Geriatric Grand Rounds

Transcription

1 Geriatric Grand Rounds Tuesday, May 20, :00 noon Dr. Bill Black Auditorium Glenrose Rehabilitation Hospital In keeping with Glenrose Rehabilitation Hospital policy, speakers participating in this event have been asked to disclose to the audience any involvement with industry or other organizations that may potentially influence the presentation of the educational material. Disclosure will be done both verbally and using a slide or handout. Visit web sites: for handouts, poster, schedule, subscription: for on-demand archive of previous presentations: Gleanings from the 2007 CCCD & 2008 CGS Meeting: A Brief Review Peter N McCracken Professor Emeritus of Medicine University of Alberta Disclosure I have participated in Advisory Boards for Hoescht, Pfizer, Jansen-Ortho, Novartis, Bayer, Lundbeck, and Wyeth I have provided teaching activities for Pfizer, Janssen-Ortho, Novartis, Lundbeck I have conducted research trials as P.I. for Pfizer, Janssen-Otho, Sanofi-Aventis, & Lundbeck Objectives To select topics from the last two national meetings for the purpose of keeping ourselves informed about key issues To maintain awareness of work in other academic centres To learn about the hard-drive approach to treating Alzheimer s Disease Creativity in Dementia Bruce L Miller, MD Art begins with a mental image, be it realistic or improbable, past or present. During creative process artist manipulates materials to actualize this mental image Art communicates Art is original Art and Brain Art is uniquely human Absent in neanderthals & non-human primates Sudden appearance 40,000 years ago Complex art in paleolithic caves 20,000 years ago 1

2 The Joy of Clinical Medicine! Art and Brain Right brain (posterior brain) dominant copying internal imagery transmodal association Left brain (anterior brain) symbolic/ linguistic conceptual aspects of art Anterior ---- inhibition/ planning/ motor Posterior brain ---- perception Art & Dementia Visuospatial deficits in AD lead to less precision & attention to spatial relationships. In some cases of FTD, artistic creativity appears de novo as the disease progresses This artware is approached in a compulsive manner, & is often realistic or surrealistic in style Provides a unique window into cognitive processes of various brain regions & an OPPORTUNITY FOR REHAB? Previous work In FTD FTD patients can develop new artistic skills after disease onset Visual creativity more common when anterior temporal lobes show degeneration Of 12 patients showing emergence of musical or visual ability, 9 had Semantic Dementia Semantic Dementia Along with primary progressive aphasia, SD is a subtype of fronto-temporal lobar degeneration, within focal atrophy of the L frontal & temporal lobes Many FTLD pts subsequently become visual artists, even though they did not paint before Are these a loss in the inhibitory activity to the posterior temporal & parietal lobes involved in visuospatial & Visuoconstructive processes? Observations FTD pts not much different from normal controls on visual tracking SD pts avoid the canonical features of scenes, such as the vanishing point and faces SD pts spend less time on any given point FTD & SD pts show less focus on the eyes 2

3 Art Reflects emotional, perceptual, conceptual motor systems of the artist Art offers insights into wopkings of the brain Art is healing Art is possible, even enhanced, with neurological disease Art in dementia is a model for recognizing strength--- not just weakness in Neurology Art in FTD Commonly heralds dementia Work is literal, non-symbolic, often realistic & compulsively performed Artists draw what they see internally & their world is different As the right amygdala degenerates, the human face disintegrates (emotion in faces distorted early) Jancy Chang Premorbidly good artist Work becomes wilder, disinhibited, freer with progressive aphasia Most exciting and original pieces performed when nearly mute Anne Adams Most complex transmodal work (sound, music, vision, feeling) produced in early stage of progressive non-fluent aphasia Imaging in1996 showed left inferior frontal atrophy & expansion of right posterior parietal cortex Adams compelled by Ravel 6 yrs before manifesting PNFA while Ravel writes Bolero 6 yrs before manifesting PNFA Both die from CBDd Why Art in FTD? Disinhibition releases better art? Jancy Chang Linguistic left hemisphere processing blocks visual creativity? Slow re-wiring of cortex. Posterior right parietal cortex becomes larger (Anne Adams) Paradoxical Function Facilitation? SD Understanding & Treating Delirium in Dementia Kenneth Rockwood, Dalhousie University 3

