von Känel R, Mausbach BT, Dimsdale JE
… +7 more, Mills PJ, Patterson TL, Ancoli-Israel S, Ziegler MG, Roepke SK, Allison M, Grant I
Cardiovasc Psychiatry Neurol
· 2012 · PMID 22848795
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Objective. To investigate the relationship between coping and atherothrombotic biomarkers of an increased cardiovascular disease (CVD) risk in the elderly. Methods. We studied 136 elderly caregiving and noncaregiving men...Objective. To investigate the relationship between coping and atherothrombotic biomarkers of an increased cardiovascular disease (CVD) risk in the elderly. Methods. We studied 136 elderly caregiving and noncaregiving men and women who completed the Ways of Coping Checklist to assess problem-focused coping, seeking social support (SSS), blamed self, wishful thinking, and avoidance coping. They had circulating levels of 12 biomarkers measured. We also probed for potential mediator and moderator variables (chronic stress, affect, health behavior, autonomic activity) for the relation between coping and biomarkers. Results. After controlling for demographic and CVD risk factors, greater use of SSS was associated with elevated levels of serum amyloid A (P = 0.001), C-reactive protein (CRP) (P = 0.002), vascular cellular adhesion molecule (VCAM)-1 (P = 0.021), and D-dimer (P = 0.032). There were several moderator effects. For instance, greater use of SSS was associated with elevated VCAM-1 (P < 0.001) and CRP (P = 0.001) levels in subjects with low levels of perceived social support and positive affect, respectively. The other coping styles were not significantly associated with any biomarker. Conclusions. Greater use of SSS might compromise cardiovascular health through atherothrombotic mechanisms, including elevated inflammation (i.e., serum amyloid A, CRP, VCAM-1) and coagulation (i.e., D-dimer) activity. Moderating variables need to be considered in this relationship.
Knecht KM, Alosco ML, Spitznagel MB
… +8 more, Cohen R, Raz N, Sweet L, Colbert LH, Josephson R, Hughes J, Rosneck J, Gunstad J
Cardiovasc Psychiatry Neurol
· 2012 · PMID 22745901
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Background. Prior research indicates that heart failure (HF) patients exhibit significant cognitive deficits on neuropsychological testing. Sleep apnea is associated with both HF and reduced cognitive function, but the c...Background. Prior research indicates that heart failure (HF) patients exhibit significant cognitive deficits on neuropsychological testing. Sleep apnea is associated with both HF and reduced cognitive function, but the combined impact of these conditions on cognitive function is unknown. Methods. In the current study, 172 older adults with a dual diagnosis of HF and sleep apnea or HF alone completed a battery of cognitive tests measuring attention, executive functioning, and memory. Results. Relative to patients with HF alone, persons with both HF and sleep apnea performed worse on measures of attention after adjusting for demographic and medical variables. Conclusions. The current findings suggest that HF patients with comorbid sleep apnea may be at greater risk for cognitive impairment relative to HF patient without such history. Further work is needed to clarify mechanisms for these findings and to determine whether the interactive effects on cognitive function lead to poorer patient outcomes.
