The annual Alzheimer’s Association International Conference (AAIC) took place in London, UK in Ju... more The annual Alzheimer’s Association International Conference (AAIC) took place in London, UK in July 2017. In an expert interview, Roxana Carare recaps on the topic of her presentation during the ‘Emerging Concepts in Basic Science’ session, clearance of interstitial fluid of the brain and pathogenesis of dementia.1
Journal of Alzheimer's disease : JAD, Jan 21, 2016
The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment ... more The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.
Alzheimer's disease is characterized by accumulation of a... more Alzheimer's disease is characterized by accumulation of amyloid-β (Aβ) in the brain and in the walls of cerebral arteries. The focus of this work is on clearance of Aβ along artery walls, the failure of which may explain the accumulation of Aβ in Alzheimer's disease. Periarterial basement membranes form continuous channels from cerebral capillaries to major arteries on the surface of the brain. Arterial pressure pulses drive peristaltic flow in the basement membranes in the same direction as blood flow. Here we forward the hypothesis that flexible structures within the basement membrane, if oriented such they present greater resistance to forward than retrograde flow, may cause net reverse flow, advecting Aβ along with it. A solution was obtained for peristaltic flow with low Reynolds number, long wavelength compared to channel height and small channel height compared to vessel radius in a Darcy-Brinkman medium representing a square array of cylinders. Results show that retrograde flow is promoted by high cylinder volume fraction and low peristaltic amplitude. A decrease in cylinder concentration and/or an increase in amplitude, both of which may occur during ageing, can reduce retrograde flow or even cause a transition from retrograde to forward flow. Such changes may explain the accumulation of Aβ in the brain and in artery walls in Alzheimer's disease.
An exploratory investigation is reported into the role of spirituality and religious practice in ... more An exploratory investigation is reported into the role of spirituality and religious practice in protecting against depression among older people living in rural villages in Bulgaria and Romania, two neighbouring countries with similar cultural, political and religious histories, but with differing levels of current religiosity. In both countries, interviews were conducted with samples of 160 persons of 60 years and over in villages of similar socio-economic status. The Hospital Anxiety and Depression-D scale and the Royal Free Interview for Religious and Spiritual Beliefs were used to assess depression and spiritual belief and practice respectively. In addition social support, physical functioning and the presence of chronic diseases were assessed. One year later, follow-up interviews were conducted with 58 of the original sample in Bulgaria, in which additional measures of depression and of spiritual belief and practice were also included. The study demonstrates, as expected, significantly lower levels of spiritual belief in the Bulgarian sample (Bulgarian mean 29.7 (SD = 19.1), Romanian mean 47.6 (SD = 11.2), t = 10.2, p < 0.001), as well as significantly higher levels of depression (Bulgarian mean 12.0 (SD = 4.9), Romanian mean 7.3 (SD = 4.1), t = 9.3, p < 0.001), the latter attributable in large part to higher morbidity and disability rates, but less evidently to differences in strength of belief. However, analyses from both the cross-sectional study and the one-year follow-up of the Bulgarian sample do suggest that spiritual belief and practice may both influence and reflect physical and mental illness. Much of Eastern Europe displays high rates of depression among its older population and provides opportunities for investigation of the role of religious belief and practice in preventing and coping with depression. Further research is encouraged in populations of diverse religiosity.
Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid an... more Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer's disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. The motive force for the elimination of Aβ along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, Aβ rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E ε4 (ApoE4) mice. For drainage of Aβ to occur in a direction contrary to the pulse wave, some form of attachment to basement membrane would be required to prevent reflux of Aβ back into the brain during the passage of the subsequent pulse wave. ...
Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CA... more Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brai...
Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is a... more Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is accompanied by parenchymal amyloid-β (Aβ) deposition in the brain and by hypertensive nephropathy with tubulointerstitial damage. N-acetylcysteine (NAC) promotes blood-brain barrier (BBB) breakdown in SHRSP and may thus accelerate the failure of vascular and perivascular clearance of Aβ. In this study, we test the hypothesis that treatment with NAC increases the cerebral Aβ load and improves renal damage in the SHRSP model. A total of 46 SHRSP (ages 18-44 weeks) were treated daily with NAC (12 mg/kg body weight) and 74 no-treated age-matched SHRSP served as controls. The prevalence of parenchymal Aβ load, IgG positive small vessels, and small perivascular bleeds was assessed in different brain regions. Tubulointerstitial kidney damage was assessed through a) the presence of erythrocytes in peritubular capillaries and b) tubular protein cylinders. SHRSP treated with NAC had an age-dependen...
ABSTRACT IntroductionPrimary age-related tauopathy (PART) [7] is characterised by a limited distr... more ABSTRACT IntroductionPrimary age-related tauopathy (PART) [7] is characterised by a limited distribution of tau pathology, compared with Alzheimer’s disease (AD), and an absence of amyloid-β (Aβ) plaques. Clinically, patients with PART are older and only a minority have profound cognitive impairment. Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau spread in an age-related manner from brainstem to cerebral cortical areas [3] and the presence of Aβ plaques is associated with acceleration in the propagation of NFTs in the pathogenesis of AD [11, 18]. The amyloid cascade [8] appears to drive the hyperphosphorylation and propagation of tau [6, 16] and Aβ oligomers have a toxic effect upon synapses [16].In the context of PART, we ask the question “Why is there relatively limited spread of NFTs and few if any Aβ plaques in PART compared with AD?” In order to answer these questions, we examine evidence that ageing of cerebral arteries is a trigger for the amyloid cascade and propagati ...
Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of ce... more Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer's disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA.
Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel... more Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer's disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. We test the hypothesis that characteristic features of CSVD are associated with the accumulation of Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Amyloid-β protein precursor (AβPP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for BBB examination were performed in 38 SHRSP (age 12-44 weeks) and Aβ (n = 29) and ptau (n = 17) immunocytochemistry in 20-44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12-44 weeks). In 20 week-old SHRSP, cortical AβPP expression was signif...
The annual Alzheimer’s Association International Conference (AAIC) took place in London, UK in Ju... more The annual Alzheimer’s Association International Conference (AAIC) took place in London, UK in July 2017. In an expert interview, Roxana Carare recaps on the topic of her presentation during the ‘Emerging Concepts in Basic Science’ session, clearance of interstitial fluid of the brain and pathogenesis of dementia.1
Journal of Alzheimer's disease : JAD, Jan 21, 2016
The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment ... more The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.
Alzheimer's disease is characterized by accumulation of a... more Alzheimer's disease is characterized by accumulation of amyloid-β (Aβ) in the brain and in the walls of cerebral arteries. The focus of this work is on clearance of Aβ along artery walls, the failure of which may explain the accumulation of Aβ in Alzheimer's disease. Periarterial basement membranes form continuous channels from cerebral capillaries to major arteries on the surface of the brain. Arterial pressure pulses drive peristaltic flow in the basement membranes in the same direction as blood flow. Here we forward the hypothesis that flexible structures within the basement membrane, if oriented such they present greater resistance to forward than retrograde flow, may cause net reverse flow, advecting Aβ along with it. A solution was obtained for peristaltic flow with low Reynolds number, long wavelength compared to channel height and small channel height compared to vessel radius in a Darcy-Brinkman medium representing a square array of cylinders. Results show that retrograde flow is promoted by high cylinder volume fraction and low peristaltic amplitude. A decrease in cylinder concentration and/or an increase in amplitude, both of which may occur during ageing, can reduce retrograde flow or even cause a transition from retrograde to forward flow. Such changes may explain the accumulation of Aβ in the brain and in artery walls in Alzheimer's disease.
