What s New in Dementia? Howard Rosen Professor, Department of Neurology UCSF and Aging Center Disclosure Biogen pharmaceuticals Small grant for clinical trials planning Dementia is a growing source of morbidity 50M people in the world have dementia 1 in 3 seniors in US dies with dementia Cost dementia in 2010 was estimated at $600 billion Higher than revenues of Walmart, Exxon- Mobil In California more than 1 million unpaid caregivers serve loved ones with dementia Numbers are growing 135M by 2050 Largest growth in Asia The Old View of Dementia Can t be diagnosed Alzheimer s is diagnosis of exclusion Can t be predicted Patient s complaint are meaningless Can t be prevented Can t be treated How has this view changed? Sources: Alzheimer s Disease International; Alzheimer s Association
Overview Alzheimer s disease Diagnosis New tools Treatments Other forms of dementia Differential diagnosis Impact on treatment development Alzheimer s disease Most common cause of dementia > age 65 Symptoms Recent events Most common Earliest problem Also Word finding Planning Organizing Getting lost Depression Apathy Irritability Slowly progressive Impacting activities of daily living encoding in AD List-learning task: fourth recitation of the list After ten minutes
Causative proteins in AD accumulate in microscopic deposits Plaques, extracellular Tangles, intracellular Plaques in AD are made of β- amyloid, which comes from Amyloid Precursor Protein (APP) Neurofibrillary Tangles Amyloid Plaques image obtained from: www.realage.com image obtained from Monroe Street Clinic: www.rienstraclinic.com/.../2006/2006nov.html Diagnosis typically relies on recognition of the characteristic pattern of spread through the brain We have new diagnostic tools β-amyloid PET Imaging (since ~2006) Cognitively Normal Alzheimer s Disease Cognitively Healthy Minimal Complaints Moderate Complaints And Other Complaints
Pathology Validation Median 5 raters vs. autopsy Sensitivity 92% (69%-95%) Specificity 95% (90%-100%) Current treatments: AD causes reduction in Acetylcholine FDA approval: Florbetapir (Amyvid TM ) 2012 Flutemetamol (Vizamyl TM ) 2013 Florbetaben (Neuraceq TM ) 2014 Clark et al. JAMA 2011, Lancet Neurol 2012 Cholinesterase inhibitors raise levels of acetylcholine Risk Factors for Dementia Change in Test Scores Donepezil Placebo 2 1 0-1 -2-3 0 n=135 n=137 p=0.053 Donepezil Placebo 12 127 128 p<0.001 24 36 Study Week 121 120 p=0.019 104 105 p=0.001 52 91 98 p<0.001 Endpoint (135) (137) Improvement Worsenin g Head trauma Stroke Hypertension Diabetes Poor sleep Cholesterol Homocysteine Low exercise Specific genes Social isolation Winblad B, et al. Stockholm/Springfield Symposium, 1999.
Modification of Risk Factors Can Have a Significant Impact Norton et al, Lancet Neurol 2014 20% reduction in prevalence would prevent 15.6 M cases worldwide by 2050 Other treatments depend on symptoms Psychiatric symptoms: Apathy Depression Anxiety Psychosis No FDA approved treatments specifically for behavioral symptoms in dementia Focus on non-pharmacological management Use of medications is still often necessary Experience, habits, best guess of physician Where will future treatments come from? Most drugs in development try to decrease production of A 42 Antiamyloid vaccines antibodies beta secretase inhibitor Recent trials of anti-aβ therapy in AD disappointing But there are signs to justify hope Anti-amyloid drugs can decrease amyloid burden gamma secretase inhibitor Salloway et al. NEJM 2014 Subject Before Treatment Subject After Treatment
New strategies: diagnose earlier Cognition Cognitively normal Dementia 10 years Age Alzheimer s disease Most common cause of dementia > age 65 Symptoms Recent events Most common Earliest problem Slowly progressive Impacting activities of daily living Also Word finding Planning Organizing Getting lost Depression Apathy Irritability Mild cognitive impairment (MCI) Symptoms Recent events Most common Earliest problem Slowly progressive Impacting activities of daily living Also Word finding Planning Organizing Getting lost Depression Apathy Irritability MCI is often early phase of AD Progression to dementia 20-39% in specialty settings 5 10% annually Potential for early treatment Opportunities for prevention
β-amyloid imaging can identify MCI patients with amyloid Cognitively Normal Older person No β-amyloid MCI No β-amyloid MCI With β-amyloid AD 82 year-old NC, Aβ- 73 year-old NC, Aβ+ Up to 30% of elders with normal cognitive function have amyloid Presence of amyloid increases risk of progression to dementia 75 year-old NC, Aβ+ Clinical features can predict conversion in MCI to dementia scores at baseline Volumes of brain structure Hippocampus Blennow et al., Lancet 2006 New Strategies Treat earlier Current studies of anti-amyloid agents enrolling MCI Some studies also enrolling asymptomatic patients with amyloid Anti-amyloid treatment in asymptomatic Alzheimer s disease (A4 study)