Eagan DE, Gonzales MM, Tarumi T
… +3 more, Tanaka H, Stautberg S, Haley AP
Cardiovasc Psychiatry Neurol
· 2012 · PMID 22461977
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C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In t...C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In this study we examined the relationship between CRP and markers of neuronal integrity and cerebral metabolism in middle-aged adults with intact cognitive function, using proton magnetic resonance spectrocospy. We hypothesized that increased levels of circulating CRP would correlate with changes in brain metabolites indicative of early brain vulnerability. Thirty-six individuals, aged 40 to 60, underwent neuropsychological assessment, a blood draw for CRP quantification, and (1)H MRS examining N-acetyl-aspartate, myo-inositol, creatine, choline, and glutamate concentrations in occipito-parietal grey matter. Independent of age, sex and education, serum CRP was significantly related to higher cerebral myo-inositol/creatine ratio (F(4,31) = 4.74, P = 0.004), a relationship which remained unchanged after adjustment for cardiovascular risk (F(5,30) = 4.356, CRP β = 0.322, P = 0.045). Because these biomarkers are detectable in midlife they may serve as useful indicators of brain vulnerability during the preclinical period when mitigating intervention is still possible.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 22216404
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The literature emphasizes the risk of depression after a stroke. Less well known is the fact that depression may be as big a risk factor for strokes as hypertension, particularly in the older age group. This article revi...The literature emphasizes the risk of depression after a stroke. Less well known is the fact that depression may be as big a risk factor for strokes as hypertension, particularly in the older age group. This article reviews the risk for stroke and cognitive impairment consequent to depression, and describes the cardiovascular and immunological mechanisms that would appear to link depression to its cerebrovascular consequences. As well, the article refers to the brain imaging signatures that may allow prediction of impending brain injury. Finally, some questions that might be explored by future research are suggested, and some practical means to identify and help those at risk for the development of depression-associated vascular disease of the brain are suggested.
Garcia S, Spitznagel MB, Cohen R
… +7 more, Raz N, Sweet L, Colbert L, Josephson R, Hughes J, Rosneck J, Gunstad J
Cardiovasc Psychiatry Neurol
· 2011 · PMID 22195274
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Persons with heart failure (HF) frequently exhibit cognitive impairment with deficits in attention and memory. Depression is common in HF though its possible contribution to cognitive impairment is unknown. Cognitive dys...Persons with heart failure (HF) frequently exhibit cognitive impairment with deficits in attention and memory. Depression is common in HF though its possible contribution to cognitive impairment is unknown. Cognitive dysfunction and depression may share common mechanisms in HF, as both are associated with similar abnormalities on neuroimaging. A total of 116 participants with HF (68.53 ± 9.30 years) completed a neuropsychological battery and self-report measures of depression. Regression models showed depression incrementally and independently predicted test performance in all cognitive domains. Follow-up partial correlations revealed that greater depressive symptoms were associated with poorer performance on tests of attention, executive function, psychomotor speed, and language. These results indicate that depressive symptoms are associated with poorer cognitive performance in HF though further work is needed to clarify mechanisms for this association and possible cognitive benefits of treating depression in persons with HF.
Huis In 't Veld EM, Makine C, Nouwen A
… +4 more, Karşıdağ C, Kadıoğlu P, Karşıdağ K, Pouwer F
Cardiovasc Psychiatry Neurol
· 2011 · PMID 22195273
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The Problem Areas in Diabetes (PAID) scale is a widely used self-report measure that can facilitate detection of diabetes-specific emotional distress in clinical practice. The aim of this study was to assess the factor s...The Problem Areas in Diabetes (PAID) scale is a widely used self-report measure that can facilitate detection of diabetes-specific emotional distress in clinical practice. The aim of this study was to assess the factor structure and validity of the Turkish version of the PAID. A validation study was conducted among 154 patients with insulin-naïve type 2 diabetes. Participants completed the PAID, Centre for Epidemiological Studies Depression Scale (CES-D), Insulin Treatment Appraisal Scale (ITAS), and World Health Organization-Five Well-Being Index (WHO-5) questionnaires. Exploratory factor analyses yielded a 2-factor structure, identifying a 15-item "diabetes distress" factor and a 5-item "support-related issues" factor. The total PAID-score and the two dimensions were associated with higher levels of depression and poor emotional well-being. In the present study, the Turkish version of the PAID had satisfactory psychometric properties, however, the factorial structure was found to differ from factor solutions from other countries.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 22175000
