1、Alzheimers DiseaseStephen S.Flitman,MDMedical Director21st Century Neurologya division of Xenoscience,Inc.Phoenix,ArizonaAlzheimers Disease The leading cause of dementia in the US Progressive loss of cognitive functions:Memory Language Motor control(praxis)Spatial ability Executive function and beha
2、viorRisk Factors in AD Age-Between the ages of 65 and 85,the prevalence of AD doubles with each increase of 5 years.Head Injury-AD patients report higher incidence of prior head injury than non-AD individuals.Genetics-Several genes are associated with ADProtective Factors in AD Estrogen Antioxidants
3、(Vitamin E)Anti-inflammatory Agents Education?Smoking?NINCDS-ADRDA Criteria for AD Probable Alzheimers Disease Dementia with onset between ages 40&90 Cognitive deficits in two or more areas Progressive memory and cognitive deterioration No other illness that could account for such deficits No distur
4、bance of consciousness Definite Alzheimers Disease Clinical criteria for probable AD Histopathologic evidence from autopsy or brain biopsyPrevalence of Alzheimers Using NINCDS-ADRDA criteria:Age 65-74:3.0%Age 75-84:18.7%Age 85+:47.2%Overall over age 65:10.3%Fourth leading cause of death in the US af
5、ter heart disease,cancer,and stroke3.59.017.935.8105.3237.505010015020025061-6465-6970-7475-7980-8485-93Years of AgeRate per 1,000Prevalence of Dementia(Framingham Study)Source:Bachman et al.Neurology.1992;42:115-119.Signs and Symptoms at Different Stages of AD Confusion and memory loss Disorientati
6、on in space Problems with routine tasks Changes in personality and judgment Impaired activities of daily living Anxiety,paranoia,agitation Sleep disturbances Cannot recognize family and friends Loss of speech Loss of appetite;weight loss Loss of bladder and bowel control Total dependence on caregive
7、r Source:Gwyther LP.American Health Care Association and Alzheimers Disease and Related Disorders Association,Chicago,IL:1985.PathologyAnatomic Progression Phase I-Entorhinal Cortex connectivity correlates with progression Phase II-Hippocampus CA1 region Phase III-Neocortex,plus Hippocampus CA4 regi
8、on and Subiculum Cortical Medial Nuclei of Amygdala PutamenBrain of Alzheimer Patient shows numerous plaques of amyloid beta-protein in specific brain areas.These plaques become centers for the degeneration of neurons.Courtesy of James King-Holmes and Science Photo LibraryAxial CT scan section throu
9、gh the temporal lobes:(A)Normal;(B)Alzheimers DiseaseAnteriorPosteriorAnteriorPosterior(A)(B)Alzheimers disease vs.Picks diseaseNeuropathology of Alzheimers Neuritic plaques consist of a core of b-amyloid formed by beta protein fibrils from the aggregated 42 amino acid A/b peptide,surrounded by swol
10、len,dystrophic neurites.Neurofibrillary tangles fill the interior of degenerating neurons.The presence of plaques and tangles at autopsy is used to confirm a diagnosis of AD.Plaque of Amyloid Beta-Protein.Visible as a black globular mass when stained.The plaque is surrounded by abnormal neurites and
11、 degenerating neurons.Plaques and Neurofibrillary TanglesLight micrographs of human brain in Alzheimers DiseaseCourtesy of James King-Holmes and Science Photo LibraryPlaque surrounding amyloid depositNeurons filled with neurofibrillary tanglesInflammation Evidence for inflammatory processes Acute ph
12、ase proteins in serum and plaques Activated microglia,inflammatory cytokine Complement components on degenerating neurites,including membrane attack complex Serum cortisol levels reported higher in AD HPA axis abnormalitiesAmyloid Precursor ProteinAmyloid Beta-42 42 amino acid A/b peptide Produced f
13、rom APP by b/g secretase Will self-associate to form toxic fibrils Insoluble and resistant to proteolysis once aggregatedmolbio.nih.govTau Protein Six isoforms in adult CNS(single gene)Abnormal tau in AD is phosphorylated Normally dephosphorylated by phosphatases Binds and stabilizes microtubules no
