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.
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.
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
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.
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.
Author Response: Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study
Piazza F, Basso G, Pascarella R, Carare RO and Zedde M
Author Response: Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study
Piazza F, Basso G, Pascarella R, Carare RO and Zedde M
α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression
Hawkes CA, Heath CJ, Sharp MM, Górecki DC and Carare RO
α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression
Hawkes CA, Heath CJ, Sharp MM, Górecki DC and Carare RO
α-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.
The Lymphatic System in Neurological Disease and Alzheimer's Disease. A Brief Editorial
Pappolla MA, Carare RO, Poeggeler B, Wisniewski T and Sambamurti K
The Lymphatic System in Neurological Disease and Alzheimer's Disease. A Brief Editorial
Pappolla MA, Carare RO, Poeggeler B, Wisniewski T and Sambamurti K
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.