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Biomedical subjects

John T O'Brien

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

At least 55 records · Page 3Linked to original sources
PubMed2004

Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression.

OBJECTIVE: Few studies have examined pathological changes in serotonergic neurons in depression, particularly in elderly patients and in elderly patients in which depression occurs in dementia. The authors hypothesized that greater neurofibrillary pathology and fewer serotonergic neurons would be found in the dorsal raphe nuclei in depressed elderly subjects, compared with nondepressed elderly subjects, and in Alzheimer's disease patients with depression, compared to Alzheimer's disease patients without depression. METHOD: In a postmortem study, immunocytochemistry and two-dimensional image analysis were used to measure neuronal density and neuritic pathology in serotonergic neurons in the dorsal raphe nuclei of elderly subjects with primary major depression (N=14), elderly Alzheimer's disease patients with (N=8) and without (N=7) comorbid depression, and nondepressed elderly comparison subjects (N=10). RESULTS: No differences in neuritic pathology or neuronal density were found between the subjects with primary major depression and the nondepressed comparison subjects. The Alzheimer's disease subjects showed markedly fewer serotonergic neurons and associated higher levels of neuritic pathology, compared with the subjects with primary depression and the nondepressed comparison subjects, but the Alzheimer's disease subjects with comorbid major depression did not differ from the Alzheimer's disease subjects without depression on these measures. CONCLUSIONS: The study found no evidence of a loss of serotonergic neurons or of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid Alzheimer's disease. These findings suggest that if serotonergic dysfunction occurs in older depressed subjects, it is not due to neuronal loss in the brainstem. Pathophysiological changes may lie elsewhere, such as in the frontal-subcortical circuits.

Aged↗
PubMed2004

Hippocampal volume change in depression: late- and early-onset illness compared.

BACKGROUND: Evidence for structural hippocampal change in depression is limited despite reports of neuronal damage due to hypercortisolaemia and vascular pathology. AIMS: To compare hippocampal and white matter structural change in demographically matched controls and participants with early-onset and late-onset depression. METHOD: High-resolution volumetric magnetic resonance imaging (MRI) and rating of MRI hyperintensities. RESULTS: A total of 51 people with depression and 39 control participants were included. Participants with late-onset depression had bilateral hippocampal atrophy compared with those with early-onset depression and controls. Hippocampal volumes did not differ between control participants and those with early-onset depression. Age of depression onset correlated (negatively) with hippocampal volume but lifetime duration of depression did not. Hyperintensity ratings did not differ between groups. CONCLUSIONS: Results suggest that acquired biological factors are of greater importance in late-than in early-onset illness and that pathological processes other than exposure to hypercortisolaemia of depression underlie hippocampal atrophy in depression of late life.

Age Factors↗
PubMed2004

A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome.

BACKGROUND: Although few placebo-controlled neuroleptic discontinuation studies have been conducted in people with dementia, such studies are essential to inform key clinical decisions. METHOD: A 3-month, double-blind, placebo-controlled, neuroleptic discontinuation study (June 2000 to June 2002) was completed in 100 care-facility residents with probable or possible Alzheimer's disease (according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria) who had no severe behavioral disturbances and had been taking neuroleptics for longer than 3 months. The Neuropsychiatric Inventory (NPI) was used to measure changes in behavioral and psychiatric symptoms. Quality of life was evaluated using Dementia Care Mapping. RESULTS: Eighty-two patients completed the 1-month assessment (36 placebo, 46 active). The number of participants withdrawing overall (N = 14 [30%] placebo, N = 14 [26%] active treatment) and because of exacerbation of behavioral symptoms (N = 6 [13%] placebo, N = 5 [9%] active treatment) was similar in the neuroleptic- and placebo-treated patients. As hypothesized, patients with baseline NPI scores at or below the median (< or = 14) had a particularly good outcome, with a significantly greater reduction of agitation in the patients receiving placebo (Mann-Whitney U test, z = 2.4, p =.018), while patients with higher baseline NPI scores were significantly more likely to develop marked behavioral problems if discontinued from neuroleptics (chi(2) = 6.8, p =.009). There was no overall difference in the change of quality of life parameters between groups. DISCUSSION: A standardized evaluation with an instrument such as the NPI may be a clinical indicator of which people with dementia are likely to benefit from discontinuation of neuroleptic treatment.

Aged↗
PubMed2003

Neuropathological evidence for ischemia in the white matter of the dorsolateral prefrontal cortex in late-life depression.

