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Biomedical subjects

Perminder Sachdev

Publications and source records attributed to Perminder Sachdev.

At least 19 recordsLinked to original sources
PubMed2007

Progression of white matter hyperintensities in elderly individuals over 3 years.

OBJECTIVE: The aims of this study were to examine white matter hyperintensities (WMHs) in the brains of elderly individuals, the rate of progression, the anatomic regions most vulnerable, and the predictors of change. METHODS: We examined 51 healthy volunteers (mean age 71 years) with T2-weighted brain MRI on the same scanner 3 years apart. WMH volumes were determined by an automated method, and the anatomic location of change was determined for both deep WMHs (DWMHs) and periventricular WMHs (PVWMHs). RESULTS: The total brain WMH volume increased by 39.6%, i.e., 13.2% per year, with the change in DWMH being 43.8% and 29.7% in PVWMH. The increase was significant in all regions except the occipital lobe and cerebellum. Age, sex, and cerebrovascular risk factors were not significant predictors of WMH progression. The main predictor of progression was baseline level of WMH. The number of WMH lesions increased by a mean of 1.78, and the progression was mainly accounted for by an increase in very large (>16 mm) lesions. Eight subjects showed a slight decrease in WMH. CONCLUSIONS: White matter hyperintensities are progressive in most elderly individuals with an increasing rate of progression as the burden of lesions increases. The rate of progression is greater in deep white matter and in the anterior brain regions. Risk factors for progression are not well understood, and genetic and other environmental factors must be examined. Quantitation of white matter hyperintensities may serve as a surrogate marker of the progression of small vessel disease.

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PubMed2006

Assessment of complex mental activity across the lifespan: development of the Lifetime of Experiences Questionnaire (LEQ).

BACKGROUND: Brain reserve is a property of the central nervous system related to complex mental activity which may mediate the course and clinical expression of brain injury. Since there is no instrument that comprehensively assesses complex mental activity through the lifespan, we developed and tested the Lifetime of Experiences Questionnaire (LEQ) in a prospective study of healthy ageing. METHOD: The LEQ assesses educational, occupational and cognitive lifestyle activities at different stages through life. Test-retest, item analysis and Item Response Theory (IRT) were used to determine reliability. Dimensionality was evaluated using factor analysis. Validity was established through IRT analysis of test performance, correlation with an extant contemporaneous instrument (Cognitive Activities Scale; CAS) and prediction of global cognitive change over 18 months controlling for age, baseline cognition and hypertension. RESULTS: In a sample of healthy older individuals (n=79) the LEQ was found to be consistent, coherent and discriminate between individuals with high and low mental activity levels. Factor analysis revealed a dominant factor which loaded heavily on education, occupation and leisure activity. Total LEQ was significantly correlated with the CAS. Furthermore, individuals with higher LEQ scores showed less cognitive decline over 18 months, independent of covariates (r=0.37, p=0.003). CONCLUSIONS: The LEQ is a reliable and valid instrument for assessing complex lifespan mental activity which is protective against cognitive decline. The LEQ is therefore proposed as a useful tool for estimating brain reserve in older individuals and further development is anticipated.

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PubMed2006

The brain reserve hypothesis, brain atrophy and aging.

BACKGROUND: Researchers have used the concept of brain reserve to explain the dissociation between pathological brain damage and cognitive and functional performance. A variety of brain reserve hypotheses exist, and different empirical strategies have been employed to investigate these variants. OBJECTIVE: The study investigates (i) the relationship between measures of brain burden (atrophy, white matter hyperintensities (WMH)) and measures of reserve (education, creativity, and intelligence); (ii) the relationship between cognitive decline and reserve; (iii) whether measures of reserve mediate the effect of atrophy on estimated cognitive change, and (iv) the association between brain risk factors, education and atrophy. METHODS: A cross-sectional study of a sample of 446 individuals 60-64 years of age who underwent MRI scans as part of a large epidemiological study. Measures were taken of education, intelligence, creativity, cognitive speed, brain volume, WMH, estimated cognitive decline from earlier in life and brain atrophy. RESULTS: No association was found between estimated cognitive decline and brain burden (atrophy, WMH). Risk factors for brain insult were not associated with greater brain atrophy in the less well educated. Neither education, nor any other measure including intelligence or creativity, provided a buffer for cognitive decline in individuals with high levels of brain atrophy. CONCLUSION: Little support was found for the brain reserve hypothesis.

Aging↗
PubMed2006

Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study.

