Dementia and Longevity

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1 Dementia and Longevity Clementine E. Karageorgiou MD, PhD Department of Neurology Athens Medical Group, Marousi A REALISTIC GOAL Longevity Athens Hilton Athens 8-9/September/2017

2 Disclosures Member of Advisory Boards, Presentations at congresses satellite symposia, Participation at educational seminars, Participation at research studies, for the companies: Allergan, Βayer, Biogen Ιdec, Elpen, Gengyme-Sanofi, Genesis- Pharma, Merck-Serono, Μenarini, Novartis, Pfizer, Teva

3 Objectives I) Dementia: What is it? a Global Approach (Definitions, Epidemiology, Clinical & Lab Approach, Influence of different Factors) II) Management of Dementia: Is it viable? (Approved Therapies, Prevention Strategies, Diet, etc. III) Longevity and Dementia: There is relation?

4 I) Dementia : a Global Approach

5 Definitions Dementia Cognitive or behavioral impairment interfering with a person s ability to perform Activities of Daily Living (ADLs) Mild cognitive or behavioral impairment (MCI/MBI) Cognitive or behavioral impairment present, but without affecting ADLs Caveat: Not all people perform tasks of same demand on a daily basis. So?... Miller & Boeve eds Behavioral Neurology of Dementia 2009

6 What are ADLs? Basic ADLs Instrumental ADLs (IADLs) Mobility Managing finances Bathing/Hygiene Completing work tasks Dressing House chores Feeding Meal preparation Taking medications Shopping Driving and transportation Telephone use And that s why it s important

7 Cognitive & Behavioral Domains Cognitive domains Behavioral domains Memory Empathy and Sympathy Language Motivation Visuospatial Social decorum and inhibition Executive Eating habits Compulsions and stereotypies Performance Modulators Processing speed Alertness etc. Lezak. Neuropsychological Assessment 1995

8 Dementia is an umbrella term Dementia AD DLB FTD Vascular

9 Epidemiology The world wide population is growing fast. Between elderly population(subjects >65y) will increase: Continent: Americas: from 63 to 137 million Africa: Europe: Asia: (ADAMS Study)

10 Epidemiology(cont.) Memory Study (ADAMS) in the USA: 14% of people 71+y Dementia. (Plassman BL et al. Neuroepidemiology 2007) 22% (5.4 million)71+y Cognitive Impairement without Dementia ( Plassman BL et al Ann Int Med 2008) Dementia risk factors: Age (greatest risk factor) Apolipoprotein gene E4 alleles (APOE4) Low educational Occupational attainment, Family History of Dementia, Traumatic Brain Injuries Cardiovascular risk factors Gender : W>M 2/3 patients with Dementia Women Genetic Hormonal Race (African Americans + Hispanics >Caucacian) (Herbert LE et al Arch Neur 2003)

11 Dementia in an ideal world Clinical syndromes Phenotype A Phenotype B Phenotype C Brain atrophy Brain Pattern A Brain Pattern B Brain Pattern C Proteinopathies Disease A Disease B Disease C

12 Dementia in an ideal world Clinical syndromes Phenotype A Phenotype B Phenotype C Brain atrophy Brain Pattern A Brain Pattern B Brain Pattern C Proteinopathies Disease A Disease B Disease C

13 Clinical syndromes Brain atrophy patterns Dementia in the real world simplified AD * bvftd nfvppa svppa FTLD PPA Diagnostic Biomarkers Biological markers Functional H&P NP tests fmri FDG-PET MEG/EEG Blood/CSF tests PSG/Actigraphy Structural smri Blood/CSF tests Treatments Symptomatic Pharmacologic AChEi SSRI trazodone Non-pharmacologic driving avoidance family education family respite speech therapy exercise sleep schedule Proteinopathies Genetic associations β-amyloid, Tau APP, PS1, PS2, ApoE4, TREM2 UPS CHMP2B FUS Ubiquitin FUS TDP-43 A-D GRN, DCTN1, TARDBP, C9Orf72, VCP Tau 3R tau MAPT Tau 4R Surrogate biomarkers Molecular PET Blood/CSF tests IHC Genetics Potential etiologic interventions Pharmacologic Ab/tau-antibodies progranulin enhancers antisense oligonucleotides anti-inflammatory drugs Modified from Karageorgiou & Miller. Seminars in Neurology 2014