AD is also associated with Tau Tau Imaging will provide additional data for treatment 75 yo with Amnestic MCI Amyloid [ 11 C]PIB Tau [ 18 F]AV1451 image obtained from: www.webbooks.com Ossenkoppele et al., HAI 2015 82 year-old NC, Aβ- 73 year-old NC, Aβ+ VaD 18% Beyond AD: Prevalence of dementia etiologies varies by age PDD/DLB 13% UNDER AGE 65 AD 29% VaD 30% OVER AGE 65 AD 44% 75 year-old NC, Aβ+ HD 22% FTD 18% PDD/D LB 15% FTD 11% Ratnavalli E, Brayne C, Dawson K, Hodges JR. (2002)
Beyond AD: Other symptoms, other proteins Alzheimer s (amyloid, tau) Frontotemporal degeneration (tau, TDP-43) Parkinsonian Dementias (tau, synuclein) Language Social behavior/psychiatric Motor Frontotemporal dementia (FTD) presents primarily with socioemotional changes Disinhibition/antisocial behavior Loss of concern for others Exceedingly poor judgment Overeating Compulsive behaviors (collecting) Apathy Overly friendly Loss of disgust FTD and disinhibition FTD is associated with bizarre socioemotional changes because of its specific neuroanatomy Regions of gray matter atrophy in FTD and AD FTD vs. Controls Right Hemisphere Left Hemisphere Bottom Mid-Sagittal Section AD vs. Controls p<0.05, corrected for multiple comparisons
Amyloid prevalence (%) Clinical criteria for FTD Sensitivity and specificity above 80% Autopsy-confirmed cases Pathology in FTD Two main protein pathologies Each accounting for about 50% of FTD Tau TDP-43 100 90 80 70 60 50 40 30 Prevalence of Amyloid PET+ in Dementia Syndromes Tau PET imaging in 66 yo male with FTD due to autosomal dominant mutation L R L R 20 10 0 AD PCA LPA FTD SD PNFA bvftd VaD DLB PDD CBS N= 1358 54 70 287 62 59 24 138 51 22 56 Clinical diagnosis AD=Alzheimer s disease; PCA=Posterior cortical atrophy; LPA=Logopenic aphasia; (bv)ftd= (behavioral variant) Frontotemporal dementia; SD=Semantic dementia; PNFA= Progressive non-fluent aphasia; VaD=Vascular dementia; DLB=Dementia with Lewy bodies; PDD=Parkinson s disease dementia; CBS=Corticobasal syndrome. 0.0 2.2 AV1451 SUVR Ossenkoppele et al., JAMA 2015 Rabinovici et al., HAI 2015
More recently recognized causes of dementia Chronic Traumatic Encephalopathy (CTE) Repeated traumatic head injury Symptoms Cognitive impairment Emotional dysfunction Depression Apathy Irritability/Aggression Impulsivity Substance Abuse CTE is also a tauopathy Overlap in proteins is driving interest in various types of dementia Tau AD FTD CTE Others (PSP, CBD) TDP-43 FTD Also found in AD Treatment for one protein may address several diseases McKee et al. J Neuropathol Exp Neurol. 2009
Tau treatment strategies Boosting cellular breakdown Stabilizing microtubules Inhibiting spread of misfolded tau Tau vaccines Reducing expression Inhibiting assembly Disrupting aggregates Reducing expression mirnas, sirnas Antisense Oligonucleotides (ASO) Success in SMA trials Reduced human tau mrna, reduced tau deposition, hippocampal volume loss and increased survival, nesting behavior. Holtzman et al 2016 DeVos et al 2017 CADC Dementia Diagnostic Toolkit CA legislation SB833 Augmentation to CADC budget Guidance for diagnosis History Testing Billing guidance Questions Do you have any problems with your memory or thinking? Answers typical of normal aging Patient Going into a room and not remembering what I am going for Misplacing my glasses or keys but I find them pretty quickly, and it s occasional Difficulty remember names, words BUT it comes back to them later on Answers typical of normal aging Partner/Caregiv er No problem Their memory is better than mine Occasionally might forget a word or misplace something but it s not often Answers concerning for cognitive impairment Patient I m having difficulty recalling recent events (e.g. forgot I paid a bill) Lost my car in the parking lot several times I misplace things often, disrupts my schedule Can t find the words I want to use; Talking less in conversations because I am embarrassed Answers concerning for cognitive impairment Partner/Caregiv er Informant reports patient can t remember what they did yesterday Difficulty with remembering appointments and events, needs reminders Repetitive questioning, story telling Needs to write everything down (notebook, sticky notes) Answers typical for AD Patient Person may deny or minimize memory problems I can t remember what I did yesterday I can t remember a conversation or event that others recall Answers typical for AD Partner/Caregiv er I can t remember what I did yesterday I can t remember a conversation or event that others recall Conclusions Progress in biology Leads for treatment Improved diagnosis Better recognition New tools Treatment still lacking Proteins, symptoms Much progress needed to improve delivery and coordination of care Efforts ongoing/growing Quiet in groups, relying on others to fill in during conversation, can t finish sentences