Military-related risk factors for dementia
In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer’s disease in veterans. Building on that discussion, and subsequent to a special issue of Alzheimer’s & Dementia published in June 2014, which focused on military risk factors, the Alzheimer’s Association convened a continued discussion of the scientific community on December 1, 2016. During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans’ risk for later life dementia. The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.
Snyder HM, Carare RO, DeKosky ST, de Leon MJ, et al.
A control mechanism for intra-mural periarterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain.
The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer’s disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.
Lymphatic Drainage of the CNS and Its Role in Neuroinflammation and Neurodegenerative Disease.
CSF in ventricles and subarachnoid spaces and interstitial fluid (ISF) in the extracellular spaces of the CNS parenchyma both drain to lymph nodes but by largely separate routes. CSF drains along lymphatic vessels that allow traffic of antigen presenting cells (APC) to lymph nodes. ISF, on the other hand, drains to lymph nodes along 100–150 nm thick basement membranes in the intramural periarterial pathways that do not allow traffic of APC from the CNS parenchyma to lymph nodes. This is one factor that may account for immune privilege in the CNS; the other factor is the highly controlled entry of T lymphocytes into CNS tissues. Lymphatic drainage of CSF and ISF and draining lymph nodes play a role in neuroimmunological diseases. Lymphatic drainage of ISF maintains homeostasis of the CNS but fails with age and this is associated with failure of elimination and accumulation of amyloid β in the brain in Alzheimer’s disease. Understanding lymphatic drainage of the CNS may aid the development of therapies for neuroimmunological disorders and Alzheimer’s disease.
The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats.
We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17-44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.
Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.
Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the “glymphaticsystem” that proposes tracers enter the brain along periarterial “spaces” and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basementmembranes as there are no perivascular “spaces” around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basementmembranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enterand leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer’s disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA.
Small vessels, dementia and chronic diseases – molecular mechanisms and pathophysiology.
Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.
The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS.
Meninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine the development of leptomeninges and their role as barriers and facilitators in the foetal CNS. There are two separate CSF systems during early foetal life, inner CSF in the ventricles and outer CSF in the subarachnoid space. As the foramina of Magendi and Luschka develop, one continuous CSF system evolves. Due to the lack of arachnoid granulations during foetal life, it is most likely that CSF is eliminated by lymphatic drainage pathways passing through the cribriform plate and nasal submucosa. (2) We then review the fine structure of the adult human and rodent leptomeninges to establish their roles as barriers and facilitators for the movement of fluid, cells and pathogens. Leptomeningeal cells line CSF spaces, including arachnoid granulations and lymphatic drainage pathways, and separate elements of extracellular matrix from the CSF. The leptomeningeal lining facilitates the traffic of inflammatory cells within CSF but also allows attachment of bacteria such as Neisseria meningitidis and of tumour cells as CSF metastases. Single layers of leptomeningeal cells extend into the brain closely associated with the walls of arteries so that there are no perivascular spaces around arteries in the cerebral cortex. Perivascular spaces surrounding arteries in the white matter and basal ganglia relate to their two encompassing layers of leptomeninges. (3) Finally we examine the roles of ligands expressed by leptomeningeal cells for the attachment of inflammatory cells, bacteria and tumour cells as understanding these roles may aid the design of therapeutic strategies to manage developmental, autoimmune, infectious and neoplastic diseases relating to the CSF, the leptomeninges and the associated CNS.
The fine anatomy of the perivascular compartment in the brain. Relevance to dilated perivascular spaces in cerebral amyloid angiopathy.
Cerebral white matter hyperintensities (WMH) observed on magnetic resonance imaging (MRI), or low attenuation on computed tomographic scanning (CT), are the most frequent brain imaging finding in patients with small vessel disease or dementia. It has been assumed that WMH are due to arteriosclerosis or blood-brain barrier breakdown, though recently it was demonstrated that WMH have distinct molecular signatures in Alzheimer’s disease (AD) where markers of Wallerian degeneration are present, compared to normal ageing. Dilated perivascular spaces (PVS) are of particular interest for the study of interstitial fluid (ISF) dynamics because they are related to the intramural periarterial drainage (IPAD) of ISF and solutes along arterial basement membranes and can potentially be detected by MRI.
Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways.
Editorial: Clearance Pathways for Amyloid-β. Significance for Alzheimer’s Disease and Its Therapy.
The perivascular pathways for influx of cerebrospinal fluid are most efficient in the midbrain.
Dobson H, MacGregor Sharp M, Cumpsty R, Criswell TP, Wellman T, Finucane C, et al.
The structure of the perivascular compartment in the old canine brain: a case study.
Criswell TP, MacGregor Sharp M, Dobson H, Finucane C, Weller RO, Verma A, et al
The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice.
Banerjee G, Carare R, Cordonnier C, Greenberg SM, Schneider JA, Smith EE, et al.
Arterial pulsations cannot drive intramural periarterial drainage: Significance for Aβ drainage.
Diem A.K, MacGregor Sharp M, Gatherer M, Bressloff N.W, Carare R.O & Richardson G.
Hypercholesterolemia induced cerebral small vessel disease.
Kraft P, Schuhmann MK, Garz C, Jandke S, Urlaub D, Mencl S, et al.
Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways.
Wojtas AM, Kang SS, Olley BM, Gatherer M, Shinohara M, Lozano PA, et al.
Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease.
Held F, Morris AWJ, Pirici D, Niklass S, MacGregor Sharp M, Garz C, et al.
The movers and shapers in immune privilege of the CNS.
Engelhardt B, Vajkoczy P, Weller RO.
Quantitative assessment of cerebral basement membranes using electron microscopy.
MacGregor Sharp M, Page A, Morris AWJ, Weller RO, Carare RO.
Investigating the Lymphatic Drainage of the Brain: Essential Skills and Tools.
Albargothy JN, MacGregor Sharp M, Gatherer M, Morris AWJ, Weller RO, Hawkes CA, Carare RO.
Cerebrovascular pathology: the dark side of neurodegeneration.
Systems proteomic analysis reveals that Clusterin and Tissue Inhibitor of Metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy.
Vascular, glial, and lymphatic immune gateways of the central nervous system.
Pulsations with reflected boundary waves: a hydrodynamic reverse transport mechanism for perivascular drainage in the brain.
Vascular basement membranes as pathways for the passage of fluid into and out of the brain.
Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer’s Disease Mouse Model.
Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases.
Increased Abeta pathology in aged Tg2576 mice born to mothers fed a high fat diet.
A Simulation Model of Periarterial Clearance of Amyloid-beta from the Brain.
Chapter 19 – Pathophysiology of Lymphatic Drainage of the Central Nervous System: Implications for the Pathophysiology of Multiple Sclerosis.
Deposition of Amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.
Quantification of molecular interactions between apoE, Amyloid-beta (Aβ) and laminin: Relevance to accumulation of Aβ in Alzheimer’s disease.
Zekonyte J, Sakai K, Nicoll J, Weller RO, Carare RO.
Clearance systems in the brain-implications for Alzheimer disease.
Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H, Nicholson C, Zlokovic BV, Frangione B, Blennow K, Ménard J, Zetterberg H, Wisniewski T, de Leon MJ.
Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?
Weller RO, Hawkes CA, Carare RO, Hardy J.
Peristalsis with oscillating flow resistance: A mechanism for periarterial clearance of amyloid beta from the brain.
White matter changes in dementia: role of impaired drainage of interstitial fluid.
Are you also what your mother eats: Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse.
Are the effects of APOE ϵ4 on cognitive function in nonclinical populations age- and gender-dependent?
Rusted J & Carare RO.
Prenatal high fat diet alters the cerebrovasculature and clearance of beta-amyloid in adult offspring.
Hawkes CA, Gentleman S, Nicoll JAR, Carare RO.
The cerebrovascular basement membrane: role in the clearance of β-amyloid and Cerebral Amyloid Angiopathy.
Failure of perivascular drainage of beta-amyloid in cerebral amyloid angiopathy.
Impact of N-acetylcysteine on cerebral parenchymal Aβ plaques and kidney damage in spontaneously hypertensive stroke-prone rats.
Aß immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy.
Amyloid and tau in the brain in sporadic Alzheimer’s disease: defining the chicken and the egg.
Hawkes C, Carare RO, Weller RO.
