Ging-Yuek Robin Hsiung, MD MHSc FRCPC FACP Division of Neurology, UBC Clinic for Alzheimer Disease & Related Disorders

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1 Ging-Yuek Robin Hsiung, MD MHSc FRCPC FACP Division of Neurology, UBC Clinic for Alzheimer Disease & Related Disorders

2 Case Presentation 70+ year old man: 2 year of progressive memory decline, diagnosed with mild Alzheimer Disease Past history of diabetes and hypertension Initially improved with a ChEI and SSRI After a bladder procedure, developed confusion in the hospital, paranoia, fluctuating delusions, slow movements, falls 4 months in hospital with rehabilitation and psychiatry management

3 Case Presentation con t Developed tremor and stiffness on psychotropic medications Remained slow and stiff even after medications titrated off Developed very brisk reflexes and stiffness afterwards Clinical course declined rapidly in a care facility

4 CT / MRI Scans Volume Loss and some white spots (non-specific) Seen by multiple specialists Geriatrics most likely Alzheimer Neurology may have Vascular Disease and Lewy Body Disease Component as well? Psychiatry why the stiffness? ALS Electrodiagnostics normal, no ALS

5 Pathology study Read by Dr. Ian Mackenzie

6 Interpretation Evidence for multiple neurodegenerative processes as well as cerebrovascular disease: Degree of amyloid plaques and neurofibrillary pathology is sufficient to cause dementia Lewy Bodies in brainstem and cortex likely also contributed to cognitive and motor dysfunction Degree of TDP-43 pathology in motor neurons is mild and may represent early stage of disease The number of small chronic infarcts may have also contributed to the patient s neurological presentation

7 DEMENTIA Clinical state characterized by a loss of function in multiple cognitive domains in an alert attentive person Alzheimer Strokes Syphilis CJD HIV Chronic Traumatic Encephalopathy Others Frontotemporal Dementia Lewy Body Disease & Parkinson s with Dementia Huntington

8 Alzheimer Disease Most common Usually presents with short term memory loss followed by planning / decision making (other presentations: Frontal behavioural, Logopenic Aphasia, Posterior Cortical Atrophy.)

9 ALZHEIMER S DISEASE Normal

10 ALZHEIMER S DISEASE: PLAQUES (BETA AMYLOID) L AND TANGLES (TAU) K

11 Lewy Body Disease May have movement disorders like Parkinson s Commonly associated with visual spatial problems and sleep disorders May be associated with visual hallucinations Very sensitive to some psychotropic medications Symptoms may fluctuate

12 PATHOLOGY OF PARKINSON S DISEASE Lewy body (contains a-synuclein) in a pigmented neuron in substantia nigra (H&E stain)

13 Frontotemporal Dementia If predominantly frontal can lead to behavioural problems Left sided frontal can lead to language production difficulties Superior temporal can lead to semantic loss and language comprehension problems May be associated with motor neuron disease (ALS) Progressive Supranuclear Palsy Corticobasal Degeneration

14 Frontotemporal Dementia Tau / Pick bodies TDP-43 FUS From Mackenzie 2010

15 Protein immunostaining Diseases Tau 3 repeats Pick s disease 4 repeats PSP, CBD, FTDP17 3 & 4 repeats Alzheimer s, Down s, Niemann-Pick C, GSS, ALS/PDC of Guam, postencephalitic Parkinsonism, AGD Ubiquitin TDP-43 Type 1 GRN mutation Type 2 Semantic Dementia Type 3 FTD-ALS (C9ORF72 muation) Type 4 IBMPFD (VCP mutation) TDP-43 ALS without FTD FUS ALS without FTD Atypical FTLD-U NIFID (Neuronal Intermediate Filament Inclusion Disease) BIBD (Basophililc Inclusion Body Disease) FTLD-UPS CHMP2B mutation (unknown) Remaining U+, TDP-, FUS- Dementia Lacking Distinct Histopathology Tau-, U- (TDP-, FUS-)

16 Cerebrovascular Disease Multiple Large Ischemic Strokes (lack of blood to the brain in a large territory) Hemorrhagic Stroke (blood vessel damage and bleeding) Lacunar Stroke (small vessel ischemia) Confluent white matter disease

17 Vascular Dementia Stepwise progression for the overt strokes May have slow decline with covert strokes? Symptoms depend on location in brain (memory, planning / judgment, slowing) Will likely responsive to vascular risk factors reduction (blood pressure, blood sugar, cholesterol, weight control, exercise, blood thinners for ischemic type strokes)

18 How frequent is multiple pathology? From the ACCORD Study Dementia with Mixed Causes are clinically suspected in 38.2% of the patients MIXED Feldman et al, 2003

19 How correct is our clinical impression? Follow up autopsy study from ACCORD: 45 Autopsy Cases 24/45 have single pathology (53%) 21/45 have multiple pathology (47%) Overall clinical impression is correct in only 19/45 (42%) Correct in Single pathology 17/24 (71%) Correct in Multiple pathology 2/21 (9.5%) Woodward et al, 2010

20 AUTOPSY STUDY IN ALZHEIMER CLINICAL TRIAL PATIENTS AT UBC 47 AD trial participants Inclusion Criteria Age 50 NINCDS criteria for probable AD No existing comorbidities Psychiatric illness Unstable systemic disease No other suspected cause of cognitive decline 1 Non-AD pathology (AGD) 16 patients had autopsy 15 AD pathology 7 AD/VaD Wang et al, pure AD 2 AD/VaD/DLB 1 AD/Other

21 RESULTS Mixed AD pathology found in majority of AD clinical trial participants (63%), although most (94%) do have AD Even more common in studies of older population (Barker 2002, Jellinger 2008, Schneider 2007, White 2009) 3MS and MMSE performance could not distinguish mixed pathology Mixed pathology is associated with poorer non-cognitive function (FRS) in early disease

22 DEMENTIA Vascular DLB FTD Alzheimer

23 IMPLICATIONS: WHY DO WE WANT TO KNOW? Dementia with mixed pathology is very common, but extremely hard to recognize clinically May affect clinical studies results (targeted disease modifying therapy may not work in various pathologies) Existing diagnostic modalities are inadequate (some emerging ones are promising, but not confirmed) Improvements in biomarkers and imaging are needed Autopsy study is not just about donating the brain it is the only way to confirm what type of abnormality in the brain lead to the observed changes in the patient during life

24 OUR RESEARCH TEAM AT UBCH CARD UBC Hospital Clinic for Alzheimer and Related Disorders (Drs. Phil Lee, Dean Foti, Lynn Beattie, Howard Feldman, Margo Genge) Neuropathologist (Dr. Ian Mackenzie) Neuropsychology (Drs. Claudia Jacova, Sheeri Hayden, Brad Hallam) Social work (Amy Freeman) Research coordinators / technicians Alice Fok, Phoenix Bouchard-Kerr, Penny Slack, Bonnie Leung, Benita Mudge, Michele Assaly, Emily Corenblith