Cerebrovascular dysfunction and cardiovascular (CV) risk factors in Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA)
Our studies focus on establishing the mechanisms responsible for vascular cell death and neurovascular dysfunction in AD and CAA, and the additive or synergistic effects of cardiovascular/cerebrovascular risk factors such as hypertension, high homocysteine, and hypoperfusion, often comorbid with AD.
Our previous research assessed the effects of different variants of Amyloid beta (Aβ) on vascular and neural cell death pathways. These Aβ variants are linked to different forms of the disease, presenting with parenchymal and/or vascular deposition, and resulting preferentially in dementia and/or cerebral hemorrhage. Our work showed that different Aβ variants triggered mitochondrial apoptotic pathways with different kinetics, parallel to their aggregation propensity and to the formation of intermediate oligomeric and protofibrillar forms of the peptides, which are responsible for the apoptotic outcome. Different Aβ aggregation species such as oligomers and protofibrils also cause differential effects on the blood brain barrier (BBB), being preferentially associated with either endothelial cell death or BBB permeability .
We are currently evaluating how the presence of cardiovascular risk factors and cerebral hypo-perfusion contribute to these mechanisms, focusing on apoptosis and mitochondrial dysfunction pathways. We aim to determine if these different challenges on neurovascular cell health are synergistic or additive in nature. We are also using animal models of AD/CAA to assess the effects of CV risk factors on cognitive impairments, synaptic function, neurovascular unit integrity, inflammation, neuropathology, and biomarkers.
These pre-clinical studies are accompanied by clinical studies on patients spanning the normal aging to AD spectrum, with or without comorbid cardiovascular risk, aimed to establish imaging and blood biomarkers that could differentiate these patients and aid with diagnosis and prognosis. For these clinical studies, we are collaborating with multiple groups (such as Crozer Keystone Hospital, Temple Psychology department, and others).
Selected Publications:
1- Alber J, Alladi S, Bae HJ, Barton DA, Beckett LA, Bell JM, Berman SE, Biessels GJ, Black SE, Bos I, Bowman GL, Brai E, Brickman AM, Callahan BL, Corriveau RA, Fossati S, Gottesman RF, Gustafson DR, Hachinski V, Hayden KM, Helman AM, Hughes TM, Isaacs JD, Jefferson AL, Johnson SC, Kapasi A, Kern S, Kwon JC, Kukolja J, Lee A, Lockhart SN, Murray A, Osborn KE, Power MC, Price BR, Rhodius-Meester HFM, Rondeau JA, Rosen AC, Rosene DL, Schneider JA, Scholtzova H, Shaaban CE, Silva NCBS, Snyder HM, Swardfager W, Troen AM, van Veluw SJ, Vemuri P, Wallin A, Wellington C, Wilcock DM, Xie SX, Hainsworth AH. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. Alzheimers and Dementia (NY). 2019 Apr 9;5:107-117. DOI: 10.1016/j.trci.2019.02.001. eCollection 2019. Review. PMID: 31011621
2- Parodi-Rullán R, Sone JY, Fossati S. Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer's Disease. J Alzheimers Dis. 2019 Jul 8. DOI: 10.3233/JAD-190357. [Epub ahead of print] PMID: 31306129
3-Carare RO, Aldea R, Agarwal N, Bacskai BJ, Bechman I, Boche D, Bu G, Bulters D, Clemens A, Counts SE, de Leon M, Eide PK, Fossati S, Greenberg SM, Hamel E, Hawkes CA, Koronyo-Hamaoui M, Hainsworth AH, Holtzman D, Ihara M, Jefferson A, Kalaria RN, Kipps CM, Kanninen KM, Leinonen V, McLaurin J, Miners S, Malm T, Nicoll JAR, Piazza F, Paul G, Rich SM, Saito S, Shih A, Scholtzova H, Snyder H, Snyder P, Thormodsson FR, van Veluw SJ, Weller RO, Werring DJ, Wilcock D, Wilson MR, Zlokovic BV, Verma A. Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy. Alzheimers Dement (Amst). 2020 Aug 3;12(1):e12053. DOI: 10.1002/dad2.12053. PMID: 32775596; PMCID: PMC7396859.
4- Parodi R., Ghiso J., Cabrera E., Rostagno A. and Fossati S. Alzheimer’s amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain barrier integrity, and angiogenesis. Aging Cell. 2020 Nov;19(11):e13258. https://doi.org/10.1111/acel.13258. Epub 2020 Nov 6. PMID: 33155752
5- Canepa E, Fossati S. Impact of Tau on Neurovascular Pathology in Alzheimer's Disease. Front Neurol. 2021 Jan 7;11:573324. DOI: 10.3389/fneur.2020.573324. PMID: 33488493; PMCID: PMC7817626.
6- Parodi-Rullán RM, Javadov S, Fossati S. Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer's Disease. Cells. 2021 Oct 27;10(11):2903. DOI: 10.3390/cells10112903. PMID: 34831125; PMCID: PMC8616424.
