Amyloid and the Vessels. David Weisman, M.D.

Transcription

1 Amyloid and the Vessels David Weisman, M.D.

2 CMA I conduct Alzheimer/amyloid clinical research in conjunction with: Toyoma, ADRC, Genentech, Eisai, Envivo, Accera, Elan, Merck. Previously served on speaker s bureau for Pfizer. Data is from drug studies in AD over the last decade, part of the public domain.

3 Cerebral Amyloid Angiopathy: Deposition of amyloid in small and mid-sized vessel walls of the cerebral cortex and meninges. Amyloid is a vestigial word, starch, after Virchow misidentified the collections as a starch, based on common iodine staining. Amyloid: fibular protein aggregates from abnormally folded proteins or oligimers.

4 ARIA: Amyloid Related Imaging Abnormalities Usually hemorrhages (ARIA- H): Microhemorrhages (MH s), also superficial siderosis. Seen with gradient recalled echo (GRE and SWI) images. ARIA-H: associated with CAA Drug trials: started noting Edema (ARIA-E), vasogenic edema.

5 Typical presentation of ARIA, due to Cerebral Amyloid Angiopathy: CAA A: Acute CT. B: CTA C: White matter changes on FLAIR MRI. D: Microhemes: multiple susceptibilities on gradient echo MRI sequence, probable CAA. JakubovicR, Aviv, RI. Intracerebral hemorrhage. Front. Neurol 2012

6 Microhemorrhages: Non-specific CAA weakens vessel walls, makes them brittle, microleaks of blood Small-vessel angiopathies due to age (5-15% among normal >65 yo s) Accelerated by vascular risk factors, especially hypertension. Described following cardiac bypass surgery, attributed to microemboli

7 See MH, is it Amyloid? Cortical MH or siderosis: CAA. Deep or brainstem MH: other angiopathy. If CAA, is it AD? Look to the company it keeps But how do I order a history? Alzheimer s disease at all stages: pre-clinical, prodromal/mci, and AD.

8 Overlap. There is nearly universal overlap of CAA pathology with Alzheimer's pathology. But not vice versa, cases of pure AD. Pure CAA found in familial case reports. With loss of smooth muscle cells, an inflammatory reaction, and tortuous small vessels. AD CAA

9 Where the amyloid comes from APP is found in many tissues, but higher concentrations near synapses. Adapted from J.Hardy and D.J. Selkoe Science Jul 19;297(5580):353-6.

10 Subject Patient with mild memory loss which is annoying, but does not produce any dysfunction in appointments, finances, going places or ability to live independently. Mild progression over 1-2 years.

11 MRI has both MH and superficial hemosiderosis

12 Amyloid PET scans If the tracer binds to beta-amyloid, then the brain becomes radioactive. If not, not. Does not distinguish between vascular and cerebral amyloid. (Morris et al. PIB scans. Arch Neurol 2009) Very controversial for routine clinical use (no change in management without a disease modifying agent). Trials: enrich MCI for those + for amyloid (who will progress).

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14 Patient s scan is positive.

15 Co-morbid pathology with AD CAA is commonly found in AD at autopsy, prevalence at about 80%. Both AD and CAA hallmarks of AD pathology. Amyloid stain in black, stains both vessels and Plaques. Wiki. Copyright 2011 Nephron

16 Treatment trials and ARIA

17 Passive Immunization Give monoclonal antibodies against amyloid. Incite an immune reaction: activates microglial phagocytosis and cytokine production. Results in clearance of amyloid and, hopefully, protection of brain tissue function. Two monoclonal antibodies recently failed to achieve meaningful outcomes. But

18 We know Ab s have effect on amyloid : Bapineuzumab Phase 3 trials in mild to moderate Alzheimer s disease, Safety and PiB PET Amyloid Imaging

19 In many cases we have ONE proteinopathy, TWO overlapping diseases When targeting amyloid for removal from the brain, we unmask CAA and get Amyloid Related Imaging Abnormalities ARIA-H ARIA-E, vasogenic edema.

20 Baseline MRI pre-dose

21 Post-dose

22 1 month: ARIA-E better, not ARIA-H

23 N=1, follow up. Clinically unchanged throughout. Testing showed no significant decline. Withdrew from treatment arm, followed with cognitive metrics.

24 ARIA-E after bapineuzumab is generally without consequence Affects 10% of subjects % ARIA-E had symptoms: headache, confusional state, hemiparesis, agitation, fatigue, and gait disturbance. Bapineuzumab Phase 3 trials in mild to moderate Alzheimer s disease, Safety and PiB PET Amyloid Imaging

25 Clinically significant hemorrhage: not seen Bapineuzumab: of those who had ARIA-E (10%), half also developed ARIA-H, all MH s. Correlated with time and space. Seems ARIA-E and ARIA-H are related to same increases in vascular permeability Solanezumab slightly decreased ARIA-H (4.9% vs 5.6%) Because exclusion criteria: two or more microhemorrhages or a single prior hemorrhage larger than 1 cm 3?

26 Is there an ARIA benefit? CAA might open the door to monoclonal antibodies, opens both ways. Clearing amyloid from vessels seems to increase vascular permeability, allowing better antibody penetration, better amyloid clearance from brain.

27 ARIA benefit? PiB retention was reduced in ARIA-E regions followed by ARIA-H. ARIA in bapineuzumab: A retrospective analysis Sperling, Salloway.

28 Questions