14 Medical practice is an art Now that I know everything about dementia, how do I approach my patient? Start by explaining what you re going to do: History (personal, family, medications etc.) Exam Cognitive testing (± NPT) Impression and Plan (imaging, blood, CSF workup if needed) Always interview surrogate (family, friend) Take control of who speaks Proactively inform not to interrupt each other Ease into discussion Patients are already nervous coming to see you

15 But which dementia? The neurological method dictates strategy Where? Localization of affected brain networks Identify syndrome What? Pathophysiology Identify disease Now what? Therapies Symptomatic vs. etiologic

dementias affect specific networks Disease spreads from an area to another through brain hubs Brain

16 Syndrome Characterization: Primary Principles Traverse a mental brain map according to the temporal evolution of symptoms Identify vulnerable network and clarify first symptoms Specific degenerative dementias affect specific networks Disease spreads from an area to another through brain hubs Brain networks involved in dementia syndromes Braak NFT staging in AD Seeley et al. Neuron 2009; Braak & Braak. Acta Neuropath. 1991

17 History, history, history Progression Gradual vs. stepwise vs. stable Memory Executive Constitutional Incontinence, orthostatic dizziness, constipation etc. Language Word finding, spelling, comprehending, grammar Visuospatial Navigation, visual perception (e.g. distances, faces) Motor Sensory Behavior Empathy, social decorum, eating habits, motivation, sleep NB: Almost everyone complains of memory problems, clarify what they mean. Our vocabulary is different from our patients

18 Neurological exam Identify signs that coexist with specific syndromes and think of localization Vertical eye movements (PSPS) Pyramidal signs (ALS) Extrapyramidal signs (synucleinopathies [PD,DLB,MSA MSA], PSPS/CBS) Proprioceptive deficits (CBS) Visuospatial deficits (CBS, PCA) Gait & balance (ALS, synucleinopathies,tauopathies)

19 Ancillary testing Structural imaging review it yourself Always try and obtain an MRI without contrast to verify degenerative process and clinico -anatomical association T1, FLAIR, T2, GRE/BOLD, DWI/ADC (guideline recommended) Sagittal (T1, FLAIR), Axial (all), Coronal (T1, FLAIR) Formal neuropsychological testing Allows for objective/quantifiable evaluation of deficits 1-3 hours depending on center(aim for shorter but across-domain) Become familiar with basic tests beyond MMSE, MoCA (e.g. CVLT) Laboratory and biomarker workup B12, Thyroid (guideline recommended) CSF and PET biomarkers Rapidly progressive dementia biomarkers(autoimmune, paraneoplastic etc.)

20 II)Management of Dementia: Is it viable? Evidence for prevention strategies? Evidence for brain exercise efficacy? Evidence for ACI use in MCI?

21 FDA Approved Therapies Cholinesterase Inhibitors Donepezil Rivastigmine Galantamine NMDA Receptor Antagonist Memantine Caprylic triglyceride FDA- medical food

22 Cholinesterase inhibitors for MCI? Cooper et al., 2013 BJP reviewed 9 trials: Transition to AD - no effect in 4 high quality trials Effect on cognition - pos effect in 2 small trials - no effect in 5 large high quality trials Global functioning -1 neg effect (primary endpoint) -1 pos effect trial (secondary endpoint) Cochrane review (Russ and Morling, 2014): There is very little evidence that cholinesterase inhibitors affect progression to dementia or cognitive test scores in MCI. This weak evidence is overwhelmed by the increased risk of AEs, particularly GI. CIs should not be recommended for MCI. ACIs not formally recommended in MCI

23 Prevention Strategies Cognitive exercise? Sleep? Diet? Physical exercise?

Video game training enhancing cognitive function in older adults Single task: driving Single task: sign response Multitask: drive + sign Neuro Racer 1

24 Video game training enhancing cognitive function in older adults Single task: driving Single task: sign response Multitask: drive + sign Neuro Racer 1 hour 3x/week for 1 month 6 months: improved working memory and vigilance in multitask group Commercial version under development Anguera et al., Nature 2013

25 Are brain games effective? Scientific evidence does not support the brain game claims, Stanford scholars say Sixty-nine scientists at Stanford University and other institutions issued a statement that the scientific track record does not support the claims that so-called "brain games" actually help older adults boost their mental powers. [2014] "We object to the claim that brain games offer consumers scientifically grounded avenue to reduce or reverse cognitive decline when there is no compelling scientific evidence to date that they do.