OBJECTIVE: To examine whether euthymic bipolar patients engage similar or contrasting brain regions as healthy subjects when responding to implicit affect induction. METHODS: The study examined 10 euthymic patients with bipolar I disorder, and 10 age- and gender-matched healthy subjects using event-related functional magnetic resonance imaging (fMRI) while subjects engaged in a modified word-based memory task designed to implicitly evoke negative, positive or no affective change. The activation paradigm involved nominating whether a target word was contained within a previously presented word list using specified response keys. RESULTS: The fMRI task produced significantly greater activation in healthy subjects as compared to patients in response to both negative and positive affect in the anterior and posterior cingulate, medial prefrontal cortex, middle frontal and right parahippocampal gyri. Only negative affect produced significantly greater activation in the postcentral gyrus, inferior parietal lobule, thalamus and putamen and only positive affect achieved the same in the precentral, superior temporal and lingual gyri, precuneus, cuneus, caudate, pons, midbrain and cerebellum. There were no brain regions in which responses were greater in patients as compared to healthy subjects. There were no statistically significant differences between the groups with respect to speed or accuracy. CONCLUSIONS: Diminished prefrontal, cingulate, limbic and subcortical neural activity in euthymic bipolar patients as compared to healthy subjects is suggestive of emotional compromise that is independent of cognitive and executive functioning. This finding is of clinical importance and has implications both for the diagnosis and treatment of bipolar disorder. Future studies should aim to replicate these findings and examine the development of bipolar disorder, investigating in particular the effects of medication.

Adult↗
PubMed2006

Brain reserve and cognitive decline: a non-parametric systematic review.

BACKGROUND: A previous companion paper to this report (Valenzuela and Sachdev, Psychological Medicine 2006, 36, 441-454) suggests a link between behavioural brain reserve and incident dementia; however, the issues of covariate control and ascertainment bias were not directly addressed. Our aim was to quantitatively review an independent set of longitudinal studies of cognitive change in order to clarify these factors. METHOD: Cohort studies of the effects of education, occupation, and mental activities on cognitive decline were of interest. Abstracts were identified in MEDLINE (1966-September 2004), CURRENT CONTENTS (to September 2004), PsychINFO (1984-September 2004), Cochrane Library Databases and reference lists from relevant articles. Eighteen studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Cognitive decline studies were integrated using a non-parametric method after converting outcome data onto a common effect size metric. RESULTS: Higher behavioural brain reserve was related to decreased longitudinal cognitive decline after control for covariates in source studies (phi=1.70, p<0.001). This effect was robust to correction for both multiple predictors and multiple outcome measures and was the result of integrating data derived from more than 47000 individuals. CONCLUSIONS: This study affirms that the link between behavioural brain reserve and incident dementia is most likely due to fundamentally different cognitive trajectories rather than confound factors.

Brain↗
PubMed2006

Inhibition of indoleamine 2,3 dioxygenase activity by H2O2.

Indoleamine 2,3-dioxygenase is the first and rate limiting enzyme of the kynurenine pathway of tryptophan metabolism, has potent effects on cell proliferation and mediates antimicrobial, antitumorogenic, and immunosuppressive effects. As a potent cytotoxic effector, the mechanisms of indoleamine 2,3-dioxygenase inhibition deserve greater attention. The work presented here represents the first systematic study exploring the mechanisms by which low levels of hydrogen peroxide (10-100 microM) inhibit indoleamine 2,3-dioxygenase in vitro. Following brief peroxide exposure both enzyme inhibition and structural changes were observed. Loss of catalysis was accompanied by oxidation of several cysteine residues to sulfinic and sulfonic acids, observed by electrospray and MALDI mass spectrometry. Enzyme activity could in part be preserved in the presence of sulfhydryl containing compounds, particularly DTT and methionine. However, these structural alterations did not prevent substrate (l-tryptophan) binding. Some enzyme activity could be recovered in the presence of thioredoxin, indicating that the inhibitory effect of H(2)O(2) is at least partially reversible in vitro. We present evidence that cysteine oxidation represents one mechanism of indoleamine 2,3-dioxygenase inhibition.

Dose-Response Relationship, Drug↗
PubMed2006

Hormone replacement therapy, brain volumes and white matter in postmenopausal women aged 60-64 years.

Research on the structural and functional effects of hormone replacement therapy on the brain has produced inconsistent results. This paper reports on cross-sectional associations between hormone replacement therapy use and volumes of brain structures measured using magnetic resonance imaging in 213 postmenopausal women aged 60-64 years recruited from a large population study. Of these, 64 were current hormone replacement therapy users, 69 previous users and 80 had never used hormone replacement therapy. No differences were observed between groups in total grey matter, white matter, hippocampal or amygdalar volumes, severity or volume of white matter hyperintensities, or in different measures of brain atrophy. While acknowledging the limitations of a cross-sectional study, the results argue against hormone replacement therapy being protective against brain changes associated with ageing in women in their early 60s.

Brain↗
PubMed2006

Sex and symmetry differences in hippocampal volumetrics: before and beyond the opening of the crus of the fornix.