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Objective. We tested the association of specific psychological characteristics in patients having stable coronary disease with the reporting of anginal symptoms during daily activities, and positive exercise testing. Met...Objective. We tested the association of specific psychological characteristics in patients having stable coronary disease with the reporting of anginal symptoms during daily activities, and positive exercise testing. Methods. One hundred and ninety-six patients with documented CAD enrolled in the Psychophysiological Investigations of Myocardial Ischemia (PIMI) Study completed an anginal history questionnaire and a battery of psychometric tests. They also underwent standardized exercise treadmill tests. Results. Patients with a recent history of angina were more likely to be female, and had higher Beck Depression (P = .002), State Anxiety (P = .001), Trait Anxiety (P = .03), Harm Avoidance (P = .04) and Muscle Tension (P = .004) scores than patients who had no recent history of angina. Along with several treadmill variables indicating more severe disease state and reduced exercise tolerance, patients who developed angina on a positive treadmill test also displayed higher scores on the Beck Depression Inventory (P = .003) and State Anxiety (P = .004) scales. Conclusions. Several psychological characteristics, and most notably anxiety and depression, are strong correlates of recent angina and angina in the presence of ischemia provoked by treadmill testing.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 22162800
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Peripheral microvascular complications in diabetes are associated with concurrent cerebrovascular disease. As detailed cognitive assessment is not routinely carried out among diabetic patients, the aim was to establish w...Peripheral microvascular complications in diabetes are associated with concurrent cerebrovascular disease. As detailed cognitive assessment is not routinely carried out among diabetic patients, the aim was to establish whether the presence of clinical "peripheral" microvascular disease can identify a subgroup of patients with early evidence of cognitive impairment. Detailed psychometric assessment was performed in 23 diabetic patients with no microvascular complications (Group D), 27 diabetic patients with at least one microvascular complication: retinopathy, neuropathy, and/or nephropathy (Group DC), and 25 healthy controls (Group H). Groups D and DC participants had significantly lower scores on reaction time (P = 0.003 and 0.0001, resp.) compared to controls. Similarly, groups D and DC participants had significantly lower scores on rapid processing of visual information (P = 0.034 and 0.001, resp.) compared to controls. In contrast, there was no significant difference between Groups D and DC on any of the cognitive areas examined. The results show that diabetes, in general, is associated with cognitive dysfunction, but the additional presence of peripheral microvascular disease does not add to cognitive decline. The study, however, indirectly supports the notion that the aetiology of cognitive impairment in diabetes may not be restricted to vascular pathology.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21755032
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Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells) possess b...Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells) possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC) communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21687589
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Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, structural and functional changes in the microvesse...Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, structural and functional changes in the microvessels may contribute directly to the pathogenesis of the disease. Since vascular dysfunction often precedes cognitive impairment, understanding the role of the blood-brain barrier (BBB) in AD may be key to rational treatment of the disease. We propose that water regulation, a critical function of the BBB, is disturbed in AD and results in abnormal permeability and rates of water exchange across the vessel walls. In this paper, we describe some of the pathological events that may disturb microvascular water exchange in AD and examine the potential of a relatively new imaging technique, dynamic contrast-enhanced MRI, to quantify water exchange on a cellular level and thus serve as a probe of BBB integrity in AD.
Stolp HB, Johansson PA, Habgood MD
… +3 more, Dziegielewska KM, Saunders NR, Ek CJ
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21547250
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Several neurological disorders have been linked to inflammatory insults suffered during development. We investigated the effects of neonatal systemic inflammation, induced by LPS injections, on blood-brain barrier permea...Several neurological disorders have been linked to inflammatory insults suffered during development. We investigated the effects of neonatal systemic inflammation, induced by LPS injections, on blood-brain barrier permeability, endothelial tight junctions and behaviour of juvenile (P20) and adult rats. LPS-treatment resulted in altered cellular localisation of claudin-5 and changes in ultrastructural morphology of a few cerebral blood vessels. Barrier permeability to sucrose was significantly increased in LPS treated animals when adult but not at P20 or earlier. Behavioural tests showed that LPS treated animals at P20 exhibited altered behaviour using prepulse inhibition (PPI) analysis, whereas adults demonstrated altered behaviour in the dark/light test. These data indicate that an inflammatory insult during brain development can change blood-brain barrier permeability and behaviour in later life. It also suggests that the impact of inflammation can occur in several phases (short- and long-term) and that each phase might lead to different behavioural modifications.
