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J T O'Brien

Publications and source records attributed to J T O'Brien.

At least 37 records · Page 2Linked to original sources
PubMed2003

Atrophy of the putamen in dementia with Lewy bodies but not Alzheimer's disease: an MRI study.

OBJECTIVE: To compare the volume of the putamen on MRI in subjects with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and age-matched normal control subjects, along with the relationship between putamen volume and severity of both extrapyramidal signs and cognitive impairment. METHODS: MRI-based volumetric measurements at 1.5 T of total intracranial volume, total brain volume, and putamen volume were acquired in elderly patients with AD (n = 27; 77.6 years) and DLB (n = 14; 76.2 years) and normal control subjects (n = 37; 75.4 years). Patients and control subjects also underwent a standardized neuropsychiatric examination including the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Cambridge Cognitive Examination (CAMCOG) with Mini-Mental State Examination (MMSE). RESULTS: Patients with DLB had smaller raw putamen volumes than control subjects (right 12.5% reduction, p = 0.007; left 13.7% reduction, p = 0.003). When putamen volume was normalized to total intracranial volume, patients with DLB had significantly smaller volume ratios than both controls and patients with AD. Patients with AD did not differ from control subjects on any measure of putamen volume. Putamen volume did not correlate with age or with scores on UPDRS III, CAMCOG, or MMSE in any of the groups. CONCLUSIONS: Atrophy of the putamen is a feature of DLB. This may be important in understanding the etiology of parkinsonian features seen in DLB, though in this study, no direct correlation was found between degree of volume loss and severity of parkinsonism.

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PubMed2003

Changes in DWI and MRS associated with white matter hyperintensities in elderly subjects.

OBJECTIVE: To assess normal-appearing white matter (NAWM) characteristics by magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in elderly subjects. METHODS: The authors studied 60 volunteers (mean age 72.6 years; SD 4.7; range 64 to 84 years) without signs of neurologic illness. They used DWI and spectroscopic imaging to investigate whether there were changes in the NAWM that related to the presence of white matter hyperintensities (WMH). RESULTS: The authors found a correlation (p < 0.001) between the apparent diffusion coefficient in the NAWM and the total volume of WMH. The metabolite ratios N-acetylaspartate/creatine and N-acetylaspartate/choline of the NAWM also correlated significantly with total WMH volume. These correlations were independent of age. CONCLUSIONS: Damage associated with WMH is detectable in NAWM.

Aged↗
PubMed2003

Clinical predictors of response to Acetyl Cholinesterase Inhibitors: experience from routine clinical use in Newcastle.

BACKGROUND: Acetyl Cholinesterase Inhibitors (AChEIs) have been in clinical use for the past five years in the UK for the symptomatic treatment of Alzheimer's disease (AD). There are few data on the patterns and predictors of response to AChEI therapy in routine clinical practice. We therefore investigated clinical variables that may distinguish between AChEI responders and non-responders. METHODS: A retrospective sample of 160 consecutive patients with dementia who were treated on clinical grounds with an AChEI was studied. Treatment response was defined in two ways: (a) A clinical response was achieved when there was no deterioration or there was an improvement on a global clinical assessment (CGI) and (b) a Mini-Mental-State-Examination (MMSE) response when there was an improvement of 2 or more MMSE points. RESULTS: A total of 62 (45%) patients achieved an MMSE response. A diagnosis of dementia with Lewy Bodies (DLB) and Parkinson's disease+Dementia (PDD) was associated with a MMSE response, as were hallucinations, and lower MMSE scores at baseline. 125 (78%) patients achieved a CGI response for which there were no clinical predictors. CONCLUSIONS: Severity of illness, a diagnosis of DLB and PDD, and presence of hallucinations at baseline were predictive of a MMSE response. Non-AD dementia and severe dementia responded equally well to AChEI treatment and results of further randomised, placebo-controlled studies are needed to clarify the role of AChEI in the treatment of these disorders.

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PubMed2003

A comprehensive study of gray matter loss in patients with Alzheimer's disease using optimized voxel-based morphometry.

Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimer's disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

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PubMed2003

Regional cerebral blood flow in Parkinson's disease with and without dementia.

Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.

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PubMed2003

Effects of acute tryptophan depletion on cognitive function in Alzheimer's disease and in the healthy elderly.

BACKGROUND: The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects. METHOD: Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions. RESULTS: Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group. CONCLUSION: Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific 5HT receptors may be helpful in SDAT.

Affect↗
PubMed2003

Depression with late onset is associated with right frontal lobe atrophy.

