The Predictability of Eye Disease for Alzheimer Disease 由眼睛疾病預測阿茲海默症 臺北市立聯合醫院 翁林仲 陳少鈞

Alzheimer's disease (AD) Age associated >65y/o: 6.7% Senile plaque ( 老年斑 ) Neurofibrillary tangle ( 神經纖維 ) Dementia ( 老年癡呆 )

 Data sources:  Relative hazards ratio of Alzheimer‘s disease in the diabetic ( 糖尿病 ) and control groups 4

Relative hazards of AD in relation to diabetes and various covariates  Diabetes, female, >65y/o, low insurance premium, north and south geographic area

Relative hazards of AD in relation to diabetes and various covariates  Cerebrovascular ( 腦血管 ) disease, cardiovascular ( 心血管 ) disease, hypertension ( 高血壓 )

W Why Alzheimer’s disease relate to ocular problem

Retina ( 視網膜 ) The integral part of CNS

Ohno-Matsui K. Prog Retin Eye Res RPE 視網膜色素 層

E Evidence of Alzheimer’s disease in eye problem

 Relative hazards ratio of Alzheimer's disease in the diabetic and control groups (2012)  Adjusted odds ratio of Alzheimer‘s disease in the diabetic retinopathy ( 糖尿病視網膜病變 ), glaucoma ( 青光眼 ), age-related macular disease ( 老年性黃斑部病變 ) and control groups (2013)

Diabetic Retinopathy ( 糖尿病視網膜病變 )

Odds Ratio of AD (DMR: ) VariableNumber of Patients(%) Number of Events (prevalence) Adjusted OR(AOR) 95% CIP value Age <65 y/o 2850(49.2%) 2(0.070%) 1.00 ≥65 y/o 2946(50.8%) 6(0.204%) Sex Male3066(52.9%) Female2730(47.1%)8(0.293%) > Diabetic retinopathy No 4830(83.3%) 2(0.041%) 1.00 Yes 966(16.67%) 6(0.621%) * Total57968(0.138%) 14 Woung LC, Chen SC. 2013

Age-related Macular Degeneration ( 老年性黃斑部病變 ) 15

Age-related Macular Degeneration and Alzheimer’s Disease 16 Rotterdam Study, prospective population-based study, aged 75 years or older (n = 1,438), advanced age-related maculopathy increased risk of Alzheimer's disease. Am J Epidemiol. Is age-related maculopathy associated with Alzheimer's Disease? The Rotterdam Study. 1999

Woung LC, Chen SC Odds Ratio of AD (AMD: ) VariableNumber of Patients(%) Number of Events (prevalence) Adjusted OR(AOR) 95% CIP value Age <65 y/o 516(20.5%) 1(0.194%) 1.00 ≥65 y/o 1988(79.5%) 8(0.402%) Sex Male 1530(60.9%) 4(0.261%) 1.00 Female 984(39.1%) 5(0.508%) Age-related macular disease No 2095(83.3%) 1(0.048%) 1.00 Yes 419(16.7%) 8(1.909%) * Total2514 9(0.358%) 17

Glaucoma ( 青光眼 )

Woung LC, Chen SC Odds Ratio of AD ( Glaucoma : 365.* ) VariableNumber of Patients(%) Number of Events (prevalence) Adjusted OR(AOR) 95% CIP value Age <65 y/o 5630(34.6%) 5(0.089%) 1.00 ≥65 y/o 10632(65.4%) 38(0.357%) * Sex Male 7466(45.9%) 15(0.201%) 1.00 Female 8796(54.1%) 28(0.318%) Glaucoma No 13550(83.3%) 7(0.052%) 1.00 Yes 2712(16.7%) 36(1.327%) <.0001** Total (0.264%) 19

ADGlaucomaAMD LocationRGC, NFLRGC, NFL, ONH RPE, phtotreceptor Amyloid deposition Senile plaqueRGCDrusen pTauNGT Inner retina, vitreous, ONH No Oxidative & metabolic stress Metal deficiency Neural damage Metabolic strain Visual cycle Drusen Glial reactivity Around senile plaque In NFL, ONH Around drusen Genetic linkage APOE Amyloid deposition Senile plaqueRGCDrusen pTauNGT Inner retina, vitreous, ONH No Jeremy M. Sivak. IOVS 2013

RVP ( 網膜血管 ) RNFL thickness ( 視網膜神經纖維層厚度 ) VEP ( 視覺誘發電位 ) Eye-hand coordination ( 手眼協調 )

Retinal Vessels Calibers ( 網膜血管口徑 ) and Dementia  Population-based Rotterdam Study: 1065 persons (mean age, 67.5 y and 51% women)  Narrower retinal arteriolar and wider retinal venular calibers associated with smaller brain volume primarily white matter. Alzheimer Dis Assoc Disord, Retinal Vascular Calibers Associate Differentially With Cerebral Gray Matter and White Matter Atrophy Ikram MK, Alzheimer Dis Assoc Disord. 2013

Ocular (Optical) Coherence Tomography ( 斷層掃描 ) Retinal nerve fiber layer

He XF. Int J Ophthalmol μm RNFL thickness 24 He XF. Int J Ophthalmol.2012

Flash-Visual Evoked Potentials ( 閃光視覺誘發電位 ) under open- or close- eyes changed in Alzheimer‘s disease Tartaglione A, BMC Neurol. 2012

F-VEP: P2 latency (mean ± SE) Control AD Eye-open (EO) ± ± 3.1 Eye-closed (EC) ± ± 3.9 EC – EO 3.7 ± ± 2.2 F-VEP can be viewed as a reliable marker of AD Tartaglione A. BMC Neurol. 2012

Eye-hand coordination

Eye-hand Coordination Impaired in Early- Alzheimer’s Disease (damage to the parietal lobe) J Alzheimers Dis. Visuomotor impairment in early-stage Alzheimer's disease: changes in relative timing of eyeand hand movements  Eyeball movement AD Normal  Hand movement AD Normal

Conclusions  This national population-based cohort study provides support for the putative link between diabetes (retinopathy), glaucoma, AMD, and AD  A link is particularly evident in female and in older diabetes. for  We suggest a need for routine mental and cognitive examinations in diabetic patients in order for early detection ( 檢測 ) and therapeutic treatments of ad.  Female and older diabetic patients and their family should be particularly informed of such increased risk, and avoidance of other risk factors for ad should be exercised accordingly.

Additional Conclusions  Several degeneration diseases of optic nerve ( 視神經 ) or retina are associated with AD.  Various ophthalmological or neuro- ophthalmological examinations could detect or predict AD.  Ophthalmologists will take important part in AD diagnosis and monitoring.

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