UNIVERSITY OF WESTERN ONTARIO
Vladimir Hachinski, CM, MD, FRCPC, DSc Department of Clinical Neurological Sciences University of Western Ontario London, Ontario, Canada Vladimir.hachinski@lhsc.on.ca
ALZHEIMER DISEASE: BETWEEN THE INEVITABLE AND THE MODIFIABLE I CHANGES WITH AGE III INTERACTIVE PATHOLOGIES III WHAT CAN BE DONE?
CHANGES IN COGNITION WITH AGING Diminished Memory Processing speed Executive Function Preserved Language bilingualism Social graces Enhanced Judgement
Different stages of tau deposition in Alzheimer's disease. Earliest area of tau deposition is usually found in the enthorinal cortex and hippocampal formation. Cognitive impairment becomes apparent when tau deposition involves cortical polymodal association areas (Braak Stages IV VI).
PRIMITIVE BRAINS
FRONTAL-SUBCORTICAL NEURONTAL CIRCUITS INVOLVED IN EXECUTIVE FUNCTIONS Orbitofrontal Circuit Dorsolateral Prefrontal Circuit Anterior Cingulate Circuit Diagram created by Sposato & Hachinski, broadly based on Tekin S, Cummings JL J Psychosom Res 2002;53:647-654.
HIGH DENSITY OF EXECUTIVE FUNCTION CIRCUITS IN BRAIN REGIONS PRONE TO HYPERTENSION- MEDIATED INJURY Diagram created by Sposato & Hachinski, broadly based on Tekin S, Cummings JL J Psychosom Res 2002;53:647-654. Sörös P Hachinski V. Nat Rev Neurol 2013;9:174-178
ALZHEIMER DISEASE: BETWEEN THE INEVITABLE AND THE MODIFIABLE I CHANGES WITH AGE III INTERACTIVE PATHOLOGIES III WHAT CAN BE DONE?
Contribution of Cerebrovascular Disease in Autopsy Confirmed Neurodegenerative Disease Cases National Alzheimer s Coordinating Centre Database 6205 autopsy cases Prevalence of Vascular Pathology (%) Vascular findings reaching or not a threshold sufficient enough to contribute to clinical status Toledo JB, Arnold SE, et al. Brain 2013;135:2697-2706
Main Proposed Risk & Protective Factors Common for Stroke & Dementia Non-modifiable Modifiable Risk Factors Risk Factors Protective Factors Advanced age Cerebrovascular disease/stroke High education Genetic factors (Apo E4) Cardiovascular diseases Physical activity Family history Hypertension Antihypertensives Hypercholesterolemia Obesity Diabetes Smoking Homocysteine Stress Depression Atrial fibrillation (added) Statins Active lifestyle Mediterranean diet (added) Anticoagulation (added) Modified from Solomon A..Kivipelto M. et al. JIM 2014
INTERACTIONS BETWEEN VASCULAR RISK FACTORS AND ALZHEIMER PATHOLOGY BP increases amyloid deposition especially in APO-E4 carriers (Rodrigue et al. JAMA Neurol. 2013;70:600-606) Pulse pressure is associated with β-amyloid and tau CSF markers (Nation et al Neurol. 2013;81:2024-2027) Arterial stiffness is associated with increased β-amyloid deposition (Hughes et al. JAMA Neurol. 2014) Homocysteine levels are associated with tau deposition at autopsy (Hooshmand et al. Brain 2013;135:2707-2716)
Figure Legend: Mean β-amyloid deposition by genetic risk and hypertensive subgroup. Individuals with uncontrolled hypertension and at least 1 apolipoprotein E (APOE) ϵ4 allele show greater β-amyloid deposition. SUVR indicates standardized uptake value ratio. *Significant interaction (P =.02) between vascular risk group and genetic status, with unmedicated ϵ4 + participants with hypertension showing the greatest amounts of β-amyloid deposition. Rodrigue KM. et al. JAMA Neurol. 2013;():1-7. doi:10.1001/jamaneurol.2013.1342 Date of download: 4/2/2013 Copyright 2012 American Medical Association. All rights reserved.
PLASMA HOMOCYSTEINE AND NEUROFIBRILLARY TANGLE COUNT 601 individuals aged 85 years followed for 10 years 291 died post mortem Highest homocysteine quartile OR 2.60 (CI 95% 1.28-5.28) Hooshmand et al. Brain 2013:136;2707-2716
TRAJECTORY OF COGNITIVE DECLINE AFTER INCIDENT STROKE REGARDS Study N = 23, 572 participants 45 years Follow up 6.1 years 515 incident strokes Acute global cognition new learning verbal memory Post stroke faster global cognition executive function but not new learning or verbal memory change compared to pre stroke slopes Levine et al. JAMA 2015;314:41-51
Preliminary Data and Survivability Cognitive Deficits Pathology GFAP GFAP Control * **** Endo Endo Aβ/endo Ab Infarct Size Ab & Endo
CAN WE DO BETTER? II AT PATIENT LEVEL a) Screen for cognitive impairment b) Identify vascular component c) Treat it!
ISCHEMIC SCORE WITH 5 COMPOSITE ITEMS* Item No. Item Description Score if Answer is Yes 1 / 2 Abrupt onset or stepwise deterioration 3 / 4 Fluctuating course or nocturnal confusion 6/8 Depression or emotional incontinence 9/11 History of hypertension or atherosclerosis 10/12 History of stroke or focal neurological symptoms Total Scored electronically Scored electronically Scored electronically Scored electronically Scored electronically Scored electronically * A vascular component of cognitive impairment may be indicated after electronic computation Hachinski V. et al Arch Neurol 2012:69(2):169-175
A Canadian Multi-Center, Randomized, Controlled, Open-Labeled, Blinded Adjudication Clinical Trial
EFFECT OF STROKE ON INCIDENT DEMENTIA Systematic Review A doubling of the risk of incident dementia in those with stroke compared with those without (5 studies) Savva et al Stroke 2010; 41:e41-e46
RESULTS OF ONTARIO STROKE SYSTEM discharges to chronic facilities 30 day mortality treatment in stroke units use of thrombolysis use of antiplatelet therapy Kapral et al, CMAJ. 2013; 185(10)E483-912
Incidence per 1.000 Population 5.5 5.0 4.5 3.5 3.0 Dementia Stroke 2.5 p-value for trend in stroke incidence < 0.001 p-value for trend in dementia incidence = 0.009 (Jonckheere-Terpstra Test) 2.0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Fiscal Year
Stroke and Potentially Preventable Dementias Proclamation Updated World Stroke Day Proclamation Vladimir Hachinski, MD, DSc; on behalf of the World Stroke Organization Stroke 2015;46 and International Journal of Stroke 2015;