Published normative volumetrics of the hippocampus (HC) vary substantially. While the protocol suggested by Watson et al. (Neurology 42 (1992) 1743-1750; Arch Neurology 54 (1997) 1521-1531) is the most frequently adhered to, this leaves the posterior section of the HC tail unmeasured, which has been estimated to be in the order of 2-4 mm, representing 5-10% of total HC volume. The objective of the current study was to compare HC volumes according to the method of Watson et al. (Neurology 42 (1992) 1743-1750; Arch Neurology 54 (1997) 1521-1531) against those measured to include the posterior tail section. From a random community sample of 60-64 yr old individuals, 478 subjects underwent magnetic resonance imaging brain scans. Of these, 452 scans (238 males and 214 females) were adequate for hippocampal measurement. The scans comprised whole brain T1- weighted and T2-weighted FLAIR images. One hundred and fifty scans were randomly selected for the measurement of HC volumes beyond the opening of the crus of the fornix by manual tracings on T1-weighted images by a trained operator. Intracranial volume (ICV) and total brain volume (TBV) were measured using an automated program. We found that the posterior HC tail extended for a mean of just over 5 mm and comprised 11% of total HC volume. Males had significantly larger raw HC volumes, and while normalization with ICV or TBV reversed this pattern, it was significant only when the posterior HC tail was included in the measurement. In conclusion, this study showed that including the posterior part of the tail can influence the results of HC measurement. An argument is presented that accurate HC volumes should include the entire HC and not exclude the tail.

Adult↗
PubMed2005

Brain reserve and dementia: a systematic review.

BACKGROUND: Behavioural brain reserve is a property of the central nervous system related to sustained and complex mental activity which can lead to differential expression of brain injury. Behavioural brain reserve has been assessed using autobiographical data such as education levels, occupational complexity and mentally stimulating lifestyle pursuits. So far there have been several epidemiological reports but no systematic review to put conflicting results into context. Our aim was to quantitatively review evidence for the effect of brain reserve on incident dementia. METHOD: Cohort studies of the effects of education, occupation, premorbid IQ and mental activities on dementia risk were of interest. Abstracts were identified in MEDLINE (1966-September 2004), CURRENT CONTENTS (to September, 2004), PsychINFO (1984-September 2004), Cochrane Library Databases and reference lists from relevant articles. Twenty-two studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Studies were combined through a quantitative random-effects meta-analysis. RESULTS: Higher brain reserve was associated with a lowered risk for incident dementia (summary odds ratio, 0.54; 95% confidence interval, 0.49-0.59). This effect was found over a median of 7.1 years follow-up and resulted from integrating data across more than 29000 individuals. Notably, increased complex mental activity in late life was associated with lower dementia rates independent of other predictors; a dose-response relationship was also evident between extent of complex mental activities in late life and dementia risk. CONCLUSIONS: This study demonstrates robust evidence that complex patterns of mental activity in the early, mid- and late-life stages is associated with a significant reduction in dementia incidence. Randomized control trials based on brain-reserve principles are now required.

Brain↗
PubMed2005

Within-occasion intraindividual variability and preclinical diagnostic status: is intraindividual variability an indicator of mild cognitive impairment?

Intraindividual variability in cognitive test performance has the potential to be a good marker of preclinical Alzheimer's disease status (S. C. Li & U. Lindenberger, 1999). Using cross-sectional community data from 2,317 individuals aged 60-64 years, the authors of this study found that variability was greater in individuals who met criteria for mild cognitive impairment or aging-associated cognitive decline but not for age-associated memory impairment. Higher variability was associated with lower education and a non-English-speaking background. In contrast to previous findings, variability in this study did not contribute uniquely to meeting criteria for mild cognitive impairment. The reasons for the differences may reside in the authors' method of estimating mean independent variability, the use of an occasion-specific measure, or the relatively younger age of the participants. Follow-up of the cohort in 4 years will yield data on the prospective validity of variability as a risk factor for impairment.

Adult↗
PubMed2005

Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: a pilot investigation.

In an open study, four subjects with a stable deficit syndrome of schizophrenia received high frequency repetitive transcranial magnetic stimulation (15 Hz at 90% of motor threshold, 1800 pulses each session, daily for 20 sessions over 4 weeks) over the left dorsolateral prefrontal cortex. Subjects showed a significant reduction in negative symptoms and improvement in function, with no change in positive symptoms. This improvement was maintained at the 1 month follow up. Repetitive transcranial magnetic stimulation as a treatment of the deficit syndrome of schizophrenia is feasible, safe and may be beneficial. A systematic study in randomized control trials would be appropriate.

Adult↗
PubMed2005

MRI hyperintensities and depressive symptoms in a community sample of individuals 60-64 years old.

