Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease
Mehta NH, Suss RA, Dyke JP, Theise ND, Chiang GC, Strauss S, Saint-Louis L, Li Y, Pahlajani S, Babaria V, Glodzik L, Carare RO and de Leon MJ
Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease
Mehta NH, Suss RA, Dyke JP, Theise ND, Chiang GC, Strauss S, Saint-Louis L, Li Y, Pahlajani S, Babaria V, Glodzik L, Carare RO and de Leon MJ
Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aβ), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.
Decreased CSF clearance and increased brain amyloid in Alzheimer's disease
Li Y, Rusinek H, Butler T, Glodzik L, Pirraglia E, Babich J, Mozley PD, Nehmeh S, Pahlajani S, Wang X, Tanzi EB, Zhou L, Strauss S, Carare RO, Theise N, Okamura N and de Leon MJ
Decreased CSF clearance and increased brain amyloid in Alzheimer's disease
Li Y, Rusinek H, Butler T, Glodzik L, Pirraglia E, Babich J, Mozley PD, Nehmeh S, Pahlajani S, Wang X, Tanzi EB, Zhou L, Strauss S, Carare RO, Theise N, Okamura N and de Leon MJ
In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aβ) deposition is believed to be a consequence of impaired Aβ clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels.
Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut
Nimmo JT, Smith H, Wang CY, Teeling JL, Nicoll JAR, Verma A, Dodart JC, Liu Z, Lin F and Carare RO
Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut
Nimmo JT, Smith H, Wang CY, Teeling JL, Nicoll JAR, Verma A, Dodart JC, Liu Z, Lin F and Carare RO
Alpha synuclein has a key role in the pathogenesis of Parkinson's disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.
Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain
Bown CW, Carare RO, Schrag MS and Jefferson AL
Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain
Bown CW, Carare RO, Schrag MS and Jefferson AL
Perivascular spaces (PVS) are fluid-filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on MRI. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as 2 possible mechanisms that drive ePVS formation. We describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the 2 most prominent theoretical views and review ePVS associations with other common small vessel disease markers. Because ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.
TUBE Project: Transport-Derived Ultrafines and the Brain Effects
Martikainen MV, Aakko-Saksa P, van den Broek L, Cassee FR, Carare RO, Chew S, Dinnyes A, Giugno R, Kanninen KM, Malm T, Muala A, Nedergaard M, Oudin A, Oyola P, Pfeiffer TV, Rönkkö T, Saarikoski S, Sandström T, Schins RPF, Topinka J, Yang M, Zeng X, Westerink RHS and Jalava PI
TUBE Project: Transport-Derived Ultrafines and the Brain Effects
Martikainen MV, Aakko-Saksa P, van den Broek L, Cassee FR, Carare RO, Chew S, Dinnyes A, Giugno R, Kanninen KM, Malm T, Muala A, Nedergaard M, Oudin A, Oyola P, Pfeiffer TV, Rönkkö T, Saarikoski S, Sandström T, Schins RPF, Topinka J, Yang M, Zeng X, Westerink RHS and Jalava PI
The adverse effects of air pollutants on the respiratory and cardiovascular systems are unquestionable. However, in recent years, indications of effects beyond these organ systems have become more evident. Traffic-related air pollution has been linked with neurological diseases, exacerbated cognitive dysfunction, and Alzheimer's disease. However, the exact air pollutant compositions and exposure scenarios leading to these adverse health effects are not known. Although several components of air pollution may be at play, recent experimental studies point to a key role of ultrafine particles (UFPs). While the importance of UFPs has been recognized, almost nothing is known about the smallest fraction of UFPs, and only >23 nm emissions are regulated in the EU. Moreover, the role of the semivolatile fraction of the emissions has been neglected. The Transport-Derived Ultrafines and the Brain Effects (TUBE) project will increase knowledge on harmful ultrafine air pollutants, as well as semivolatile compounds related to adverse health effects. By including all the major current combustion and emission control technologies, the TUBE project aims to provide new information on the adverse health effects of current traffic, as well as information for decision makers to develop more effective emission legislation. Most importantly, the TUBE project will include adverse health effects beyond the respiratory system; TUBE will assess how air pollution affects the brain and how air pollution particles might be removed from the brain. The purpose of this report is to describe the TUBE project, its background, and its goals.
Gadolinium enhancement of cranial nerves: Implications for interstitial fluid drainage from brainstem into cranial nerves in humans
Varatharaj A, Carare RO, Weller RO, Gawne-Cain M and Galea I
Gadolinium enhancement of cranial nerves: Implications for interstitial fluid drainage from brainstem into cranial nerves in humans
Varatharaj A, Carare RO, Weller RO, Gawne-Cain M and Galea I
Drainage of interstitial fluid and solutes from the brainstem has not been well studied. To map one drainage pathway in the human brainstem, we took advantage of the focal blood-brain barrier disruption occurring in a multiple sclerosis brainstem lesion, coupled with intravenous injection of gadolinium, which simulates an intraparenchymal injection of gadolinium tracer within the restricted confines of this small brain region. Using high-resolution MRI, we show how it is possible for interstitial fluid to drain into the adjacent trigeminal and oculomotor nerves, in keeping with a pathway of communication between the extracellular spaces of the brainstem and cranial nerve parenchyma.
The α-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix-significance for protein elimination failure arteriopathies
Sharp MM, Cassidy J, Thornton T, Lyles J, Keable A, Gatherer M, Yasui M, Abe Y, Shibata S, Weller RO, Górecki DC and Carare RO
The α-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix-significance for protein elimination failure arteriopathies
Sharp MM, Cassidy J, Thornton T, Lyles J, Keable A, Gatherer M, Yasui M, Abe Y, Shibata S, Weller RO, Górecki DC and Carare RO
The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.
The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans
Mehta NH, Sherbansky J, Kamer AR, Carare RO, Butler T, Rusinek H, Chiang GC, Li Y, Strauss S, Saint-Louis LA, Theise ND, Suss RA, Blennow K, Kaplitt M and de Leon MJ
The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans
Mehta NH, Sherbansky J, Kamer AR, Carare RO, Butler T, Rusinek H, Chiang GC, Li Y, Strauss S, Saint-Louis LA, Theise ND, Suss RA, Blennow K, Kaplitt M and de Leon MJ
The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations.
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment
Li M, Kitamura A, Beverley J, Koudelka J, Duncombe J, Lennen R, Jansen MA, Marshall I, Platt B, Wiegand UK, Carare RO, Kalaria RN, Iliff JJ and Horsburgh K
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment
Li M, Kitamura A, Beverley J, Koudelka J, Duncombe J, Lennen R, Jansen MA, Marshall I, Platt B, Wiegand UK, Carare RO, Kalaria RN, Iliff JJ and Horsburgh K
Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.
In silico exploration of amyloid-related imaging abnormalities in the gantenerumab open-label extension trials using a semi-mechanistic model
Aldea R, Grimm HP, Gieschke R, Hofmann C, Lott D, Bullain S, Delmar P, Klein G, Lyons M, Piazza F, Carare RO and Mazer NA
In silico exploration of amyloid-related imaging abnormalities in the gantenerumab open-label extension trials using a semi-mechanistic model
Aldea R, Grimm HP, Gieschke R, Hofmann C, Lott D, Bullain S, Delmar P, Klein G, Lyons M, Piazza F, Carare RO and Mazer NA
Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer's disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency.