) on measures of psychopathology, cognition and general functioning, and compared on rates of decline and incidence of dementia. RESULTS: Nine patients with late-onset schizophrenia and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, 3 dementia of unknown type) at 5-year follow-up. There appeared to be a subgroup of late-onset schizophrenia patients without signs of dementia at baseline or at 1 year follow-up who subsequently declined. CONCLUSIONS: Late-onset schizophrenia may be a prodrome of Alzheimer-type dementia. More longitudinal studies are required to determine its nosological status.

Activities of Daily Living↗
PubMed2002

Homocysteine in neuropsychiatric disorders of the elderly.

OBJECTIVE: There is increasing interest in homocysteine as a risk factor for neuropsychiatric disorders such as stroke, dementia, depression and Parkinson's disease. This article reviews the current literature on the relationship between homocysteine and these disorders to ascertain if any clinical recommendations can be made. METHOD: A MEDLINE and EMBASE search was made for English language publications between 1966 and 2002 using the search terms 'Homocysteine' and 'Stroke', 'Dementia', 'Vascular Dementia', 'Alzheimer's dementia', 'Cognition disorders or cognitive decline or memory disorders', 'Depression or depressive disorders' or 'Parkinson's disease'. In addition, individual articles were hand searched for relevant references. RESULTS: Cross-sectional studies consistently suggest that elevated homocysteine increases the risk of stroke, and may also increase the risk of leukoariosis, vascular dementia (VaD), cognitive impairment and Alzheimer's disease (AD). Longitudinal studies of homocysteine as a risk factor are few and inconsistently supportive of these associations. No intervention trials to determine the effect of lowering homocysteine levels have yet been published. The pathological mechanisms for homocysteine-mediated disease await complete elucidation. Mild hyperhomocysteinemia is common in the elderly population, and folate supplementation can decrease homocysteine levels. CONCLUSION: The epidemiological evidence for homocysteine as a risk factor for neuropsychiatric disease is an emerging area of great interest. Screening the population for hyperhomocysteinemia cannot be recommended at this stage, but individuals at increased risk of cerebrovascular disease or cognitive impairment should be investigated and treated for elevated homocysteine levels.

Aged↗
PubMed2002

Novel physical treatments for the management of neuropsychiatric disorders.

OBJECTIVE: To briefly describe the novel non-drug physical interventions currently in use in the investigation and treatment of neuropsychiatric disorders regarding their efficacy and potential future applications. METHODS: A systematic review of the literature concerning transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), vagus nerve stimulation (VNS) and neurosurgery for mental disorders (NMD) was conducted using Medline and literature known to the authors. RESULTS: A summary of each procedure is provided giving a succinct overview of efficacy, current applications and possible future indications. CONCLUSION: Novel and innovative physical interventions are currently being used to study brain function in health and disease. In particular, TMS has quickly established itself as a useful investigational tool and is emerging as a possible antidepressant therapy. Similarly, VNS has been applied successfully in the management of intractable epilepsy and is undergoing evaluation in the management of patients with treatment-resistant depression. DBS has shown significant promise in the treatment of Parkinson's disease and may have use in the management of obsessive-compulsive disorder. Finally, neurosurgical procedures for the treatment of mental disorders have been sufficiently refined to stage a comeback, although rigorous scientific study of their efficacy and indications is still necessary.

Brain Diseases↗
PubMed2002

Schizophrenia-like illness in velo-cardio-facial syndrome: a genetic subsyndrome of schizophrenia?

BACKGROUND: The study of genetic illnesses that have a behavioral phenotype resembling psychosis can provide important insights into the genetic basis of psychotic disorders and their patho-mechanisms. An important example of such a genetic disorder is the velo-cardio-facial syndrome (VCFS) associated with 22q11 microdeletion. CASE REPORT: The case of a 22-year-old male, who had the typical genotype and phenotype of VCFS and developed a psychotic illness characterized by withdrawal, catatonic posturing, inappropriate affect, stereotyped behavior, negativism and poverty of speech, is described. He had a partial response to an atypical neuroleptic, but developed myoclonus that was controlled with an anticonvulsant. CONCLUSION: The association of VCFS with schizophrenia-like psychosis is worthy of further study as it may provide insights into the molecular basis of neurodevelopment and its aberrations in psychotic disorders.

Abnormalities, Multiple↗