4 Opening the Fray Criteria for delirium, dementia and delirium vs dementia are best seen as heuristic devices Heurism: n (fr GR, irreg) the educational principle of training pupils to discover for themselves; in logic, discovery by iterative testing & refinement. O.E.D. NOT a hammer-lock on the truth More research is needed Delirium has features of complex systems failure What is Known: Delirium Criteria A Disturbance of consciousness (reduced clarity of awareness of the environment B Change in cognition (such as deficit in memory or language or orientation not better accounted for by evolving dementia C Develops over a short period & tends to fluctuate during the course of the day D DSM 1V distinguishes between general medical conditions & other etiologies Delirium & Dementia: Systematic Reviews This paper highlights the dearth of research on delirium superimposed on dementia. Fick at al, JAGS 2002;50: No studies focused on patients with prior cognitive impairment, so management of delirium in this group could not be assessed There is very little info on the management of delirium with dementia in the literature Cochrane Review 2007 Does delirium look different when it complicates Dementia? Delirium/ dementia had lower MMSE scores but NO differences found in DRS, DPRS scores or in EEG grade Trzepacz P et al Neuropsch Clin Neurosci 1998; 10(2): the severity of prior cognitive impairment influences the severity of most symptoms Voyer P et al J Neurosci Nurs 2006;38: 90 Dissenting Views Validation of syndromes as prognostic tools is a logical way out of the nosological swamp into which delirium/dementia research is sinking & Cognitive improvement should be the key distinction Macdonald A Dement Geriatr Cogn Disord 1999; 10: Under-recognition of delirium is a daily pragmatic reminder that what we are now teaching is not working Bhat R, Rockwood K, Delirium as a disorder of consciousness J Neur Neurosurg Psychiatry (!1): The Criterion of Sudden Onset In CSHA of 1132 with dementia 130 (11.5%) met criteria for delirium King et al Int Psychogeriatr 2005;17: In the CIVIC study, of people with cognitive impairment, 90 (8.5%) met criteria for acute onset King et al Am J Giatr Psychiatr 2006;14:

5 Poor Mobility (HABAM) scale: The hierarchy of balance & mobility Cannot move side to side Cannot sit up Cannot sit up The best method to determine improvement is to focus on progressive improvement in function & self mobility Amyloid Cascade Hypothesis Mis-metabolism of APP Neuropilic Tangles Non-fibrillar Amyloid deposits Conversion to fibrillar amyloid Glial cell activation Cytokines il-1 & il-6 Complement reactive O 2 species Pro-inflammatory mediators & Neurotoxic substances Diagnosing AD before Dementia Dr Stephen Salloway Brown University 5

6 Normal Aging Psychomotor Slowing taking longer to do things 75 y.o. marathon runner takes twice the time to complete the race as he did at 25 recalling names or trouble finding specific words what did I come here for? Normal Aging Troublesome signs being repetitive & not just for emphasis not coming up with words or names later not recalling that conversations or events ever took place not realizing that there is a memory problem When is the Optimal Clinical Stage for Disease Modification? Early in the Course when neuronal injury is low & there is limited functional Impairment If treatments are expensive and present significant risks, there needs to be a high level of diagnostic certainty and likelihood of disease progression during the study period Approaches Levels of certainty start with areas of agreement & high certainty Increase sensitivity & specificity of diagnostic approaches, with autopsy validation Utilize multi-modal techniques Recruit an enriched research cohort Imaging: follow hippocampal volumes & serial PET scans Further questions? Is the clinical phenotype of AD present? Evidence on neuropsych testing? Is there evidence for progression of symptoms? Is the clinical history supported by family history of dementia or by biomarkers? imaging-mri, PET? CSF markers; APO-E4? AD mutations Concerns About Early Diagnosis Do no harm Misdiagnosis either way Uncertainty re time to progression/ conversion Portability to non-experts & primary care Lack of an effective therapeutic intervention to delay progression 6

7 Disease-Modifying Drugs for AD Dr Sandra Black, University of Toronto Key Difficulties re the Holy Grail Proving to regulatory authorities that this disease progress is truly arrested is VERY difficult AchEI studies were about 6 months in duration; these studies would have to be much longer What about outcome measurements, how different? Bear in Mind that.. Some believe it COULD require months, depending on effect size, trial design, & the number of study subjects Several years could be required to demonstrate POC, & to establish optimal dosage Delay in milestone strategies would include halt in progression from MCI to AD The New Approach A new high profile candidate is Bapineuzamab a humanized monoclonal antibody that targets a- beta & is genetically engineered to act as an antigen recognition site It IS known what they are raised against & more likely to be safe & dosages can be titrated carefully BUT, they are expensive to produce & need to be topped up quite frequently Brain micro-hemorrhages? Meningo-encephalitis? Phase 2 & 3 studies underway Bapineuzumab A phase 3 double-blind, placebo-controlled study to evaluate the safety & efficacy of bapineuzumab in subjects with mild to moderate AD (MMSE 16-26) Trial will last 1.5 years; over 150 sites in 20 different countries outside of USA Outcome measures: ADAS-COG, DAD, Neurological test battery, CDR Stable doses of AchEI & memantine allowed Tramiprosate (Alzhemed) Binds to SOLUBLE A-beta & interferes with the conversion to fibillar amyloid. This step halts the amyloid cascade associated with amyloid plaque deposition and its very toxic effect on the brain neurons. Some subjects were taking AchEI s, others memantine, others antidepressants, & others vitamin E. The data addressed in the study are much more complex than that anticipated 7