Mediterranean diet Rijpma et al, (Aging Res Rev, 2014) 5/6 longitudinal, lower AD risk; 2/3 reduced MCI to AD conversion Prospective, 4 wk, improved BMs, visual memory Lourida et al, (Epidemiol 2013)

26 Mediterranean diet Rijpma et al, (Aging Res Rev, 2014) 5/6 longitudinal, lower AD risk; 2/3 reduced MCI to AD conversion Prospective, 4 wk, improved BMs, visual memory Lourida et al, (Epidemiol 2013) 11 observational, 1 RCT (2 wks), lower rates of cog decline, and AD risk 9/12 studies. MCI, inconsistent. Sofi et al, ( Am J Clin Nutr 2010) 7 longitudinal studies, 2 pt inc med diet adher, 13% less risk neurodegen disease Sing et al, (JAD 2014) 5 longitudinal; top tertile med diet, 27% / 36% less MCI/AD ~20% rr Mosconi et al (J Prev AD, 2014;) Age 25-72, nl cognition, cross-sectional study 52 subjects/dietary hx 52yo MeDi+ 50yo MeDi-

27 Nutrition/Supplements Fish consumption 4/5 longitudinal studies reduced AD risk; no prospective O-3 FA prospective: AD: no effect except one study (mild AD subgroup) MCI 3/3 small studies mild improvement; [21 sub, 3mo, mem/attn; 23 sub, 6mo, ADAS-cog; 18 sub, 1 yr, memory; (Cederholm et al, Adv Nutr, 2013) Normal aging: no effect (0/3 studies) Anti-oxidants: (E, C, β-carotine, α-lipoic acid): no effect AD or MCI Vit E: AD, 2000 IU 19% red rate decline ADLs, no cog effect; no effect with memantine. (Dysken et al, 2014) Nutrition/Supplements B vitamins: 2/5 studies benefit AD (contradictory), 1/1 MCI, if high HC Souvenaid: (1,200 mg DHA, 300 mg EPA, vits E,C,Bs; PLs, choline, uridine monophos) ; memory effects mild AD only, 2 studies; no effects similar Overall, no current evidence for efficacy/prevention Fish/O-3 FA > antioxidants/vitamins Current studies generally > 65; future: 40-65? Otaegui-Arrazola et al Eur J Nutr 2014 Rijpma et al Aging Res Rev, 2014

28 High ω-3fa levels: increased prostate cancer Prospective cohort:. ~ 40% increased prostate CA incidence Brasky et al JNCI 2013

29 Diet / Supplements Mediterranean diet: 15-25% reduced risk Coconut water/oil: no reliable data (Henderson et al Nut & Met, 2009 ) Omega-3 fatty acid DHA 1000 mg 2x/day: no overall effect in AD Vitamin E mild/mod Alzheimer s 19% reduction rate decline ADLs; no cog effects 2000 IU/d (Dysken et al, 2014) Turmeric/curcumin: UCLA negative trial < 25 nmol/l : 2.2X; < 50 nmol/l: 1.5X increased risk (Littlejohns et al, 2014) (Ringman et al2012)

30 Sleep? Yaffe et al, SDB assoc with 1.9X odds MCI at 5 yrs (JAMA 2001) Cheng et al SDB assoc with 1.7X odds dementia at 5 years (PLoS One 2013) Sleep and Alzheimer s review: Spira et al, Curr Opin Psychiatry 2014

31 Sleep disruption prevents normal morning Aβ decrease Human intrathecal catheter monitoring Aβ42 Total Protein (Ooms et al JAMA Neurology 2014)

32 Sleep, amyloid and Alzheimer s Sleep consolidation: ( Lim et al JAMA Neurol 2013) AD incidence Poor Average Good >7h E4 Sleep duration <6h 6-7h >7h Amyloid PET Spira et al JAMA Neurol 2013

33 Exercise?

34 Exercise and dementia risk: meta-analyses Sofi et al, (J Int Med 2011): 15 prospective cohort studies, 1-12 yrs f/u 35-38% reduced risk, low-moderate / high levels exercise. Hamer and Chida, (Psychol Med, 2009) 16 studies, highest vs lowest exercise levels: 45% reduced risk AD ~40% reduced risk

35 Exercise and decreased amyloid accumulation E4 - E yo normals parent-ad ± exercise past 10 years Exercisers: 30 min mod exercise 5d/wk (AHA)

Resistance Training in MCI EXCEL study Women 70-80 MCI 6 months

36 Resistance Training in MCI EXCEL study Women MCI 6 months 2X/wk resistance vs. balance/tone Exec function+ assoc memory function

37 Walking Reversal of Hippocampal Age-related Atrophy 10 40min/day walk 1year hippo hippocampus 1-2%/yr atrophy Erickson et al PNAS 2011 Mechanism? BDNF?