Hypertension drives parenchymal ß-amyloid accumulation in the brain parenchyma.
Bueche CZ, Hawkes C, Garz C, Vielhaber S, Attems J, Knight RT, Reymann K, Heinze H, Carare R, Schreiber S.
MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice.
Hawkes CA, Shaw JE, Brown MS, Anthony P, McLaurin J, Carare RO.
Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer’s disease.
Carare RO, Teeling J, Hawkes CA, Püntener U, Weller RO, Nicoll JAR, Perry V.
Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain.
Apolipoprotein E epsilon 4 (apoE4) may impair perivascular elimination of amyloid-beta (A beta).
Carare, Roxana, Teeling, Jessica, Hawkes, Cheryl A, Püntener, Ursula, Weller, Roy O, Nicoll, James AR and Perry, Victor. (2013) Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer’s disease. Acta Neuropathologica, 1, (1), 48-[11pp]. (doi:10.1186/2051-5960-1-48). PMID: 24252464
Hawkes, C.A., Gatherer, M., Sharp, M.M., Dorr, A., Yuen, H.M., Kalaria, R., Weller, R.O. and Carare, R.O. (2013) Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell, 12, (2), 224-236. (doi:10.1111/acel.12045). PMID 23413811
Hawkes, C.A., Zekonyte, J., Howard, K., Nicoll, James A.R., Weller, Roy O. and Carare, Roxana O. (2013) Apolipoprotein E epsilon 4 (apoE4) may impair perivascular elimination of amyloid-beta (A beta). Neuropathology and Applied Neurobiology, 39, supplement 1, 8. (doi:10.1111/j.1365-2990.2013.12029.x).
Teeling, Jessica L., Carare, Roxana O., Glennie, Martin J. and Perry, V. Hugh. (2012) Intracerebral immune complex formation induces inflammation in the brain that depends on Fc receptor interaction. Acta Neuropathologica, 124, (4), 479-490. (doi:10.1007/s00401-012-0995-3). PMID: 22618994
Coleman, Peter G., Carare, Roxana O., Petrov, Ignat, Forbes, Elizabeth, Saigal, Anita, Spreadbury, John H., Yap, Andrea and Kendrick, Tony. (2011) Spiritual belief, social support, physical functioning and depression among older people in Bulgaria and Romania. Aging & Mental Health, 15, (3), 327-333. (doi:10.1080/13607863.2010.519320). PMID: 21491217
2010 – 2000:
Carare, Roxana-Octavia, Preston , S.D., Subash, M. and Weller, R.O. (2009) Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease. Alzheimer’s Research & Therapy, 1, (2) (doi:10.1186/alzrt6). PMID: 19822028
Weller, Roy O., Djuanda, Effie., Yow, Hong-Yeen and Carare, Roxana O. (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathologica, 117, (1), 1-14. (doi:10.1007/s00401-008-0457-0). PMID: 19002474
Weller, R.O., Boche, D. & Nicoll, J.A. Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol, 87-102 (2009).
Keage, H.A., et al. Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review. BMC Neuro, 3 (2009).
Campbell, S.J., Carare-Nnadi, R.O., Losey, P.H. and Anthony, D.C. (2007) Loss of atypical inflammatory response in juvenile and aged rats. Neuropathology and Applied Neurobiology, 33, (1), 108-120. (doi:10.1111/j.1365-2990.2006.00773.x). PMID 17239013
Schley, D., Carare-Nnadi, R., Please, C.P., Perry, V.H. and Weller, R.O. (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of Theoretical Biology, 238, (4), 962-974. (doi:10.1016/j.jtbi.2005.07.005). PMID: 16112683
O’Sullivan, E., Carare-Nnadi, R., Greenslade, J. and Bowyer, G. (2005) Clinical significance of variations in the nterconnections between flexor digitorum longus and flexor hallucis longus in the region of the knot of Henry. Clinical Anatomy, 18, (2), 121-125. (doi:10.1002/ca.20029). PMID: 15696523
Li, R., et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57, 310-326 (2005).
Salzman, K.L., et al. Giant tumefactive perivascular spaces. AJNR Am J Neuroradiol, 298-305 (2005).