8 Tramiprosate (Alzhemed) A Canadian glycosaminoglycans mimetic that binds to a-beta peptides, preventing them from forming a-beta aggregates Completed study: all pts had been on licensed therapy for 4 mon: then placebo vs. 100 mg BID vs 150 mg BID Results did NOT meet target: the analysis plan had a poor fit with the collected data & a large degree of variance among sites Tramiprosate (Alzhemed) A panel of experts has been convened to review, re-analyze, & probe deeper into the data, & then will recommend to Neurochem what future steps are necessary for Alzhemed Bruno Vellas (University of Toulouse If we have a drug that is very active, then of course we will see an effect; if it is moderately active, it will be very difficult to assess objectively the true effectiveness of the compound. Bis(7) Tacrine Girl walk An anti-alzheimer dimer The main action is to inhibit BACE, or beta-secretase It is also believed to increase alphasecretase activity (the normal pathway of APP metabolism Modulation of these secretase activities might be a promising disease-modifying threrapeutic approach for AD Tarenflurbil (Flurizam) A stereo-isomer of an NSAID but without cyclooxygenase effects but WITH gamma secretase inhibitory activity An 18 month USA phase 3 trial is just now being completed, with 1000 American subjects & 800 European ones A phase 2 12-month study was positive on two out of 3 outcome measures, including ADL activity & CDR (global scale) The diverging slopes point to disease modification LY Inhibits gamma secretase, which plays a key role in A-beta formation In the phase 2 study, pts received 140mg or 100mg daily for 6-12 weeks. 43 of 51 pts with mild to moderate AD completed the study, blood concentrations of A-beta were reduced 8.2% in the 100mg group & 64.6% in the 140 mg group Phase 3 trial planned for

9 Amyloid Cascade Hypothesis Neuropilic Tangles Conversion to fibrillar amyloid Cytokines il-1 & il-6 Complement reactive O 2 species Mis-metabolism of APP Non-fibrillar Amyloid deposits Glial cell activation Pro-inflammatory mediators & Neurotoxic substances Dimebon Blocks multiple targets within brain cells, some the same & some entirely different from from currently marketed Ad drugs A Russian compound, commercially available during the 1980 s as an antihistamine but removed from the market as that class evolved In an extension study, 70% of pts exposed stabilized or improved after one year Dimebon Dimebon Mode of action just coming to light Has both a cholinesterase inhibition & NMDA receptor antagonism but rather weak Lon Schneider (USC): It has created undeserved hype: scanty pre-clinical work & metabolic effect on mitochondria are highly questionable Smith-Doody: The drug showed a definite signal in phase 2: I would rather be there than with a drug with a great mechanism of action and NO clinical activity. AC-1202 (Ketasyl( Ketasyl) This novel approach to AD provides glucosedeprived neurons with an alternate source of energy Actually, this is ketone bodies which can be metabolized when glucose cannot Taken each morning in a milk-shake, it is a bioenergetic approach to AD A phase 2b study of 152 mild-to moderate AD pts in 25 US cities showed encouraging & statistically significant results in APO E4 negative subjects Key Biomarkers: CSF In AD, CSF A-beta declines and p-tau increases Because these measures reflect the AD activity, a pharmacological effect on these could be regarded as an effect on the disease process But, how much of a change in these biomarkers is needed to affect ADAS- COG scores? (unknown) 9

10 CSF Biomarkers Akin to AD, CSF in MCI has decreased beta-amyloid & elevated tau level A combination of CSF T-tau & A-beta 42 yielded a sensitivity of 95% and a specificity of 83% for the detection of incipient AD in patients with MCI This association was much stronger than & independent of established risk factors such as age, sex, education, APOE genotype, and plasma homocysteine Amyloid Imaging Pittsburgh Compound B (PIB) binds to A-beta & FDNNP binds to a-beta & tau. These scans reflect the process of A-beta deposition & are thus are intimately related to the target for agents that effect A-beta aggregation & plaque formation However, PIB binds to ALL types of amyloid, including vascular, & it might be difficult to detect changes in the oligomeric fraction of A-beta, which is the target of most therapies Writing These New Protocols The current trend has been to take the standard placebo-controlled trials TWEAK them slightly by extending them to 18 months allowing ongoing treatment with an AchEI, add a bio-marker & a secondary outcome to assess efficacy But they are the basic measures to assess SYMPTOMATIC treatments Another Issue Stephen dekosky (U Pitt.): The two major trial networks (ADCS & EADC) are underfunded,we must be more efficient in how we do the trials but we must have more resources to do them properly. Privatepublic collaboration? Small pharma will need support in this area. Be Sure to Watch Everything Carefully! 10