OBJECTIVE: Previous studies have found associations of magnetic resonance imaging (MRI) signal hyperintensities with depression in the elderly. The present study investigates the association in a younger community sample (age 60-64 years) of depressed subjects and comparison groups for potential mediating and confounding variables. METHOD: A subsample of 475 persons 60-64 years of age from a larger community survey underwent brain MRI scans. White matter hyperintensities were quantified by using an automated procedure, and basal ganglia hyperintensities were quantified by using semiquantitative visual ratings. The study also assessed depressive symptoms and use of antidepressant medication. Potential mediating or confounding variables assessed included physical disability, hypertension, stroke, diabetes, head injury, cortisol, thyroid-stimulating hormone, cognitive functioning, smoking, and alcohol use. RESULTS: Depressive symptoms were found to be related to total brain white matter hyperintensities but not to basal ganglia hyperintensities. However, associations disappeared when statistical adjustment was made for physical disability and smoking. CONCLUSIONS: Depressive symptoms are related to white matter hyperintensities in mid-adult life in a community sample. Physical disability appears to play an important role in this association.

Age Factors↗
PubMed2004

Hippocampal and amygdalar volumes in relation to handedness in adults aged 60-64.

We evaluated the association between handedness and manual tracings of hippocampal and amygdalar volumes. Brain MRI and handedness data were obtained for 441 community dwelling participants aged 60-64 years of whom 31 were left-handed. Both absolute and normalized hippocampal volumes were larger in left-handed women than right-handed women. Hippocampal volume was not associated with handedness in men, and amygdalar volume was not associated with handedness in men or women. There was no right-left asymmetry in hippocampal or amygdalar volumes in either gender. We conclude that volumetric differences by handedness must be taken into account where hippocampal volumes are of clinical importance. Our results may also explain reports of lower rates of dementia in left-handed individuals.

Adult↗
PubMed2004

Homocysteine, cerebrovascular disease and brain atrophy.

Homocysteine (Hcy) is known to increase the risk of cerebrovascular disease (CVD). Recent evidence suggests its direct contribution to brain atrophy, cognitive impairment and possibly Alzheimer disease (AD). This paper reports the results of two studies of the impact of Hcy on the brain. In the Sydney Stroke Study (N=131 stroke patients, 81 healthy controls), higher Hcy levels were related to increased number of strokes and greater cognitive impairment, in particular, frontal-executive function and attention. In the control group, Hcy was related to increased subcortical atrophy. In the PATH Through Life Study, involving 60-64 years old community-dwelling individuals (N=385), Hcy was related to an increase in white matter hyperintensities, as well as impairment in verbal memory and fine motor speed. Hcy increases the risk of micro- and macrovascular disease as well as brain atrophy, and thereby impaired cognition. Remediation of high Hcy levels should begin early in life.

Aged↗
PubMed2004

Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia.

Vascular cognitive impairment (VCI) was proposed as an umbrella term to include subjects affected with any degree of cognitive impairment resulting from cerebrovascular disease (CVD), ranging from mild cognitive impairment (MCI) to vascular dementia. VCI may or may not exclude the host of "focal" circumscribed impairments of specialized functions such as language (aphasia), intentional gesture (apraxia), or categorical recognition (agnosia), among others, that may result from a stroke. Therefore, there are no universally accepted diagnostic criteria for VCI. We conclude that this concept could be more useful if it were to be limited to cases of vascular MCI without dementia, by analogy with the concept of amnestic MCI, currently considered the earliest clinically diagnosable stage of Alzheimer disease (AD). In agreement with our view,the Canadian Study on Health and Aging successfully implemented a restricted definition of VCI, excluding cases of dementia (i.e., vascular cognitive impairment no dementia, VCI-ND). The Canadian definition and diagnostic criteria could be utilized for future studies of VCI. This definition excludes isolated impairments of specialized cognitive functions. Vascular dementia (VaD): The main problem of this diagnostic category stems from the currently accepted definition of dementia that requires memory loss as the sine qua non for the diagnosis. This may result in over-sampling of patients with AD worsened by stroke (AD+CVD). This problem was minimized in controlled clinical trials of VaD by excluding patients with a prior diagnosis of AD, those with pre-existing memory loss before the index stroke, and those with amnestic MCI. We propose a definition of dementia in VaD based on presence of abnormal executive control function, severe enough to interfere with social or occupational functioning. Vascular cognitive disorder (VCD): This term, proposed by Sachdev [P. Sachdev, Vascular cognitive disorder. Int J Geriat Psychiatry 14 (1999)402-403.] would become the global diagnostic category for cognitive impairment of vascular origin, ranging from VCI to VaD. It would include specific disease entities such as post-stroke VCI, post-stroke VaD, CADASIL, Binswanger disease, and AD plus CVD. This category explicitly excludes isolated cognitive dysfunctions such as those mentioned above.

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