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John T O'Brien

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

At least 19 recordsLinked to original sources
PubMed2007

Soluble cell adhesion molecules in late-life depression.

BACKGROUND: Late-life depression has been associated with vascular diseases and with increases in circulating cytokines and cell adhesion molecules in the prefrontal cortex. We hypothesized that soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) would be increased in late-life major depression. METHODS: Serum levels of sICAM-1 and sVCAM-1 were measured in subjects over 60 with major depression (N = 23), subsyndromal depression (N = 20) and controls (N = 25). Depression severity was assessed using the Montgomery-Asberg (MDRS) and Geriatric Depression (GDS) rating scales. RESULTS: There was no significant increase in sICAM-1 (p = 0.240) or sVCAM-1 (p = 0.600) in depression nor was there any correlation of either molecule with depression severity. Adjusting for differences in cognitive impairment did not alter these findings. There was also no difference between subjects with an early onset of depression (before 60) and those with late-onset depression. CONCLUSIONS: These findings do not provide evidence that previously reported increases in serum cytokines in depression are due to peripheral vascular disease. Although we assessed subjects for vascular diseases it is possible that subtle but important differences between groups may still have been present and may have contributed to our negative findings. Our results suggest central nervous system mechanisms, such as related to HPA axis activation, may be responsible for the enhanced inflammatory response in depression.

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PubMed2007

Subjectively reported sleep quality and excessive daytime somnolence in Parkinson's disease with and without dementia, dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: We compared subjective sleep quality and excessive daytime somnolence (EDS) in controls, Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We investigated whether sleep dysfunction and EDS associate with motor phenotype in PD, PDD and DLB. METHOD: Assessments included the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: EDS was more frequent in PD, DLB and PDD patients than in AD. PDD, PD and DLB patients also had worse sleep quality when compared with AD and controls. Baseline postural instability-gait difficulty (PIGD) motor phenotype in PDD was associated with a higher ESS score and frequency of EDS, but this association was lost at two years. PSQI scores did not differ between PIGD dominant and non-dominant PD, PDD and DLB patients. CONCLUSION: EDS and poor sleep quality are greater in PD, PDD and DLB, compared with AD. The dissociation of EDS and motor phenotype suggests their pathophysiology is anatomically and/or temporally distinct.

Activities of Daily Living↗
PubMed2006

Effects of donepezil on central processing speed and attentional measures in Parkinson's disease with dementia and dementia with Lewy bodies.

BACKGROUND: We examined attention-enhancing effects of the cholinesterase inhibitor donepezil in Dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) by means of open label study. METHODS: 22 DLBs and 23 PDDs were assessed over 20 weeks using the Cognitive Drug Research Computerized Attentional Tasks. We examined how much closer our patients moved towards being normal for their age by comparing them to a non-demented elderly control sample (n = 183, aged 71-75 years). RESULTS: Donepezil treatment improved power of attention, continuity of attention and reaction time variability. The deficit in responses was moved towards normal by 38 and 56% for power of attention and 22 and 10% for continuity of attention in PDD and DLB, respectively. CONCLUSIONS: Improvements in attention were found with donepezil in PDD and DLB.

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PubMed2006

In vivo SPECT imaging of muscarinic acetylcholine receptors using (R,R) 123I-QNB in dementia with Lewy bodies and Parkinson's disease dementia.

INTRODUCTION: Alterations in cholinergic function have been reported to be associated with dementia. The aim of this study was to investigate differences in the distribution of muscarinic acetylcholine receptors (mAChRs) using (R,R) 123I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD) and age-matched controls. 123I-QNB binding was also compared to the corresponding cerebral perfusion changes in the same subjects. METHODS: 63 subjects (24 controls, 14 DLB, 25 PDD) underwent 123I-QNB and perfusion 99mTc-exametazine SPECT scanning. Image analysis, using statistical parametric mapping (SPM99), involved spatial normalisation of each image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean whole brain uptake. Group effects and correlations were assessed using two sample t tests and linear regression respectively. RESULTS: Relative to controls, significant elevation of 123I-QNB binding was apparent in the right occipital lobe in DLB and right and left occipital lobes in PDD (height threshold p<or=0.001 uncorrected). PDD also showed significant loss in uptake in frontal regions and temporal lobes bilaterally that was not present in DLB. These patterns appeared to be independent of any corresponding rCBF changes. CONCLUSION: Significant elevation of mAChRs in the occipital lobe was associated with DLB and PDD. This may relate to the visual disturbances that are prevalent in these disorders. Further studies are required in order to establish the role of mAChRs in visual function.

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PubMed2006

Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors.

Stroke is an important risk factor for dementia, but the exact mechanisms involved in cognitive decline remain unclear. In this study, we related baseline MRI brain measures with later cognitive decline. Seventy-nine stroke survivors aged 75+ years without dementia were recruited 3-month post-stroke. They underwent yearly neuropsychological assessments and had an MRI at baseline and 2 years. Medial temporal lobe atrophy (MTA) was scored and volume of white matter hyperintensities (WMH) was measured at baseline. The rate of ventricular enlargement was measured by comparing the baseline and repeat images. Linear regression indicated that memory loss was related to both baseline memory and MTA (p=0.001; standardized regression coefficient beta=-0.35) but not WMH volume. The only independent predictor of ventricular enlargement was MTA (p=0.003; beta=0.47). However, no baseline MRI variable differed between those who did (18%) and did not (82%) develop dementia. The association of MTA but not WMH with subsequent cognitive decline and increasing brain atrophy suggests a greater role for Alzheimer type than vascular pathology in delayed cognitive impairment after stroke.

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PubMed2006

White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.

BACKGROUND AND PURPOSE: "Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved. METHODS: A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury. RESULTS: PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04). CONCLUSIONS: The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.

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PubMed2006

Effects of rapid tryptophan depletion on salivary cortisol in older people recovered from depression, and the healthy elderly.

Reduced serotonin (5-HT) function and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are thought to play a role in the aetiology of major depression. We sought to examine this issue in the elderly by assessing the effects of lowering brain 5-HT on salivary and plasma cortisol in elderly patients who had recovered from at least one episode of major depression and in a healthy, age matched comparison group. A double-blind, cross-over design involving administration of two nutritionally balanced amino acid mixtures (with or without tryptophan) was used. Salivary cortisol was measured at intervals before and after the drink. There was no effect of acute tryptophan depletion (ATD) on salivary cortisol (ATD by time; F=0.97, df=7,210, p=0.454) but a significant interaction between group and time (F=3.91, df=7,210, p=0.010). Healthy subjects showed a marked increase in cortisol levels 2-3 hours into the procedure regardless of drink composition while recovered depressed subjects did not. In elderly patients who had recovered from depression there was no evidence of greater vulnerability of hypothalamic 5-HT pathways to 5-HT depletion. However, they demonstrated reduced reactivity of the HPA axis compared to healthy subjects.

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PubMed2006

Cholinesterase inhibitors in advanced Dementia with Lewy bodies: increase or stop?

INTRODUCTION: There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB. METHOD: We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms. RESULTS: The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment. CONCLUSION: Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Cholinesterase Inhibitors↗
PubMed2006

Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study.

BACKGROUND: Both types of cerebral white matter hyperintensities, periventricular (PVL) and deep white matter lesions (DWML) have been previously associated with the development of depression in older subjects. However, it remains controversial as to whether PVL, DWML, or both are most strongly associated with depression and this was the aim of the current study. METHODS: In a pan-European multicentre study of 626 older subjects, we examined the relationship between PVL and DWML, depressive symptoms (GDS quintile), cognitive status (MMSE), hypertension and history of stroke. RESULTS: In univariate analysis we found that depressive symptoms as assessed by GDS were associated with both types of white matter lesions (Spearman rho = 0.12 p = 0.002 for DWML and rho = 0.09 p = 0.01 for PVL). Using ordinal logistic regression analysis the total DWML score (p = 0.041), rather than PVL (p = 0.9) was found to predict GDS scores. CONCLUSIONS: DWML, but not PVL, were most strongly associated with depressive symptoms in this sample. As DWML (unlike PVL) are associated with vascular ischaemic damage, our findings are consistent with the 'vascular depression' hypothesis. Longitudinal studies are needed to clarify the time course of these relationships, in particular, whether modifying DWML alters the natural history of depression.

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PubMed2006

Characteristics of visual hallucinations in Parkinson disease dementia and dementia with lewy bodies.

