Update on dementia: Focus on AD

Transcription

1 Update on dementia: Focus on AD Pedro Rosa-Neto MD PhD Alzheimer s disease research unit McGill University Research Centre for Studies in Aging Douglas Research Institute

2 Disclosures and Funding Consultant to: Eli Lilly, Pfizer, Abbvie Clinical Trial Site Investigator: TauRx, Janssen Clinical Trial Site co-investigator: Eli Lilly, Biogen Funding and collaborations

3 MCSA

4 Outline 1. What is dementia? 2. What causes dementia? 3. Advances in the diagnostic criteria of Alzheimer s disease 4. What is typical and atypical dementia 5. What to do with atypical cases? 6. What is on the horizon to treat or prevent Alzheimer s disease? 1. Disease modifying interventions 2. Exercises 3. Anti-hypertensive 4. Anti-amyloid therapies 5. New directions

5 What is dementia? Dementia cognitive or behavioral symptoms that: 1. Represent a decline from previous levels of functioning 2. Cognitive impairment is detected at least in two different cognitive domains 3. Interfere with the ability to function at work or at usual activities 4. Are not explained by delirium or major psychiatric disorder

6 Protein Misfolding and aggregation Causes of dementia Native state Biological process Misfolded / Aggregated No biological function X Vascular Factors 2% body weight 15% cardiac output 20% total body oxygen consumption 25% of total glucose consumption High production of biological waste

7 Dementia pathology Protein abnormalities (misfolded and aggregated) Alzheimer s disease (Amyloid and tau) Frontotemporal dementia (tau, TDP43) Lewy body dementia (synuclein) Argyrophilic grain disease (tau) Corticobasal degeneration (tau) Progressive supranuclear palsy (tau) Chronic traumatic encephalopathy (tau) Vascular dementia Infarcts Small vessel disease

8 Alzheimer s Disease Auguste Detter, fem 51 Admitted November 26, Cognition Memory Problems Language Deficits Loss of autonomy Neuropsychiatric symptoms Persecutory Delusions Apathy After 5 years of evolution Died as a consequence of septicemia PS1 mutation: Chr C526T->C Alois Alzheimer s laboratory (neuroscience) 1906 description (thought to be a rare disease) Brain atrophy Extracellular deposition of Amyloid plaques miliary foci Intraneuronal inclusions of Neurofibrilary tangles 1984 George Glenner peptide AB Brion, Iqbal,Lee tau Hyperphosphorylation

9 Disease starts before the symptom s onset (Heiko Braak, 1991) Amyloid pathology (Braak) 1991 Neurofibrillary (Braak) Neurodegeneration Stage I-II Stage III-IV Stage V-VI

10 The continuum of Alzheimer s disease Preclinical Normal Aging Cognition 2011 Reisa A. Sperling Alzheimers Dement May;7(3): Prodromal AD } Mild cognitive Impairment Dementia 2007 Bruno Dubois Lancet Neurol. Aug;6(8): Ronald C. Petersen Arch. Neurol. 56, Years NIA-AA Preclinical Workgroup Sperling R et al Guy McKhann, M.D

11 Advances of the 2011 operational criteria Larger Clinical Spectrum Preclinical Alzheimer s disease Mild Cognitive impairment Dementia Genetic cases Atypical presentations of AD Biomarkers MCI: Alzheimers Dement May;7(3):270-9; AD: Alzheimers Dement May;7(3):263-9.; Preclinical: Alzheimers Dement May;7(3):280-92

12 Biomarkers: a window to AD pathology Def. Biological marker (biomarker): A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Clin Pharmacol Ther 69 (3) Biomarkers amyloid load neuro degeneration Fluid plasma CSF Decline Aß1-42 Decline Aß1-42 n/a Increased total-tau and p- tau181 Absolute quantification; high variability and invasive. Imagin g MRI n/a MRI and fmri PET [ 11 C]PIB [ 18 F]Florbetapir [ 18 F]florbetapen [ 18 F]flutemetamol [ 18 F]FDG [ 18 F]T807 Lack of sensitivity to detect MCI; specificity issues Quantification issues due to slow kinetics (binary reading) and white matter binding

13 MRI scans in AD Rated area

14 Signatures of AD High Amyloid load is specific for AD [ 11 C]PIB signature (amyloid load) Hypometabolism lacks specificity [ 18 F]FDG signature (neurodegeneration) NCI MCI AD SUVR Frontal cortex Inferior parietal cortex Posterior cingulate cortex Frontal cortex Inferior parietal cortex Posterior cingulate cortex Neurology Rounds 2015

15 Equivalence between PET scans and pathology Clark, Jet al. AMA. 2011;305(3): CANM 2013

16 Proposed pathophysiological mechanism underlying AD Abnormal Amyloid- accumulation (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI) Neocortical Tau-mediated neuronal injury Brain structure (volumetric MRI) Cognition Clinical function Normal Preclinical MCI Dementia Clinical Disease Stage Figure adapted from Jack et al. 2010, Sperling et al. 2011

17 Who needs biomarkers? Younger than 65 y.o Atypical presentations: Behavioral Language Visuospatial Dysexecutive Motor Symptoms Appropriate use of criteria or guidelines

18 Appropriate of use criteria or guidelines Detect the presence of Alzheimer s disease pathophysiology Consider intervention with cholinesterase inhibitors Alzheimer s & Dementia 9 (2013) e1 e16 ; Imaging: Canadian Journal of Neurological Sciences Volume 43, Issue 4 July 2016]; Alzheimers Res Ther Jul 8;5(Suppl 1): Alzheimers Res Ther Nov 25;5(Suppl 1):S8

19 MRI and PET [ 18 F]AZD4694 SUVR in a patient with difficulties to speak Female 53 y.o max min

20 MRI and PET [ 18 F]AZD4694 SUVR in a patient with difficulties to speak Male 61 y.o max min

21 Interventions

22 Association of Lifetime Cognitive Engagement and Low β-amyloid Deposition Individuals with greater early- and middle-life cognitive activity had lower brain amyloid Landau et al. Arch Neurol May; 69(5):

23 Amyloid therapy Aducanumab Solanezumab

24 Amyloid Related Imaging Abnormalities (ARIA) ARIA E Vasogenic edema (VE) ARIA H Microhemorrhage and superficial siderosis

25 Outline 1. What causes dementia? 2. Advances in the diagnostic criteria of Alzheimer s disease 3. What is typical and atypical dementia 4. What to do with atypical cases? 5. What is on the horizon to treat or prevent Alzheimer s disease? 1. Disease modifying interventions 2. Physical exercises 3. Risk factors for cerebrovascular disease 4. New directions

26 Take home messages: 1. AD research diagnostic criteria incorporated advances in genetics and dementia physiopathology 2. There is a wide spectrum of atypical presentations of AD 3. Patients with atypical presentation can benefit from further investigation with biomarkers 4. Physical exercise and control of risk factors for cerebrovascular diseases seems to be the best preventive measures so far