38 Exercise RCTs in Alzheimer s (Farina et al Int Psychogeriatrics, 2014) Systematic review yielded 4 RCTs assessing global cognitive outcome n = subjects in exercise group min, wide range activities, 3-7 days/wk, wks

39 Summary: Prevention/Rx Strategies Medications: no overall evidence Supplements: no overall evidence (x 3 small O3-FA RCTs in MCI) Physical exercise: Lots epi ~40% risk decrease Multiple small RCTs (goal 30 min/5 days?) Sleep: Early epi, ~25% risk? No RC Cognitive exercise: No clear epi 1 RCT in res setting Diet: Lots epi ~20% risk decrease

40 III)Longevity & Dementia: There is relation? Definition Longevity =Dementia or Aging? Impact of different Factors

41 Definitions LONGEVITY: A very complex attitude totally different of the statistical term life expectancy. Determine persons that live for very long(>80y) AGING : A decline in performance and fitness with advancing age,creating difficulty in adapting to new situations.

42 Diseases associated with Aging -Diabetes -Cardiovascular diseases -Dementia -Cancer

43 What happened by Aging? Progressive failures in cellular mechanisms, leading to accumulating damage and systemic dysregulation, with accumulation of free radicals, mitochondrial dysfunction, telomere damage and hormone dysregulation

44 There is impact of Longevity to cognitive function?

45 LONGEVITY & COGNITION Aβ42 increases by aging as well incidence of dementia AD is more frequent in population >75y BUT

Diagnostic accuracy of AD Clinical AD diagnosis often does not reflect fibrillary amyloid pathology In clinical trials 36% of ApoE4 noncarriers and 6.

46 Diagnostic accuracy of AD Clinical AD diagnosis often does not reflect fibrillary amyloid pathology In clinical trials 36% of ApoE4 noncarriers and 6.5% of ApoE4 carriers diagnosed as AD were PET negative Healthy older controls are more likely to have amyloid pathology than younger controls In 75 yo ~20% of non ApoE4 carriers ~50% of ApoE4 carriers ~30% of all controls Salloway et al. NEJM 2012; Ossenkopelle et al. JAMA 2015

47 Use of PET imaging Amyloid PET correlates with pathology Cortical amyloid correlates with AD pathology White matter amyloid non-specific and may reflect other pathologies as well (e.g. CAA) Recommendations: Young onset Atypical/mixed presentation Non-progressing MCI 8-10 times more expensive than CSF markers Metabolic FDG-PET correlates with symptoms Rarely useful practically if proper history and ancillary testing done (including MRI) Image courtesy of Gil Rabonovici

48 There is impact of Longevity to cognitive function? Research from W Australia about KLOTHO in different longevity populations Schizophrenic persons (Morar B et alschizoph.research 2017) Longevity Healthy Men (Almeida OP. et al 2017) KLOTHO gene= key modulator of aging Overexpression extends lifespan & enhance cognition A functional human variant of the gene KL-VS increase expression & promotes Longevity slowing Dementia

49 Conclusions Dementia Is a term with many faces, more frequent in older Medication & Supplements no overall evidence Physical Exercise ~40% risk decrease Sleep reverse early stages of MCI Diet ~ 20% risk decrease Longevity no equation to aging and dementia KLOTHO gene is a key modulator of aging KL-VS promotes Longevity slowing progress Dementia LONGEVITY IS A REALISTIC GOAL

50 Ευχαριστώ Thank you LONGEVITY REALISTIC GOAL

What We Can Do To Prevent or Reduce the Risk for Dementia

What We Can Do To Prevent or Reduce the Risk for Dementia Colloquium on Health and Wellness October 10 th, 2018 Frank M. Longo, MD, PhD Professor and Chair Department of Neurology and Neurological Sciences