OBJECTIVE: Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) have overlapping clinical and pathologic features. Recurrent visual hallucinations (RVH) are common in both disorders. The authors have compared details of hallucination characteristics and associated neuropsychiatric features in DLB and PDD. METHODS: This is a descriptive, cross-sectional study using the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) to explore self-reported frequency, duration, and phenomenology of RVH in PDD and DLB. The caregivers' ratings of hallucinations and other neuropsychiatric features were elicited with the Neuropsychiatric Inventory (NPI). RESULTS: Fifty-six patients (35 PDD; 21 DLB) with RVH were assessed. Hallucination characteristics were similar in both disorders. Simple hallucinations were rare. Most patients experienced complex hallucinations daily, normally lasting minutes. They commonly saw people or animals and the experiences were usually perceived as unpleasant. NPI anxiety scores were higher in PDD. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbance, and anxiety. CONCLUSIONS: Patients with mild to moderate dementia can provide detailed information about their hallucinations. Characteristics of RVH were similar in PDD and DLB, and phenomenology suggests the involvement of dorsal and ventral visual pathways in their generation. The coexistence of RVH with anxiety, apathy, and sleep disturbance is likely to impair patients' quality of life and may have treatment implications.

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PubMed2006

White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study.

OBJECTIVE: Both white matter hyperintensities (WMH) and lacunar infarcts have been associated with the development of depression in older subjects, although the relative importance of the two and the influence of lesion location and concomitant vascular disease are unclear. This study investigates the relationship between location and burden of WMH and lacunes on depressive features in older people. METHOD: In a pan-European multicenter study of 626 older subjects, the authors examined the relationship between regional magnetic resonance imaging white matter hyperintensities, number of lacunar infarcts, depressive symptoms as assessed by the 15-item geriatric depression scale (GDS), cognitive status (Mini-Mental Status Examination), hypertension, and self-perceived health quality of life (QoL). RESULTS: The authors found depressive symptoms to be correlated with WMH rating in the frontal (N=626; Spearman's rho=0.161, p <0.001) and temporal (rho=0.14, p <0.001) but not occipitoparietal region (rho=0.07, p=0.07). Basal ganglia lacunes were only weakly correlated with GDS (rho=0.09, p=0.03), and lacunes in other regions showed no association. In a ordinal logistic regression model (controlling for QoL, Mini-Mental Status Examination, age, and with an interaction between WMH and hypertension), temporal WMH in the absence of hypertension independently predicted GDS, whereas neither history of stroke nor number of lacunar infarcts did. The authors compared left- versus right-sided WMH and found no effect of laterality on depressive symptoms. CONCLUSIONS: The results suggest that in this population of nondisabled older people, WMH have a greater influence on depressive symptoms than infarcts.

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PubMed2006

More severe functional impairment in dementia with lewy bodies than Alzheimer disease is related to extrapyramidal motor dysfunction.

OBJECTIVE: The objective of this study was to compare functional impairments in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and their relationship with motor and neuropsychiatric symptoms. METHODS: The authors conducted a cross-sectional study of 84 patients with DLB or AD in a secondary care setting. Patients were diagnosed according to published criteria for DLB and AD. The Bristol Activities of Daily Living Scale (BADLS) was used to assess functional impairments. Participants were also assessed using the Unified Parkinson's Disease Rating Scale (motor section), the Neuropsychiatric Inventory, and the Mini-Mental Status Examination. RESULTS: Patients with DLB were more functionally impaired and had more motor and neuropsychiatric difficulties than patients with AD with similar cognitive scores. In both AD and DLB, there were correlations between total BADLS scores and motor and neuropsychiatric deficits. There was more impairment in the mobility and self-care components of the BADLS in DLB than in AD, and in DLB, these were highly correlated with UPDRS score. In AD, orientation and instrumental BADLS components were most affected. CONCLUSION: The nature of functional disability differs between AD and DLB with additional impairments in mobility and self-care in DLB being mainly attributable to extrapyramidal motor symptoms. Consideration of these is important in assessment and management. Activities of daily living scales for use in this population should attribute the extent to which functional disabilities are related to cognitive, psychiatric, or motor dysfunction.

Activities of Daily Living↗
PubMed2006

Vascular cognitive impairment.