An exploratory investigation is reported into the role of spirituality and religious practice in ... more An exploratory investigation is reported into the role of spirituality and religious practice in protecting against depression among older people living in rural villages in Bulgaria and Romania, two neighbouring countries with similar cultural, political and religious histories, but with differing levels of current religiosity. In both countries, interviews were conducted with samples of 160 persons of 60 years and over in villages of similar socio-economic status. The Hospital Anxiety and Depression-D scale and the Royal Free Interview for Religious and Spiritual Beliefs were used to assess depression and spiritual belief and practice respectively. In addition social support, physical functioning and the presence of chronic diseases were assessed. One year later, follow-up interviews were conducted with 58 of the original sample in Bulgaria, in which additional measures of depression and of spiritual belief and practice were also included. The study demonstrates, as expected, significantly lower levels of spiritual belief in the Bulgarian sample (Bulgarian mean 29.7 (SD = 19.1), Romanian mean 47.6 (SD = 11.2), t = 10.2, p < 0.001), as well as significantly higher levels of depression (Bulgarian mean 12.0 (SD = 4.9), Romanian mean 7.3 (SD = 4.1), t = 9.3, p < 0.001), the latter attributable in large part to higher morbidity and disability rates, but less evidently to differences in strength of belief. However, analyses from both the cross-sectional study and the one-year follow-up of the Bulgarian sample do suggest that spiritual belief and practice may both influence and reflect physical and mental illness. Much of Eastern Europe displays high rates of depression among its older population and provides opportunities for investigation of the role of religious belief and practice in preventing and coping with depression. Further research is encouraged in populations of diverse religiosity.
Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid an... more Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer's disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. The motive force for the elimination of Aβ along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, Aβ rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E ε4 (ApoE4) mice. For drainage of Aβ to occur in a direction contrary to the pulse wave, some form of attachment to basement membrane would be required to prevent reflux of Aβ back into the brain during the passage of the subsequent pulse wave. ...
Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CA... more Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brai...
Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is a... more Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is accompanied by parenchymal amyloid-β (Aβ) deposition in the brain and by hypertensive nephropathy with tubulointerstitial damage. N-acetylcysteine (NAC) promotes blood-brain barrier (BBB) breakdown in SHRSP and may thus accelerate the failure of vascular and perivascular clearance of Aβ. In this study, we test the hypothesis that treatment with NAC increases the cerebral Aβ load and improves renal damage in the SHRSP model. A total of 46 SHRSP (ages 18-44 weeks) were treated daily with NAC (12 mg/kg body weight) and 74 no-treated age-matched SHRSP served as controls. The prevalence of parenchymal Aβ load, IgG positive small vessels, and small perivascular bleeds was assessed in different brain regions. Tubulointerstitial kidney damage was assessed through a) the presence of erythrocytes in peritubular capillaries and b) tubular protein cylinders. SHRSP treated with NAC had an age-dependen...
ABSTRACT IntroductionPrimary age-related tauopathy (PART) [7] is characterised by a limited distr... more ABSTRACT IntroductionPrimary age-related tauopathy (PART) [7] is characterised by a limited distribution of tau pathology, compared with Alzheimer’s disease (AD), and an absence of amyloid-β (Aβ) plaques. Clinically, patients with PART are older and only a minority have profound cognitive impairment. Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau spread in an age-related manner from brainstem to cerebral cortical areas [3] and the presence of Aβ plaques is associated with acceleration in the propagation of NFTs in the pathogenesis of AD [11, 18]. The amyloid cascade [8] appears to drive the hyperphosphorylation and propagation of tau [6, 16] and Aβ oligomers have a toxic effect upon synapses [16].In the context of PART, we ask the question “Why is there relatively limited spread of NFTs and few if any Aβ plaques in PART compared with AD?” In order to answer these questions, we examine evidence that ageing of cerebral arteries is a trigger for the amyloid cascade and propagati ...
Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of ce... more Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer's disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA.
Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel... more Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer's disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. We test the hypothesis that characteristic features of CSVD are associated with the accumulation of Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Amyloid-β protein precursor (AβPP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for BBB examination were performed in 38 SHRSP (age 12-44 weeks) and Aβ (n = 29) and ptau (n = 17) immunocytochemistry in 20-44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12-44 weeks). In 20 week-old SHRSP, cortical AβPP expression was signif...
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