BACKGROUND: Signal hyperintensities on magnetic resonance imaging in late-life depression are associated with treatment resistance and poor outcome. These lesions are probably vascular in origin and proposed sites for vascular damage include the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). METHODS: We therefore examined white matter in these areas for microvascular disease and evidence of ischemia using intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). We obtained postmortem tissue from elderly depressed (n = 20) and control (n = 20) subjects and blindly rated microvascular disease and ICAM-1 and VCAM-1 amount using quantitative image analysis in sections of the DLPFC, ACC and occipital cortex (OC; control area). RESULTS: We found a significant increase in ICAM-1 in the deep white matter of the DLPFC in the depressed group (p = 0.01) and a trend towards an increase for VCAM-1 (p = 0.10). In the gyral white matter there was a trend towards significance for both molecules (p = 0.07 and 0.10). No differences were found in the ACC or OC or for microvascular disease in any area. CONCLUSIONS: These findings are consistent with white matter ischemia in the DLPFC and lend support to the 'vascular depression' hypothesis. They implicate the DLPFC as an important site in the pathogenesis of late-life depression and have major implications for the understanding and management of late-life depression and raise the possibility of novel treatments being introduced in the future.

Aged↗
PubMed2003

Association of life events and psychosocial factors with early but not late onset depression in the elderly: implications for possible differences in aetiology.

BACKGROUND: Depression occurring for the first time in later life (after age 60, late onset depression (LOD)) may have a different, more organic, aetiology from early onset depression (EOD). We investigated the possible role of life events, the presence of a confidante and personality factors in the aetiology of depression in the elderly, testing the hypothesis that these factors would be associated with EOD but not LOD. METHODS: Subjects consisted of 66 elderly patients (aged over 60) with DSM-IV Major depression (30 EOD, 33 LOD; groups matched for age) and 38 age and sex matched controls. Life events in the 12 months prior to onset of depression (or prior to interview for controls) were recorded using a previously validated 12-item scale. Personality was assessed using the Eysenck Personality Questionnaire (EPQ). RESULTS: Subjects with EOD reported having a close confidente significantly less frequently (52%) than controls (82%, p < 0.05) or LOD (80%, p < 0.05). Bereavement life events occurred significantly more frequently in EOD (52%) than LOD (16%, p < 0.01) and were also more frequent in controls (42%) than LOD (p < 0.05). Higher EPQ 'extraversion' and 'neuroticism' were found in both EOD and LOD compared to controls, with no differences between EOD and LOD. CONCLUSIONS: LOD was associated with fewer bereavement life events and more frequent presence of a confidente than EOD. This supports a greater role for psychosocial factors in the aetiology of EOD and different, probably neurobiological, factors in LOD. Personality attributes may have a greater relevance for both EOD and LOD than previously recognized.

Age of Onset↗
PubMed2003

Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.

Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.

Aged↗
PubMed2003

Use of functional imaging in Parkinsonism and dementia.

Neuropsychiatric symptoms, including dementia, frequently coexist with parkinsonian disorders and may cause diagnostic confusion as well as management problems. Functional imaging studies include single photon emission computerised tomography (SPECT), positron emission tomography (PET), proton magnetic resonance spectroscopy, diffusion tensor imaging, and functional magnetic resonance imaging. This review addresses the utility of these techniques, from the clinician's perspective, focusing on the most common causes of parkinsonism and cognitive impairment, Parkinson's disease with dementia, dementia with Lewy bodies, and Alzheimer's disease. The potential and limitations of these techniques for accurate and early diagnosis, monitoring disease progression, and establishing the pathophysiological basis underlying key clinical features are considered. The development of new probes for SPECT and PET cameras capable of labeling protein aggregates (e.g., beta-amyloid) will offer exciting new insights into the spatial and temporal pattern of pathophysiological processes. Longitudinal studies with clinicopathological correlation represent the "gold standard" for fully evaluating functional imaging techniques.

Brain↗
PubMed2003

A neuropathological study of periventricular white matter hyperintensities in major depression.

BACKGROUND: Signal hyperintensities on magnetic resonance imaging (MRI) are increased in major depression but their pathological basis has never been assessed. We carried out a study of the neuropathological basis of periventricular hyperintensities (PVHs) in major depression. We hypothesised that different pathologies would be associated with the same MRI appearance of PVH and that such causes would be similar in depressed and control subjects. METHODS: In vitro MRI was carried out on coronal slices of brain tissue from 20 elderly subjects with major depression and 20 matched control subjects. PVHs were identified and blindly rated on the films and the tissue was subsequently prepared for neuropathological analysis. Conventional histopathological stains and immunocytochemical stains for glia and macrophages, to identify ischaemic tissue damage, were used. PVHs identified on MRI films were microscopically assessed blind to diagnosis. RESULTS: PVHs were found to be due to one of three main causes: ependymal loss, differing degrees of myelination in adjacent fibre tracts and cerebral ischaemia with associated demyelination. The causes were similar in depressed and control subjects. LIMITATIONS: All depressed subjects had been hospitalised and in spite of scanning 20 subjects only a small number of PVHs were able to be examined in depressed subjects. CONCLUSIONS: The neuropathological basis of PVH was similar in depressed and control subjects, and to previous reports in other diseases. Identical PVHs on MRI can have different causes in depression and this includes cerebral ischaemia.

Aged↗
PubMed2003

Vascular cognitive impairment.

Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias. The current narrow definitions of vascular dementia should be broadened to recognise the important part cerebrovascular disease plays in several cognitive disorders, including the hereditary vascular dementias, multi-infarct dementia, post-stroke dementia, subcortical ischaemic vascular disease and dementia, mild cognitive impairment, and degenerative dementias (including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies). Here we review the current state of scientific knowledge on the subject of vascular brain burden. Important non-cognitive features include depression, apathy, and psychosis. We propose use of the term vascular cognitive impairment, which is characterised by a specific cognitive profile involving preserved memory with impairments in attentional and executive functioning. Diagnostic criteria have been proposed for some subtypes of vascular cognitive impairment, and there is a pressing need to validate and further refine these. Clinical trials in vascular cognitive impairment are in their infancy but support the value of therapeutic interventions for symptomatic treatment.

Cerebrovascular Disorders↗
PubMed2003

Dementia with Lewy bodies.

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Aged↗
PubMed2003

Regulation of attention and response to therapy in dementia by butyrylcholinesterase.

OBJECTIVES: To determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood. METHODS: We examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment. CONCLUSIONS: These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.

Acetylcholine↗
PubMed2003

MRI study of caudate nucleus volume in Parkinson's disease with and without dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: To compare whole brain and caudate volume on MRI in subjects with Parkinson's disease without cognitive impairment (PD), Parkinson's disease with dementia with Lewy bodies (PD + DLB), Alzheimer's disease (AD) and normal control subjects. To examine the relationship between caudate volume and cognitive impairment, depression and movement disorder. METHOD: Whole brain and caudate volumes were segmented from volumetric 1.5-tesla magnetic resonance imaging (MRI) scans of older subjects with PD (n = 28; mean age 75.5 years), PD + DLB (n = 20; 73.0 years), AD (n = 27; 77.5 years) and normal controls (n = 35; 74.9 years). RESULTS: Subjects with AD had significantly reduced whole brain and caudate volume compared to controls and those with PD. Caudate atrophy in AD was proportionate to whole brain atrophy. There were no significant differences in whole brain or caudate volume between controls, PD and PD + DLB. There were no significant correlations between caudate volume and either global cognitive function, executive performance or processing speed. CONCLUSIONS: Caudate atrophy occurs in AD but not PD without dementia. Caudate atrophy is not regionally specific but part of generalised brain volume loss. Structural changes in the caudate, as assessed by in vivo MRI, do not appear to contribute to the cognitive impairment observed amongst patients with PD, PD + DLB or AD. Results indicate that the executive and attentional dysfunctions associated with PD and DLB are unlikely to be a direct and specific consequence of caudate atrophy as assessed on MRI.

Aged↗
PubMed2002

A comparison of (99m)Tc-HMPAO SPET changes in dementia with Lewy bodies and Alzheimer's disease using statistical parametric mapping.

Differences in regional cerebral blood flow (rCBF) between subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy volunteers were investigated using statistical parametric mapping (SPM99). Forty-eight AD, 23 DLB and 20 age-matched control subjects participated. Technetium-99m hexamethylpropylene amine oxime (HMPAO) brain single-photon emission tomography (SPET) scans were acquired for each subject using a single-headed rotating gamma camera (IGE CamStar XR/T). The SPET images were spatially normalised and group comparison was performed by SPM99. In addition, covariate analysis was undertaken on the standardised images taking the Mini Mental State Examination (MMSE) scores as a variable. Applying a height threshold of P < or = 0.001 uncorrected, significant perfusion deficits in the parietal and frontal regions of the brain were observed in both AD and DLB groups compared with the control subjects. In addition, significant temporoparietal perfusion deficits were identified in the AD subjects, whereas the DLB patients had deficits in the occipital region. Comparison of dementia groups (height threshold of P < or = 0.01 uncorrected) yielded hypoperfusion in both the parietal [Brodmann area (BA) 7] and occipital (BA 17, 18) regions of the brain in DLB compared with AD. Abnormalities in these areas, which included visual cortex and several areas involved in higher visual processing and visuospatial function, may be important in understanding the visual hallucinations and visuospatial deficits which are characteristic of DLB. Covariate analysis indicated group differences between AD and DLB in terms of a positive correlation between cognitive test score and temporoparietal blood flow. In conclusion, we found evidence of frontal and parietal hypoperfusion in both AD and DLB, while temporal perfusion deficits were observed exclusively in AD and parieto-occipital deficits in DLB.

Age Factors↗
PubMed2002

Ischemic basis for deep white matter hyperintensities in major depression: a neuropathological study.

