Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds
Ikeda S, Saito S, Hosoki S, Tonomura S, Yamamoto Y, Ikenouchi H, Ishiyama H, Tanaka T, Hattori Y, Friedland RP, Carare RO, Kuriyama N, Yakushiji Y, Hara H, Koga M, Toyoda K, Nomura R, Takegami M, Nakano K and Ihara M
Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds
Ikeda S, Saito S, Hosoki S, Tonomura S, Yamamoto Y, Ikenouchi H, Ishiyama H, Tanaka T, Hattori Y, Friedland RP, Carare RO, Kuriyama N, Yakushiji Y, Hara H, Koga M, Toyoda K, Nomura R, Takegami M, Nakano K and Ihara M
Cerebral microbleeds (CMBs) influence long-term prognoses of stroke patients. Streptococcus mutans expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, impairing blood brain barrier integrity and causing cerebral bleeding. Here, we examine the association of Cnm-positive S. mutans with CMBs.
Monomeric C-reactive protein: A novel biomarker predicting neurodegenerative disease and vascular dysfunction
Pastorello Y, Carare RO, Banescu C, Potempa L, Di Napoli M and Slevin M
Monomeric C-reactive protein: A novel biomarker predicting neurodegenerative disease and vascular dysfunction
Pastorello Y, Carare RO, Banescu C, Potempa L, Di Napoli M and Slevin M
Circulating C-reactive protein (pCRP) concentrations rise dramatically during both acute (e.g., following stroke) or chronic infection and disease (e.g., autoimmune conditions such as lupus), providing complement fixation through C1q protein binding. It is now known, that on exposure to the membranes of activated immune cells (and microvesicles and platelets), or damaged/dysfunctional tissue, it undergoes lysophosphocholine (LPC)-phospholipase-C-dependent dissociation to the monomeric form (mCRP), concomitantly becoming biologically active. We review histological, immunohistochemical, and morphological/topological studies of post-mortem brain tissue from individuals with neuroinflammatory disease, showing that mCRP becomes stably distributed within the parenchyma, and resident in the arterial intima and lumen, being "released" from damaged, hemorrhagic vessels into the extracellular matrix. The possible de novo synthesis via neurons, endothelial cells, and glia is also considered. In vitro, in vivo, and human tissue co-localization analyses have linked mCRP to neurovascular dysfunction, vascular activation resulting in increased permeability, and leakage, compromise of blood brain barrier function, buildup of toxic proteins including tau and beta amyloid (Aβ), association with and capacity to "manufacture" Aβ-mCRP-hybrid plaques, and, greater susceptibility to neurodegeneration and dementia. Recently, several studies linked chronic CRP/mCRP systemic expression in autoimmune disease with increased risk of dementia and the mechanisms through which this occurs are investigated here. The neurovascular unit mediates correct intramural periarterial drainage, evidence is provided here that suggests a critical impact of mCRP on neurovascular elements that could suggest its participation in the earliest stages of dysfunction and conclude that further investigation is warranted. We discuss future therapeutic options aimed at inhibiting the pCRP-LPC mediated dissociation associated with brain pathology, for example, compound 1,6-bis-PC, injected intravenously, prevented mCRP deposition and associated damage, after temporary left anterior descending artery ligation and myocardial infarction in a rat model.
Retinal arterial Aβ deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients
Shi H, Koronyo Y, Fuchs DT, Sheyn J, Jallow O, Mandalia K, Graham SL, Gupta VK, Mirzaei M, Kramerov AA, Ljubimov AV, Hawes D, Miller CA, Black KL, Carare RO and Koronyo-Hamaoui M
Retinal arterial Aβ deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients
Shi H, Koronyo Y, Fuchs DT, Sheyn J, Jallow O, Mandalia K, Graham SL, Gupta VK, Mirzaei M, Kramerov AA, Ljubimov AV, Hawes D, Miller CA, Black KL, Carare RO and Koronyo-Hamaoui M
Vascular amyloid beta (Aβ) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that the retinal vascular tight junctions (TJs) were compromised and linked to disease status.
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
One of the most complex and challenging developments at the beginning of the third millennium is the alarming increase in demographic aging, mainly-but not exclusively-affecting developed countries. This reality results in one of the harsh medical, social, and economic consequences: the continuously increasing number of people with dementia, including Alzheimer's disease (AD), which accounts for up to 80% of all such types of pathology. Its large and progressive disabling potential, which eventually leads to death, therefore represents an important public health matter, especially because there is no known cure for this disease. Consequently, periodic reappraisals of different therapeutic possibilities are necessary. For this purpose, we conducted this systematic literature review investigating nonpharmacological interventions for AD, including their currently known cellular and molecular action bases. This endeavor was based on the PRISMA method, by which we selected 116 eligible articles published during the last year. Because of the unfortunate lack of effective treatments for AD, it is necessary to enhance efforts toward identifying and improving various therapeutic and rehabilitative approaches, as well as related prophylactic measures.
Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy
Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N and Carare RO
Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy
Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N and Carare RO
This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.
Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome
Agarwal N, Lewis LD, Hirschler L, Rivera LR, Naganawa S, Levendovszky SR, Ringstad G, Klarica M, Wardlaw J, Iadecola C, Hawkes C, Carare RO, Wells J, Bakker ENTP, Kurtcuoglu V, Bilston L, Nedergaard M, Mori Y, Stoodley M, Alperin N, de Leon M and van Osch MJP
Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome
Agarwal N, Lewis LD, Hirschler L, Rivera LR, Naganawa S, Levendovszky SR, Ringstad G, Klarica M, Wardlaw J, Iadecola C, Hawkes C, Carare RO, Wells J, Bakker ENTP, Kurtcuoglu V, Bilston L, Nedergaard M, Mori Y, Stoodley M, Alperin N, de Leon M and van Osch MJP
Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.
Correction: Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy
Nimmo JT, Verma A, Dodart JC, Wang CY, Savistchenko J, Melki R, Carare RO and Nicoll JAR
Correction: Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy
Nimmo JT, Verma A, Dodart JC, Wang CY, Savistchenko J, Melki R, Carare RO and Nicoll JAR
The impairment of intramural periarterial drainage in brain after subarachnoid hemorrhage
Sun Y, Liu E, Pei Y, Yao Q, Ma H, Mu Y, Wang Y, Zhang Y, Yang X, Wang X, Xue J, Zhai J, Carare RO, Qin L and Yan J
The impairment of intramural periarterial drainage in brain after subarachnoid hemorrhage
Sun Y, Liu E, Pei Y, Yao Q, Ma H, Mu Y, Wang Y, Zhang Y, Yang X, Wang X, Xue J, Zhai J, Carare RO, Qin L and Yan J
Interstitial fluid (ISF) from brain drains along the basement membranes of capillaries and arteries as Intramural Periarterial Drainage (IPAD); failure of IPAD results in cerebral amyloid angiopathy (CAA). In this study, we test the hypothesis that IPAD fails after subarachnoid haemorrhage (SAH). The rat SAH model was established using endovascular perforation method. Fluorescence dyes with various molecular weights were injected into cisterna magna of rats, and the pattern of IPAD after SAH was detected using immunofluorescence staining, two-photon fluorescent microscope, transmission electron microscope and magnetic resonance imaging tracking techniques. Our results showed that fluorescence dyes entered the brain along a periarterial compartment and were cleared from brain along the basement membranes of the capillaries, with different patterns based on individual molecular weights. After SAH, there was significant impairment in the IPAD system: marked expansion of perivascular spaces, and ISF clearance rate was significantly decreased, associated with the apoptosis of endothelial cells, activation of astrocytes, over-expression of matrix metalloproteinase 9 and loss of collagen type IV. In conclusion, experimental SAH leads to a failure of IPAD, clinically significant for long term complications such as CAA, following SAH.
Translation of the Fugl-Meyer assessment into Romanian: Transcultural and semantic-linguistic adaptations and clinical validation
Onose G, Anghelescu A, Ionescu A, Tataranu LG, Spînu A, Bumbea AM, Toader C, Tuţă S, Carare RO, Popescu C, Munteanu C, and Daia C
Translation of the Fugl-Meyer assessment into Romanian: Transcultural and semantic-linguistic adaptations and clinical validation
Onose G, Anghelescu A, Ionescu A, Tataranu LG, Spînu A, Bumbea AM, Toader C, Tuţă S, Carare RO, Popescu C, Munteanu C, and Daia C
The Fugl-Meyer Assessment (FMA) scale, which is widely used and highly recommended, is an appropriate tool for evaluating poststroke sensorimotor and other possible somatic deficits. It is also well-suited for capturing a dynamic rehabilitation process. The aim of this study was to first translate the entire sensorimotor FMA scale into Romanian using the transcultural and semantic-linguistic adaptations of its official afferent protocols and to validate it using the preliminary clinical evaluation of inter- and intra-rater reliability and relevant concurrent validity.
Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease
Kelly L, Sharp MM, Thomas I, Brown C, Schrag M, Antunes LV, Solopova E, Martinez-Gonzalez J, Rodríguez C and Carare RO
Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease
Kelly L, Sharp MM, Thomas I, Brown C, Schrag M, Antunes LV, Solopova E, Martinez-Gonzalez J, Rodríguez C and Carare RO
Alzheimer's disease is the commonest form of dementia. It is likely that a lack of clearance of amyloid beta (Aβ) results in its accumulation in the parenchyma as Aβ oligomers and insoluble plaques, and within the walls of blood vessels as cerebral amyloid angiopathy (CAA). The drainage of Aβ along the basement membranes of blood vessels as intramural periarterial drainage (IPAD), could be improved if the driving force behind IPAD could be augmented, therefore reducing Aβ accumulation. There are alterations in the composition of the vascular basement membrane in Alzheimer's disease. Lysyl oxidase (LOX) is an enzyme involved in the remodelling of the extracellular matrix and its expression and function is altered in various disease states. The expression of LOX is increased in Alzheimer's disease, but it is unclear whether this is a contributory factor in the impairment of IPAD in Alzheimer's disease. The pharmacological inhibition of LOX may be a strategy to improve IPAD and reduce the accumulation of Aβ in the parenchyma and within the walls of blood vessels.