Small Vessel Cerebrovascular Pathology is a Major Feature in the Pathogenesis of Alzheimer’s Disease or Age-Related Dementia
Main Article Content
Abstract
Historically, cerebrovascular abnormalities were recognized as prominent in the pathology of age-related dementia. In more recent decades, however, research and funding for development of therapeutics has almost entirely been focused on β-amyloid and tau deposits (as described by Alzheimer in pre-senile dementia), despite a lack of conclusive evidence of a causal relationship or efficacy of targeted treatment on cognitive decline or dementia. Here we present a brief history of the evidence for a dominant vascular component of Alzheimer’s Disease and highlight a potential target for slowing the functional progression of the disease.
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How to Cite
SCOTT, Tammy M; ROSENBERG, Irwin H..
Small Vessel Cerebrovascular Pathology is a Major Feature in the Pathogenesis of Alzheimer’s Disease or Age-Related Dementia.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3139>. Date accessed: 24 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3139.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Jack Jr CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimer's & Dementia. 2018;14(4):535-562.
2. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. Mar 12 1997;277(10):813-7.
3. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(9):2697-2706.
4. Sweeney MD, Montagne A, Sagare AP, et al. Vascular dysfunction—the disregarded partner of Alzheimer's disease. Alzheimer's & Dementia. 2019;15(1):158-167.
5. Klohs J. An integrated view on vascular dysfunction in Alzheimer’s disease. Neurodegenerative Diseases. 2019;19(3-4):109-127.
6. Govindpani K, McNamara LG, Smith NR, et al. Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it? Journal of clinical medicine. 2019;8(5):651.
7. De la Torre J. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002;33(4):1152-1162.
8. Pasquier F, Leys D, Scheltens P. The influence of coincidental vascular pathology on symptomatology and course of Alzheimer’s disease. Alzheimer’s disease—From basic research to clinical applications. 1998:117-127.
9. Breteler MM. Vascular risk factors for Alzheimer’s disease:: An epidemiologic perspective. Neurobiology of aging. 2000;21(2):153-160.
10. Breteler MM. Vascular involvement in cognitive decline and dementia: epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Annals of the New York Academy of Sciences. 2000;903(1):457-465.
11. Ott A, Breteler MM, De Bruyne MC, Van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study: the Rotterdam Study. Stroke. 1997;28(2):316-321.
12. Ott A, Stolk R, Hofman A, van Harskamp F, Grobbee D, Breteler M. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia. 1996;39(11):1392-1397.
13. Scott TM, Bhadelia RA, Qiu WQ, Folstein MF, Rosenberg IH. Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention. J Alzheimers Dis. 2018;65(1):293-302. doi:10.3233/JAD-180366
14. Kraepelin E. Das arteriosklerotische Irresein. Psychiatrie Ein Lehrbuch für Studierende und Ärzte. 1910;2:554-593.
15. Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Gehirnkrankheiten. European Neurology. 1898;3(1):101-115.
16. Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Zentralbl Nervenh Psych. 1907 1907;18:177-179.
17. Knopman DS, Petersen RC, Jack CR. A brief history of “Alzheimer disease”: Multiple meanings separated by a common name. Neurology. 2019;92(22):1053-1059.
18. Esiri MM, Joachim C, Sloan C, et al. Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer disease: a clinicopathologic study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). Alzheimer Dis Assoc Disord. Jan-Mar 2014;28(1):30-5. doi:10.1097/WAD.0b013e31829b72f1
19. Vermeer SE, Van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2002;51(3):285-289.
20. van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke. 2008;39(10):2712-2719.
21. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. New England Journal of Medicine. 2003;348(13):1215-1222.
22. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. Sep 2011;42(9):2672-713. doi:10.1161/STR.0b013e3182299496
23. de Leeuw F-E, Kalaria R, Scheltens P. Treatment of vascular risk factors to delay Alzheimer’s disease? In: Gauthier S, Scheltens P, Cummings J, eds. Alzheimer's Disease and Related Disorders. Informa Healthcare; 2005:153.
24. Yu JT, Xu W, Tan CC, et al. Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. Nov 2020;91(11):1201-1209. doi:10.1136/jnnp-2019-321913
25. Wang Z, Zhu W, Xing Y, Jia J, Tang Y. B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis. Nutr Rev. Aug 25 2021;doi:10.1093/nutrit/nuab057
26. Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC public health. 2014;14(1):1-33.
27. Smith A, Refsum H. Homocysteine–from disease biomarker to disease prevention. Journal of Internal Medicine. 2021;290(4):826-854.
28. Carson NA, Neill D. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Archives of disease in childhood. 1962;37(195):505.
29. McCully K. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. The American journal of pathology. 1969;56(1):111.
30. Selhub J, Jacques PF, Bostom AG, et al. Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. The Journal of nutrition. 1996;126(suppl_4):1258S-1265S.
31. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Annals of internal medicine. 1999;131(5):352-355.
32. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England journal of medicine. 2002;346(7):476-483.
33. Teng Z, Feng J, Liu R, et al. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Frontiers in Aging Neuroscience. 2022;14
34. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. Mar 1996;63(3):306-14. doi:10.1093/ajcn/63.3.306
35. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A, 3rd. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. Sep 2005;82(3):627-35. doi:10.1093/ajcn.82.3.627
36. Kado DM, Karlamangla AS, Huang M-H, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. The American journal of medicine. 2005;118(2):161-167.
37. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine‐lowering B‐vitamin treatment in mild cognitive impairment: a randomized controlled trial. International journal of geriatric psychiatry. 2012;27(6):592-600.
38. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. Jan 20 2007;369(9557):208-16. doi:10.1016/S0140-6736(07)60109-3
39. Scott TM, Rogers G, Weiner DE, et al. B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. J Prev Alzheimers Dis. 2017;4(3):174-182. doi:10.14283/jpad.2017.15
40. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer disease and associated disorders. 1999;
2. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. Mar 12 1997;277(10):813-7.
3. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(9):2697-2706.
4. Sweeney MD, Montagne A, Sagare AP, et al. Vascular dysfunction—the disregarded partner of Alzheimer's disease. Alzheimer's & Dementia. 2019;15(1):158-167.
5. Klohs J. An integrated view on vascular dysfunction in Alzheimer’s disease. Neurodegenerative Diseases. 2019;19(3-4):109-127.
6. Govindpani K, McNamara LG, Smith NR, et al. Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it? Journal of clinical medicine. 2019;8(5):651.
7. De la Torre J. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002;33(4):1152-1162.
8. Pasquier F, Leys D, Scheltens P. The influence of coincidental vascular pathology on symptomatology and course of Alzheimer’s disease. Alzheimer’s disease—From basic research to clinical applications. 1998:117-127.
9. Breteler MM. Vascular risk factors for Alzheimer’s disease:: An epidemiologic perspective. Neurobiology of aging. 2000;21(2):153-160.
10. Breteler MM. Vascular involvement in cognitive decline and dementia: epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Annals of the New York Academy of Sciences. 2000;903(1):457-465.
11. Ott A, Breteler MM, De Bruyne MC, Van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study: the Rotterdam Study. Stroke. 1997;28(2):316-321.
12. Ott A, Stolk R, Hofman A, van Harskamp F, Grobbee D, Breteler M. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia. 1996;39(11):1392-1397.
13. Scott TM, Bhadelia RA, Qiu WQ, Folstein MF, Rosenberg IH. Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention. J Alzheimers Dis. 2018;65(1):293-302. doi:10.3233/JAD-180366
14. Kraepelin E. Das arteriosklerotische Irresein. Psychiatrie Ein Lehrbuch für Studierende und Ärzte. 1910;2:554-593.
15. Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Gehirnkrankheiten. European Neurology. 1898;3(1):101-115.
16. Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Zentralbl Nervenh Psych. 1907 1907;18:177-179.
17. Knopman DS, Petersen RC, Jack CR. A brief history of “Alzheimer disease”: Multiple meanings separated by a common name. Neurology. 2019;92(22):1053-1059.
18. Esiri MM, Joachim C, Sloan C, et al. Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer disease: a clinicopathologic study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). Alzheimer Dis Assoc Disord. Jan-Mar 2014;28(1):30-5. doi:10.1097/WAD.0b013e31829b72f1
19. Vermeer SE, Van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2002;51(3):285-289.
20. van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke. 2008;39(10):2712-2719.
21. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. New England Journal of Medicine. 2003;348(13):1215-1222.
22. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. Sep 2011;42(9):2672-713. doi:10.1161/STR.0b013e3182299496
23. de Leeuw F-E, Kalaria R, Scheltens P. Treatment of vascular risk factors to delay Alzheimer’s disease? In: Gauthier S, Scheltens P, Cummings J, eds. Alzheimer's Disease and Related Disorders. Informa Healthcare; 2005:153.
24. Yu JT, Xu W, Tan CC, et al. Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. Nov 2020;91(11):1201-1209. doi:10.1136/jnnp-2019-321913
25. Wang Z, Zhu W, Xing Y, Jia J, Tang Y. B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis. Nutr Rev. Aug 25 2021;doi:10.1093/nutrit/nuab057
26. Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC public health. 2014;14(1):1-33.
27. Smith A, Refsum H. Homocysteine–from disease biomarker to disease prevention. Journal of Internal Medicine. 2021;290(4):826-854.
28. Carson NA, Neill D. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Archives of disease in childhood. 1962;37(195):505.
29. McCully K. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. The American journal of pathology. 1969;56(1):111.
30. Selhub J, Jacques PF, Bostom AG, et al. Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. The Journal of nutrition. 1996;126(suppl_4):1258S-1265S.
31. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Annals of internal medicine. 1999;131(5):352-355.
32. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England journal of medicine. 2002;346(7):476-483.
33. Teng Z, Feng J, Liu R, et al. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Frontiers in Aging Neuroscience. 2022;14
34. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. Mar 1996;63(3):306-14. doi:10.1093/ajcn/63.3.306
35. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A, 3rd. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. Sep 2005;82(3):627-35. doi:10.1093/ajcn.82.3.627
36. Kado DM, Karlamangla AS, Huang M-H, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. The American journal of medicine. 2005;118(2):161-167.
37. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine‐lowering B‐vitamin treatment in mild cognitive impairment: a randomized controlled trial. International journal of geriatric psychiatry. 2012;27(6):592-600.
38. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. Jan 20 2007;369(9557):208-16. doi:10.1016/S0140-6736(07)60109-3
39. Scott TM, Rogers G, Weiner DE, et al. B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. J Prev Alzheimers Dis. 2017;4(3):174-182. doi:10.14283/jpad.2017.15
40. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer disease and associated disorders. 1999;