Friedman AR, Cacheaux LP, Ivens S
… +1 more, Kaufer D
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21547249
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Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection betw...Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures.
Jorks D, Milakara D, Alam M
… +4 more, Kang EJ, Major S, Friedman A, Dreier JP
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21541244
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There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB) opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the b...There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB) opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the brain and need special equipment for quantification. We here report a novel, simple, and fast semiquantitative algorithm to assess BBB integrity ex vivo. The method is particularly suitable for cranial window experiments, since it keeps the spatial information about where the BBB opened. We validated the algorithm using sham controls and the established model of brain topical application of the bile salt dehydrocholate for early BBB disruption. We then studied spreading depolarizations in the presence and the absence of the vasoconstrictor endothelin-1 and found no evidence of early BBB opening (three-hour time window). The algorithm can be used, for example, to assess BBB permeability ex vivo in combination with dynamic in vivo studies of BBB opening.
Marchi N, Tierney W, Alexopoulos AV
… +3 more, Puvenna V, Granata T, Janigro D
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21541221
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A wind of change characterizes epilepsy research efforts. The traditional approach, based on a neurocentric view of seizure generation, promoted understanding of the neuronal mechanisms of seizures; this resulted in the...A wind of change characterizes epilepsy research efforts. The traditional approach, based on a neurocentric view of seizure generation, promoted understanding of the neuronal mechanisms of seizures; this resulted in the development of potent anti-epileptic drugs (AEDs). The fact that a significant number of individuals with epilepsy still fail to respond to available AEDs restates the need for an alternative approach. Blood-brain barrier (BBB) dysfunction is an important etiological player in seizure disorders, and combination therapies utilizing an AED in conjunction with a "cerebrovascular" drug could be used to control seizures more effectively than AED therapy alone. The fact that the BBB plays an etiologic role in other neurological diseases will be discussed in the context of a more "holistic" approach to the patient with epilepsy, where comorbidity variables are also encompassed by drug therapy.
Williams A, Sittampalam M, Barua N
… +1 more, Mohd Nor A
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21541210
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While ischaemic stroke remains a leading cause of death and disability, there have been recent advancements in treatment modalities including thrombolysis and decompressive hemicraniectomy. A retrospective review of pati...While ischaemic stroke remains a leading cause of death and disability, there have been recent advancements in treatment modalities including thrombolysis and decompressive hemicraniectomy. A retrospective review of patients treated in our NHS teaching hospital, in Plymouth (UK), over a 2 year period identified 17 thrombolysed patients, of whom two had undergone subsequent decompressive hemicraniectomy. These were non-dominant hemisphere strokes in young patients, aged 51 and 57. Initial NIHSS scores were 16 and 17, and they received thrombolysis at 2 hrs 42 min and 5 hrs 10 min post onset of symptoms respectively. CT imaging demonstrated cerebral swelling with significant midline shift in both cases, and decompressive hemicraniectomy was undertaken at 29 hrs 8 min and 27 hrs 30 min post-thrombolysis. We found no significant intra-operative complications attributable to prior use of thrombolytics. Both patients have had acceptable psychological and physical outcomes, with Barthel Index scores of 40 and 25, and MMSE scores of 29/30 and 27/30. We conclude that the use of thrombolytic therapy does not contra-indicate subsequent decompressive hemicraniectomy in well selected patients with non-dominant hemisphere strokes. More research in this field is required to elucidate factors which would facilitate recognition of stroke patients who will benefit most from aggressive medical and neurosurgical intervention.