BACKGROUND: The objective of this study was to determine whether older adults with first-ever onset of depression after age 60 years (late onset depression, LOD) have smaller frontal lobes than elderly patients with early-onset depression (EOD) and aged controls. METHOD: Twenty-seven subjects with LOD, 24 with EOD and 37 controls underwent volumetric MRI to determine right and left frontal lobe volumes and total brain volume. RESULTS: The right frontal volume of subjects with LOD was 8.0% and 5.6% smaller than that of patients with EOD (P < 0.01) and controls (NS) respectively. Volume of the left frontal lobe was not significantly different from EOD or controls. All analyses were adjusted for age, gender and total brain volume. Unlike controls and those with EOD, patients with LOD did not display a significant positive correlation between cognitive scores and total brain, left frontal or right frontal volumes. CONCLUSION: LOD is associated with right frontal lobe atrophy and loss of the correlation between cognitive performance and brain volume. This adds support to the fronto-striatal hypothesis of depression and suggests that structural brain changes have a particular role in cases of LOD.

Age of Onset↗
PubMed2002

Characterization of nuclease-resistant ribozymes directed against hepatitis B virus RNA.

Hepatitis B virus (HBV) is responsible for > 350 million cases of chronic hepatitis B worldwide and 1.2 million deaths each year. To explore the use of ribozymes as a novel therapy for HBV infection, nuclease-resistant ribozymes that target highly conserved regions of HBV RNA were screened in cell culture. These synthetic ribozymes have the potential to cleave all four major HBV RNA transcripts and to block the HBV lifecycle by cleavage of the pregenomic RNA. A number of the screened ribozymes demonstrate activity in cell culture systems, as measured by decreased levels of HBV surface antigen, HBV e antigen and HBV DNA. In addition, a lead anti-HBV ribozyme maintains activity against a lamivudine-resistant HBV variant in cell culture. Treatment of HBV transgenic mice with lead anti-HBV ribozymes significantly reduced viraemia compared with saline-treated animals and was as effective as treatment with lamivudine. In conclusion, the therapeutic use of a ribozyme alone or in combination with current therapies (lamivudine or interferons) may lead to improved HBV therapy.

Animals↗
PubMed2002

Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study.

OBJECTIVES: Depression is a common psychiatric disorder in late life. Cerebrovascular disease has been postulated as an important aetiological factor in many cases (the "vascular depression" hypothesis). Consistent with this, an inflammatory response, most probably representing ischaemia, has been reported with increases in intercellular adhesion molecule 1 (ICAM-1), in the dorsolateral prefrontal cortex (DLPFC) in postmortem tissue from elderly depressed subjects. As ischaemia is known to cause astrogliosis, this study has further tested the "vascular depression hypothesis" by investigating the distribution of the astrocytic marker glial fibrillary acidic protein (GFAP) in the DLPFC and in the anterior cingulate cortex (ACC). METHODS: Postmortem tissue was obtained from 20 elderly patients with a history of major depressive disorder (MDD) and 20 control subjects. Sections were stained for GFAP using standard immunocytochemistry. Sets of images were obtained from all cortical layers in the DLPFC and ACC with the exception of layer IV in the ACC, and from gyral and deep white matter in both regions. The percentage of the area of each image occupied by GFAP was calculated using true colour image analysis, and mean values obtained for each region examined. RESULTS: Immunoreactivity for GFAP was low in grey matter (for example, Mean (SEM) 0.76 (0.2)% in DLPFC layer V in depressed subjects), but higher in white matter (for example, 12.02 (2.2)% in DLPFC deep white matter in depressed subjects). Pronounced gliosis was observed within grey matter in a few cases only. GFAP immunoreactivity was significantly higher in layer I of the DLPFC in depressed subjects 15.8 (2.6)% than in controls 9.7 (1.3)% (t=2.2; df=27.5, p=0.04). No difference was detected in any other region. CONCLUSIONS: The data suggest any increase in GFAP in elderly MDD patients is limited to layer 1 of the DLPFC. These results provide some support for the vascular depression hypothesis and further implicate DLPFC abnormalities in depression.

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PubMed2002

A comprehensive review of proton magnetic resonance spectroscopy studies in dementia and Parkinson's disease.

We reviewed the literature of proton magnetic resonance spectroscopy (MRS) in dementia and Parkinson's disease (PD) and quantitatively compared the reported values of the markers N-acetyl aspartate (NAA), choline, and myo-Inositol between control and disease groups. We analysed a total of 27 reports in dementia. Combining the quantitative data from these showed a relative decrease of 15% in NAA level in the temporal lobe tissue in patients with Alzheimer's disease (AD) compared with controls. The rest of the brain showed a seemingly uniform 10% decrease in NAA levels in AD compared with controls. myo-Inositol was raised by about 15%, again uniformly throughout the brain, but there was no evidence for changed levels of choline. We found 15 reports of MRS in PD, which show a small decrease (5%) in the NAA level in the lentiform nucleus compared with controls. In progressive supranuclear palsy (PSP), there is a greater decrease in NAA levels in the frontal region and the lentiform nucleus. This may aid in the diagnosis of PSP. Further research is needed to determine spectroscopic changes in other dementias, to monitor how markers change with disease progression and to establish clinical utility.