14、rmally Fails to bind when phosphorylated Paired helical filaments form tangles Axonal transport blocked degeneration Deglycosylation straightens filaments Genetics in Alzheimers Susceptibility Polymorphisms ApoE on chromosome 19 A2M and LRP on chromosome 12 Autosomal Dominant Mutations Presenilin-1(
15、PS-1)on chromosome 14 Presenilin-2(PS-2)on chromosome 1 APP on chromosome 21(same as Downs)Apolipoprotein E Modulate low-density lipoprotein levels E4/E4-high risk of MI in young patients Apolipoprotein E4 tau phosphorylation Apolipoprotein E2 tau phosphorylationAPOE genotype-specific risk of remain
16、ing unaffectedPresenilins Transmembrane proteins now identified as g-secretases,directly producing Ab42 PS1,PS2 mutations familial AD All show plasma Ab42 levels Not seen in sporadic AD Suggests mutations result in Ab42 secretion Mutations operate outside CNS as well Diagnostic WorkupTraditional Dia
17、gnosis Exclusion-Eliminate all other possible causes of dementia;“Probable AD”.Cognitive tests Neurological work-up EEG Scans-MRI,CAT,PET,SPECT Autopsy-DefinitiveDiagnostic Panel for AD Rule out reversible etiologies for dementia Hypothyroidism-TSH,T4 B12 Encephalopathy-B12 level;or MMA,HC Neurosyph
18、ilis-RPR CNS Vasculitides-ESR,ANA,RF Headache?R/O Chronic Meningitides-LPApolipoprotein E Increase confidence in the diagnosis if E4 present ApoE2/E4 94%ApoE3/E4 97%ApoE4/E4 100%Cerebrospinal fluid CSF Ab42/tau 95%specific for AD Meets Reagan criteria for a surrogate marker AD7c Neural thread protei
19、n Not clearly specific for AD,published 87%sensitivity Urine test also offeredFDA Approved TreatmentsCholinergic Drugs L-Dopa approach:Lecithin Reversible central cholinesterase inhibitors tacrine(CognexTM)QID,LFTs donepezil(AriceptTM)QD,LFTs nl rivastigmine(ExelonTM)BID,LFTs nl galanthamine(Reminyl
20、TM)BID,LFTs nl Muscarinic agonistsADAS-Cog using Donepezil-4-3-2-101230612182430Weeks of Drug TreatmentMean Change from Baseline ADAS-Cog Rating10 mg/day5 mg/dayPlaceboClinical ImprovementClinical DeclineWithdrawal phaseADAS-Cog using Rivastigmine-4-20246810121416180132639526578911046-12 mg1-4 mgPla
21、ceboStudy WeekA negative value indicates improvementaStudy B352(OC)Patients with baseline GDS 5 Mean Change from Baselinea*p0.05 Rivastigmine vs.Placebo*All Patients Receive RivastigmineMLR 130301ADAS-Cog in GalantaminePlacebo(n=157)Galantamine 24 mg(n=131)32101234ImprovementDeteriorationMonthsMean(
22、SE)Change From Baseline in ADAS-cogScore1245634*P .001 vs placebo.Raskind MA et al.Neurology.2000;54:2261-2268.*Adverse EventsAdverse event Donepezil%Rivastigmine%Galantamine%Dizziness Headache Nausea Vomiting Diarrhea Anorexia Abdominal pain 0 0 4 2 7 2 0 11 12 12 6 11 3 6 0 0 13 6 12 6 0 On The Ho
23、rizonNeuromodulators Many compounds acting at multiple sites Like cholinergic agents,may improve function but not disease process Most dramatic:AMPAkines AMPA receptor positive allosteric modulators Improve memory performance in normals 2-3x!Highly investigationalAnti-Inflammatory Agents Steroids No
24、 effect anecdotally AD may have sensitivity NSAIDs Indomethacin and others reported beneficial Ongoing trials Reasonable to use aspirinAmyloid Vaccine Immunization with Ab42 in PDAPP mice Prevents plaque formation if given to young Caused plaque to regress if given to old mice Replicated in rabbits
25、Clinical trials in progress Demonstrated safety&tolerability in humans Not yet shown to have efficacy for prevention or treatmentSchenk et al.Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature,400(6740):173-7,2019.Further On Gene therapy for PS1,PS2,APP,ApoE4 Regenerative therapies Stem cell replacement for cortical atrophy Secretase inhibitors Prevent elaboration of Ab42(Howlett et al.)Other means of amyloid clearance Manufactured antibodies(Sierks et al.)Mechanical clearance(CSFluids COGNIshunt)Questions?