Weller, R.O. & Nicoll, J.A. Cerebral amyloid angiopathy: both viper and maggot in the brain. Ann Neurol 58, 348-350 (2005).
Weller, R.O. Microscopic morphology and histology of the human meninges. Morphologie 89, 22-34 (2005).
Weller, R.O., Cohen, N.R. & Nicoll, J.A. Cerebrovascular disease and the pathophysiology of Alzheimer’s disease. Implications for therapy. Panminerva Med, 239-251 (2004).
Horstmann, S., et al. Genetic and expression profiles of cerebellar liponeurocytomas. Brain Pathol 14, 281-289 (2004).
Sun, D., Newman, T.A., Perry, V.H. & Weller, R.O. Cytokine-induced enhancement of autoimmune inflammation in the brain and spinal cord: implications for multiple sclerosis. Neuropathol Appl Neurobiol 30, 374-384 (2004).
Nicoll, J.A., Yamada, M., Frackowiak, J., Mazur-Kolecka, B. & Weller, R.O. Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25, 589-597; discussion 603-584 (2004).
Preece, N.E., Houseman, J., King, M.D., Weller, R.O. & Williams, S.R. Development of vigabatrin-induced lesions in the rat brain studied by magnetic resonance imaging, histology, and immunocytochemistry. Synapse 53, 36-43 (2004).
Fowler, M.I., Weller, R.O., Heckels, J.E. & Christodoulides, M. Different meningitis-causing bacteria induce distinct inflammatory responses on interaction with cells of the human meninges. Cell Microbiol 6, 555-567 (2004).
R.O. & Nicoll, J.A. Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain. Neurological research 25, 611-616 (2003).
Nicoll, J.A. & Weller, R.O. A new role for astrocytes: beta-amyloid homeostasis and degradation. Trends Mol Med 9, 281-282 (2003).
Hien, T.T., et al. Neuropathological assessment of artemether-treated severe malaria. Lancet 362, 295-296 (2003).
Roher, A.E., et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9, 112-122 (2003).
Zhang, B., et al. Molecular pathogenesis of subarachnoid haemorrhage. Int J Biochem Cell Biol 35, 1341-1360 (2003).
Preston, S.D., Steart, P.V., Wilkinson, A., Nicoll, J.A. & Weller, R.O. Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29, 106-117 (2003).
Nicoll, J.A., et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9, 448-452 (2003).
Weller, R.O., Yow, H.Y., Preston, S.D., Mazanti, I. & Nicoll, J.A. Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer’s disease. Ann N Y Acad Sci 977, 162-168 (2002).
Christodoulides, M., et al. Interaction of Neisseria meningitidis with human meningeal cells induces the secretion of a distinct group of chemotactic, proinflammatory, and growth-factor cytokines. Infect Immun 70, 4035-4044 (2002).
The evolution of A beta peptide burden in the APP23 transgenic mice: implications for A beta deposition in Alzheimer disease. Mol Med 7, 609-618 (2001).
Hilton, D.A. & Weller, R.O. Autopsy investigation of disorders of skeletal muscle and peripheral nerves. Curr Top Pathol 95, 207-238 (2001).
Weller, R.O. & Preston, S.D. The spectrum of vascular disease in dementia. From ischaemia to amyloid angiopathy. Adv Exp Med Biol 487, 111-122 (2001).
Weller, R.O. How well does the CSF inform upon pathology in the brain in Creutzfeldt-Jakob and Alzheimer’s diseases? J Pathol 194, 1-3 (2001).
Weller, R.O. XlVth International Congress of Neuropathology, 3-6 September, 2000, Birmingham, United Kingdom. Brain Pathol 11, 250-258 (2001).
Sun, D., et al. Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage. J Neuropathol Exp Neurol 59, 1031-1043 (2000).
Kuo, Y.M., et al. Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer’s disease. Mol Med 6, 430-439 (2000).
Hardy, S.J., Christodoulides, M., Weller, R.O. & Heckels, J.E. Interactions of Neisseria meningitidis with cells of the human meninges. Mol Microbiol 36, 817-829 (2000).
Weller, R.O., Massey, A., Kuo, Y.M. & Roher, A.E. Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer’s disease. Ann N Y Acad Sci 903, 110-117 (2000).