Cerebrovascular disease is increasingly recognized as a common cause of cognitive impairment and dementia in later life either alone or in conjunction with other pathologies, most often Alzheimer disease (AD). Progress in the field has been limited by difficulties in terminology; for example, use of the term dementia necessitates the presence of memory impairment, which is the norm in AD, but not in cognitive disorders associated with cerebrovascular disease. The term vascular cognitive impairment (VCI) has been proposed as an umbrella term to recognize the broad spectrum of cognitive, and indeed behavioral, changes associated with vascular pathology. It is characterized by a specific cognitive profile with predominantly attentional and executive impairments together with particular noncognitive features (especially depression) and a relatively stable course, at least in clinical trial populations. Subtypes of VCI have been proposed based on clinical and pathologic differences, including cortical, subcortical, strategic infarct, hypoperfusion, hemorrhagic, and mixed (with AD) type. Diagnostic criteria are emerging but require refinement and validation, especially for mixed dementias. There remain fundamental gaps in our understanding of pathophysiology, predicting prognosis and outcome, and in therapeutics. Clinical trials to date, mainly in populations selected using currently accepted criteria for vascular dementia, have generally been disappointing. A relatively modest cognitive benefit of agents such as nimodipine, memantine, and cholinesterase inhibitors has been reported, although the clinical significance of these improvements remains to be established. Further studies, focusing on particular subtypes of VCI and involving subjects at earlier stages of the disease, are required. The aim of this article is to review the concept of VCI in terms of the evidence base surrounding diagnosis, clinical features, pathophysiology, and management and to make some recommendations regarding further research in the area. It begins with a discussion on the historical background, which is important to understand the different and somewhat confusing terminology that currently exists in the field.

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PubMed2006

Progression of white matter hyperintensities in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia: a comparison with normal aging.

OBJECTIVE: The objective of this study was to investigate cross-sectional and longitudinal white matter hyperintensity (WMH) changes in older subjects with clinically diagnosed dementia. METHODS: Fluid-attenuated inversion recovery images were acquired one year apart in subjects with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Alzheimer disease (AD), and also healthy elderly comparison subjects. WMH volume was quantified using an automated technique. RESULTS: Baseline WMH (as a percent of brain volume) was significantly greater compared with healthy subjects (N=33, geometric mean WMH: 0.4%) in subjects with AD (N=23 [1.3%], analysis of variance post hoc p <0.001) but not PDD (N=13 [0.6%]) or DLB (N=14 [0.4%]). Increase in WMH volume (as a percent of brain volume) was not significantly different (Kruskal-Wallis p=0.4) between groups (AD median change: 0.08%; DLB: 0.025%; PDD: 0.07%, healthy: 0.02%). Severity of baseline WMH, rather than diagnosis or severity of dementia, was a significant predictor of lesion progression. Rate of change of WMH had no association with change in global cognitive performance. CONCLUSIONS: Significant WMH progression occurs in degenerative dementias with rates influenced by severity of lesions at baseline rather than dementia type or cognitive decline.

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PubMed2005

Change in perfusion, hallucinations and fluctuations in consciousness in dementia with Lewy bodies.

Fluctuations in consciousness and visual hallucinations are common neuropsychiatric features of dementia with Lewy bodies and Parkinson's disease dementia. To investigate potential neural correlates, we compared how changes in brain perfusion over a 1-year period were related to changes in the severity of these key clinical features. We recruited 29 subjects with either Parkinson's disease with dementia (15 subjects) or dementia with Lewy bodies (14 subjects). Cerebral perfusion was measured using HMPAO SPECT at baseline, and repeated 1 year later. The presence of hallucinations (Neuropsychiatric Inventory), severity of fluctuations in consciousness (fluctuation assessment scale) and cognitive ability (CAMCOG) were assessed at both time points. After controlling for changes in cognitive ability and effect of cholinesterase medication, we found a significant correlation between an increase in perfusion in midline posterior cingulate and decrease in hallucination severity. There was also a significant correlation between increased fluctuations of consciousness and increased thalamic and decreased inferior occipital perfusion. We have identified important neural correlates of key clinical features in Lewy body dementia and postulate that the associations can be understood through the influence of the cholinergic system on attention.

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