BACKGROUND: White matter hyperintensities on magnetic resonance imaging are increased in major depression in the deep white matter, especially in frontal areas. These lesions have been hypothesized to be ischemic in origin, but there have been no previous neuropathological studies in depression. We investigated the neuropathological basis of these lesions in depression, hypothesizing that they would be more frequently ischemic in origin in depressed subjects. METHODS: We carried out in vitro magnetic resonance imaging on 3 slices of brain tissue (2 frontal, 1 occipital) from 20 elderly subjects who had a history of major depression and 20 elderly controls. The films were blindly rated, and sections were prepared for neuropathological analysis from the same slices and stained conventionally and by means of immunohistochemistry for microglia, macrophages, and astroglia. Lesions on the films were identified in the tissue, blindly described neuropathologically, and subsequently divided into ischemic and nonischemic lesions. RESULTS: All the deep white matter hyperintensities in the depressed group were found to be ischemic, compared with less than a third of those in the control group, a highly significant difference (P<.001). This difference was due to smaller punctate lesions (<3 mm), which were predominantly ischemic in depressed subjects but not in control subjects. Larger lesions were usually ischemic in both groups. Compared with control subjects, ischemic lesions were significantly more likely to be in the dorsolateral prefrontal cortex compared with the anterior cingulate cortex (P =.003) and the occipital cortex (P =.01) in the depressed subjects. CONCLUSIONS: Deep white matter hyperintensities are more frequently due to cerebral ischemia, and such ischemic lesions are more frequently located at the level of dorsolateral prefrontal cortex in depressed subjects. Our findings strongly support the "vascular depression" hypothesis of late-life depression.

Age Factors↗
PubMed2002

Memory clinics and clinical governance--a UK perspective.

BACKGROUND: Memory clinics have developed using a range of service models but providing similar functions which include assessment, information, treatment monitoring, education, training and research. Memory clinic development is now taking place in the UK in the context of clinical governance and the drive for quality improvement. At a strategic level this process is driven by the National Service Framework for Older People and the National Institute for Clinical Excellence. METHODS: The literature describing quality issues in memory clinics is reviewed against a multi-dimensional framework for assessing quality standards. RESULTS AND CONCLUSIONS: The rationing of health care, both explicit and implicit, is discussed in view of limited capacity and financial resources of the National Health Service and the significance of this in determining quality standards is highlighted. The authors offer a generic quality specification for memory clinic development, using mild cognitive impairment as an illustration of the quality standards that might be achieved and clinical governance systems that must be present to drive forward continuous quality improvement.

Accreditation↗
PubMed2002

Cell adhesion molecule expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in major depression in the elderly.

BACKGROUND: Neuroimaging studies have demonstrated changes in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in major depression. AIMS: We investigated the expression of cell adhesion molecules (CAMs) in the prefrontal cortex in depression. METHOD: Immunohistochemistry to localise CAMs in post-mortem tissue from 20 subjects with major depression and 20 controls, and image analysis to quantify their expression. RESULTS: We found significant increases in CAMs in the grey matter of the DLPFC in the depression group but no comparable differences in the ACC or occipital cortex. In the white matter there was a non-significant increase in intercellular adhesion molecule-I in the DLPFC in the depression group but no increase in the other areas or for vascular cell adhesion molecule-I in any area. Paired tests showed specificity for the DLPFC in the depression group only. CONCLUSIONS: The increase in CAM expression in the DLPFC suggests an inflammatory reaction and is consistent with ischaemia.

Aged↗
PubMed2002

Pathologies and pathological mechanisms for white matter hyperintensities in depression.

Signal hyperintensities on magnetic resonance imaging (MRI) are increased in the white matter (WMH) and deep gray matter in dementia and depression and may have similar pathologies. However, no previous study has examined WMH in subjects with major depression. We carried out in vitro MRI on brain tissue from elderly subjects who had suffered major depression and elderly control subjects to identify and rate WMH. The tissue was subsequently prepared for histopathological analysis using a number of conventional and immunohistochemical stains, and the WMH were examined to identify their underlying pathological causes. Cerebral microvessels were also assessed and the findings compared with assessments of atheromatous disease in these subjects. PVH were found to be due to one of three causes: dilated perivascular spaces (with and without ischemia in the perivascular area), oligemic demyelination, and ischemic demyelination. DWMH also showed three types of causes: dilated perivascular spaces (with and without ischemia in the perivascular area), oligemic demyelination, and ischemic demyelination. Cerebral microvascular disease only contributed to a few of the lesions and atheromatous disease did not show associations with WMH in these subjects. These findings are similar to previous reports in other diseases and demonstrate WMH in elderly depression to be a manifestation of cerebrovascular disease. However, since large vessel and small vessel disease were not associated with WMH, our findings suggest hypotensive disease might be an important and unrecognized mechanism underlying WMH in late-life depression.

Autopsy↗