Alzheimer Disease↗
PubMed2002

Patterns of cerebral atrophy in dementia with Lewy bodies using voxel-based morphometry.

Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

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PubMed2001

Dementia with Lewy bodies and AD are not associated with occipital lobe atrophy on MRI.

Dementia with Lewy bodies (DLB) is associated with occipital changes in blood flow and metabolism, but structural changes in this region have not previously been assessed. The authors performed volumetric MRI measurement of the occipital lobe blind to the diagnosis in 23 subjects with DLB, 25 with AD, and 24 age-matched control subjects. There were no significant differences between groups in occipital lobe volume. The authors conclude gross structural changes in the occipital lobe do not occur in patients with mild to moderate DLB or AD.

Aged↗
PubMed2001

Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia.

The authors determined rates of brain atrophy, as assessed by the boundary shift integral on serial MRI, in patients with dementia with Lewy Bodies (DLB, n = 10), AD (n = 9), vascular dementia (VaD, n = 9), and age-matched controls (n = 20). Mean % +/- SD atrophy rates per year were as follows: DLB, 1.4 +/- 1.1; AD, 2.0 +/- 0.9; VaD, 1.9 +/- 1.1; and controls, 0.5 +/- 0.7. Dementia subjects had higher rates than controls (p < 0.001), but there were no significant differences between the three dementia groups. The authors found accelerating atrophy with increasing severity of cognitive impairment, further emphasizing the need for early diagnosis and intervention in dementia.

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PubMed2001

Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD.

OBJECTIVE: To compare regional cerebral blood flow (rCBF) changes using 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT in subjects with dementia with Lewy bodies (DLB) and AD and in normal age-matched control subjects; to examine the utility of SPECT changes in the differential diagnosis of AD and DLB. METHOD: Whole-brain SPECT scans were acquired using a single-headed rotating gamma camera (IGE CamStar XR/T) in elderly subjects with consensus criteria DLB (n = 23; mean age = 79.4 years), National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association AD (n = 50; 81.9 years), and normal control subjects (n = 20; 78.1 years) after injection with 500 MBq of 99mTc-HMPAO. Region-of-interest analysis was performed using a SPECT template registered in Talairach space, with rCBF normalized to cerebellum. RESULTS: Both DLB and AD subjects had significantly reduced rCBF in parietal and temporal regions compared with the control subjects. The AD group also showed a significant reduction in rCBF in the frontal and medial temporal regions and the DLB in the occipital areas compared with control subjects. AD and DLB groups differed only in occipital perfusion (p < 0.01). SPECT measures (occipital and medial temporal) correctly classified 69% of all subjects, with a 65% sensitivity and 87% specificity for DLB against AD and control subjects. CONCLUSION: Temporoparietal hypoperfusion on SPECT is common to both AD and DLB. Occipital hypoperfusion is more frequently seen in DLB. Although not diagnostically specific in individual cases, occipital hypoperfusion on SPECT should raise suspicion that DLB may be the cause of dementia, prompting careful search for other features of the disorder.

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PubMed2001

Multiple substrates of late-onset dementia: implications for brain protection.

Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Age of Onset↗
PubMed2001

Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.

CASE REPORTS: We report two cases of late life depression who became progressively more resistant to treatment, developed cognitive impairment, and began to exhibit neurological abnormalities and evidence of vascular disease. A discussion of the clinical features of the cases is accompanied by reports of neuropathology and neuroimaging findings. Extensive white matter lesions were present on computed tomography in both patients, and basal ganglia infarcts were seen in one. Neuropathology revealed evidence of cerebral atrophy, demyelination and white matter lesions in addition to cerebrovascular and generalised vascular disease. Neither patient exhibited Alzheimer pathology outwith the norm for their age. We believe this to be the first report of neuropathological findings in depression with white matter changes. LITERATURE REVIEW: The pathological basis of white matter lesions and their relationship to depression, its age of onset and clinical features is addressed in relation to the cases described. Pathological investigation of white matter lesions has not previously been carried out in depression and hypotheses regarding their nature in this illness are based on extrapolation from research in a variety of other disorders. The association of depression with vascular risk factors is considered, as is the relationship between depression and cognitive deficits. There is a need for further investigation in this area.

Age of Onset↗