Gibson LM, Allan SM, Parkes LM
… +1 more, Emsley HC
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21461380
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Late-onset epilepsy (LOE) first occurs after 60 years of age and may be due to occult cerebrovascular disease (CVD) which confers an increased risk of stroke. However, patients with late-onset epilepsy are not currently...Late-onset epilepsy (LOE) first occurs after 60 years of age and may be due to occult cerebrovascular disease (CVD) which confers an increased risk of stroke. However, patients with late-onset epilepsy are not currently consistently investigated or treated for cerebrovascular risk factors. We discuss how abnormalities of neurovascular unit function, namely, changes in regional cerebral blood flow and blood brain barrier disruption, may be caused by occult cerebrovascular disease but present clinically as late-onset epilepsy. We describe novel magnetic resonance imaging methods to detect abnormal neurovascular unit function in subjects with LOE and controls. We hypothesise that occult CVD may cause LOE as a result of neurovascular unit dysfunction.
Tomkins O, Feintuch A, Benifla M
… +3 more, Cohen A, Friedman A, Shelef I
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21436875
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Recent animal experiments indicate a critical role for opening of the blood-brain barrier (BBB) in the pathogenesis of post-traumatic epilepsy (PTE). This study aimed to investigate the frequency, extent, and functional...Recent animal experiments indicate a critical role for opening of the blood-brain barrier (BBB) in the pathogenesis of post-traumatic epilepsy (PTE). This study aimed to investigate the frequency, extent, and functional correlates of BBB disruption in epileptic patients following mild traumatic brain injury (TBI). Thirty-seven TBI patients were included in this study, 19 of whom suffered from PTE. All underwent electroencephalographic (EEG) recordings and brain magnetic resonance imaging (bMRI). bMRIs were evaluated for BBB disruption using novel quantitative techniques. Cortical dysfunction was localized using standardized low-resolution brain electromagnetic tomography (sLORETA). TBI patients displayed significant EEG slowing compared to controls with no significant differences between PTE and nonepileptic patients. BBB disruption was found in 82.4% of PTE compared to 25% of non-epileptic patients (P = .001) and could be observed even years following the trauma. The volume of cerebral cortex with BBB disruption was significantly larger in PTE patients (P = .001). Slow wave EEG activity was localized to the same region of BBB disruption in 70% of patients and correlated to the volume of BBB disrupted cortex. We finally present a patient suffering from early cortical dysfunction and BBB breakdown with a gradual and parallel resolution of both pathologies. Our findings demonstrate that BBB pathology is frequently found following mild TBI. Lasting BBB breakdown is found with increased frequency and extent in PTE patients. Based on recent animal studies and the colocalization found between the region of disrupted BBB and abnormal EEG activity, we suggest a role for a vascular lesion in the pathogenesis of PTE.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21350722
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Proper neuronal functioning depends on a strictly regulated interstitial environment and tight coupling of neuronal and metabolic activity involving adequate vascular responses. These functions take place at the blood br...Proper neuronal functioning depends on a strictly regulated interstitial environment and tight coupling of neuronal and metabolic activity involving adequate vascular responses. These functions take place at the blood brain barrier (BBB) composed of endothelial cells, basal lamina covered with pericytes, and the endfeet of perivascular astrocytes. In conventional in vitro models of the BBB, some of these components are missing. Here we describe a new model system for studying BBB and neurovascular coupling by using confocal microscopy and fluorescence staining protocols in organotypic hippocampal slice cultures. An elaborated network of vessels is retained in culture in spite of the absence of blood flow. Application of calcein-AM either from the interstitial or from the luminal side resulted in different staining patterns indicating the maintenance of a barrier. By contrast, the ethidium derivative MitoSox penetrated perivascular basal lamina and revealed free radical formation in contractile cells embracing the vessels, likely pericytes.
Cardiovasc Psychiatry Neurol
· 2011 · PMID 21350721
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Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patien...Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB) breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions.