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Alzheimer’s Disease Stephen S. Flitman, MD Medical Director 21 st Century Neurology a division of Xenoscience, Inc. Phoenix, Arizona.

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Presentation on theme: "Alzheimer’s Disease Stephen S. Flitman, MD Medical Director 21 st Century Neurology a division of Xenoscience, Inc. Phoenix, Arizona."— Presentation transcript:

1 Alzheimer’s Disease Stephen S. Flitman, MD Medical Director 21 st Century Neurology a division of Xenoscience, Inc. Phoenix, Arizona

2 Alzheimer’s Disease The leading cause of dementia in the US Progressive loss of cognitive functions: –Memory –Language –Motor control (praxis) –Spatial ability –Executive function and behavior

3 Risk 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 AD

4 Protective Factors in AD Estrogen Antioxidants (Vitamin E) Anti-inflammatory Agents Education? Smoking?

5 NINCDS-ADRDA Criteria for AD Probable Alzheimer’s 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 disturbance of consciousness Definite Alzheimer’s Disease –Clinical criteria for probable AD –Histopathologic evidence from autopsy or brain biopsy

6 Prevalence of Alzheimer’s 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 after heart disease, cancer, and stroke

7 Prevalence of Dementia (Framingham Study) Source:Bachman et al. Neurology. 1992;42:

8 Signs and Symptoms at Different Stages of AD Source:Gwyther LP. American Health Care Association and Alzheimer’s Disease and Related Disorders Association, Chicago, IL:1985. Moderate Mild Severe

9 Pathology

10 Anatomic Progression Phase I - Entorhinal Cortex –connectivity correlates with progression Phase II - Hippocampus CA1 region Phase III - Neocortex, plus –Hippocampus CA4 region and Subiculum –Cortical Medial Nuclei of Amygdala –Putamen

11 Brain of Alzheimer Patient shows numerous plaques of amyloid beta- protein in specific brain areas. These plaques become centers for the degeneration of neurons.

12 . Courtesy of James King-Holmes and Science Photo Library Axial CT scan section through the temporal lobes: (A) Normal; (B) Alzheimer’s Disease Anterior Posterior Anterior Posterior (A)(B)

13 Alzheimer’s disease vs. Pick’s disease

14 Neuropathology of Alzheimer’s 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 swollen, 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.

15 Plaque of Amyloid Beta-Protein. Visible as a black globular mass when stained. The plaque is surrounded by abnormal neurites and degenerating neurons.

16 Plaques and Neurofibrillary Tangles Light micrographs of human brain in Alzheimer’s Disease Courtesy of James King-Holmes and Science Photo Library Plaque surrounding amyloid deposit Neurons filled with neurofibrillary tangles

17 Inflammation Evidence for inflammatory processes –Acute phase 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 abnormalities

18 Amyloid Precursor Protein

19 Amyloid Beta amino acid A/b peptide Produced from APP by b/ g secretase Will self-associate to form toxic fibrils Insoluble and resistant to proteolysis once aggregated

20 Tau Protein Six isoforms in adult CNS (single gene) –Abnormal tau in AD is phosphorylated –Normally dephosphorylated by phosphatases Binds and stabilizes microtubules normally –Fails to bind when phosphorylated –Paired helical filaments form  tangles –Axonal transport blocked  degeneration –Deglycosylation straightens filaments

21 Genetics in Alzheimer’s Susceptibility Polymorphisms –ApoE on chromosome 19 –A2M and LRP on chromosome 12 Autosomal Dominant Mutations –Presenilin-1 (PS-1) on chromosome 14 –Presenilin-2 (PS-2) on chromosome 1 –APP on chromosome 21 (same as Down’s)

22 Apolipoprotein E Modulate low-density lipoprotein levels E4/E4 - high risk of MI in young patients Apolipoprotein E4   tau phosphorylation Apolipoprotein E2  tau phosphorylation

23 APOE genotype-specific risk of remaining unaffected

24 Presenilins Transmembrane proteins –now identified as  -secretases, directly producing A  42 PS1, PS2 mutations  familial AD –All show  plasma A  42 levels –Not seen in sporadic AD –Suggests mutations result in  A  42 secretion –Mutations operate outside CNS as well

25 Diagnostic Workup

26 Traditional Diagnosis Exclusion - Eliminate all other possible causes of dementia; “Probable AD”. Cognitive tests Neurological work-up EEG Scans - MRI, CAT, PET, SPECT Autopsy - Definitive

27 Diagnostic Panel for AD Rule out reversible etiologies for dementia –Hypothyroidism - TSH, T 4 –B 12 Encephalopathy - B 12 level; or MMA, HC –Neurosyphilis - RPR –CNS Vasculitides - ESR, ANA, RF –Headache? R/O Chronic Meningitides - LP

28 Apolipoprotein E Increase confidence in the diagnosis if E4 present ApoE2/E4 – 94% ApoE3/E4 – 97% ApoE4/E4 – 100%

29 Cerebrospinal fluid CSF A  42/tau –95% specific for AD –Meets Reagan criteria for a surrogate marker AD7c –Neural thread protein –Not clearly specific for AD, published 87% sensitivity –Urine test also offered

30 FDA Approved Treatments

31 Cholinergic Drugs L-Dopa approach: Lecithin Reversible central cholinesterase inhibitors –tacrine (Cognex TM )QID,  LFTs –donepezil (Aricept TM ) QD, LFTs nl –rivastigmine (Exelon TM ) BID, LFTs nl –galanthamine(Reminyl TM )BID, LFTs nl Muscarinic agonists

32 ADAS-Cog using Donepezil Withdrawal phase

33 ADAS-Cog using Rivastigmine Study Week A negative value indicates improvement a Study B352 (OC) Patients with baseline GDS >5 Mean Change from Baseline a * * ** ** *p<0.05 Rivastigmine vs. Placebo *** * All Patients Receive Rivastigmine

34 MLR ADAS-Cog in Galantamine Placebo (n = 157) Galantamine 24 mg (n = 131) –1 –2 –3 –4 Improvement Deterioration Months Mean (± SE) Change From Baseline in ADAS-cog Score *P <.001 vs placebo. Raskind MA et al. Neurology. 2000;54: *

35 Adverse Events

36 On The Horizon

37 Neuromodulators 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 investigational

38 Anti-Inflammatory Agents Steroids –No effect anecdotally –AD may have  sensitivity NSAIDs –Indomethacin and others reported beneficial –Ongoing trials –Reasonable to use aspirin

39 Amyloid Vaccine Immunization with A  42 in PDAPP mice –Prevents plaque formation if given to young –Caused plaque to regress if given to old mice –Replicated in rabbits Clinical trials in progress –Demonstrated safety & tolerability in humans –Not yet shown to have efficacy for prevention or treatment Schenk et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400(6740):173-7, 1999.

40 Further On Gene therapy for PS1, PS2, APP, ApoE4 Regenerative therapies –Stem cell replacement for cortical atrophy Secretase inhibitors –Prevent elaboration of A  42 (Howlett et al.) Other means of amyloid clearance –Manufactured antibodies (Sierks et al.) –Mechanical clearance (CSFluids COGNIshunt)

41 Questions?


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