Artistic Regression • Distortion – comic-grotesque representation Condensation – filling to overflowing • Transformation (neomorphism) – anatomic changes and strange facial features (physiognomy) • Stereotype – ornamental stereotype and repetition of particular motives • Woodenness – geometrical and diagrammatic design and pictures enclosed with a frame, lack of depth (lack of shading) and lack of movement (wooden rigidity) • Disintegration – neglect of spacial relationships between objects and loosening of physiognomy of human beings and animals. • Regression – relapse into primitive or child-like drawings and lack of perspective • Maurer K, Frolich L, ALZHEIMER INSIGHTS Paintings of and Artist With Alzheimer Disease
Life expectancy with Dementia • 3.3 years, comparable to some malignancies • In patients diagnosed with dementia • Wolfson et al NEJM 2001;344:1111-1116
Alzheimer Brain Atrophy From Whole Brain Atlas
Neurodegenerative Diseases and Prions Stanley B. Prusiner, M.D. Twenty-five years ago, little was known about the causes ofneurodegenerative diseases.
Thesis: • Degenerative Disease is caused by the accumulation of toxic substances • Deranged metabolism over long pds of time. • Primarily diseases of elderly • As in cholesterol and homocysteine in atherosclerosis
Alzheimer disease: Aβ42 Amyloid Angiopathy: Aβ42 Huntington Disease: Huntingtin Prion Disease: PrP sc “Tauopathies: Pick’s, FT dementia, PSP Parkinson Disease, Lewy body Dementia (alpha synuclein) Spino-cerebellar Degenerations: Ataxins ALS: Neurofilament Macular Degeneration: A2E Neurologic Diseases attributed to Protein deposition
Macular Degeneration=“Age Related Maculopathy” • 5% of 60 year olds, 20% of 80 year olds • Disorder of Phagocytosing cells in Retinal Pigment epithelium • Accumulation of drusen or lipofuscin in Retinal Pigment Epithelium • Genetic forms: may be “A2E” accumulation • Retinal Alzheimer’s Disease
Pathogenesis of Macular Degeneration from Scientific American 10/2001
First Hints to Causation • Genetics • Familial Alzheimer Disease • Trisomy 21
Alzheimer Genes: Chromosome #s • 21: Abn APP Gene <5%* • 14: Presenilin 1 18-50%* • 1 : Presenilin 2 <1%* • 19:APOE-epsilon 4: Incr risk in Caucasions • 19:APOE-epsilon2 on Chr 19: decr risk *of early-onset Disease
Apolipoprotein E4 • Variant alleles E2,E3 • Variants differ by only 1 amino acid • E4 is present in 64% of late-onset Alz patients as 34% of unaffected controls • 2 copies (homozygote) of E4 increases risk of Alz from 45% to 91%
All have in Common: • Increased Accumulation of b Amyloid • Abnormal Accumulation • Defective Degradation
Cerebral Amyloidosis Alzheimer Disease
Pathogenesis • Beta-Amyloid Accumulation • Decrease in Acetylcholine, AchE • Injury • Free-Radical Formation • Genetics • Polygenic • ApoE4 • FAD
Characteristic Changes • Pathology • Tangles, plaques, Granulo-vacuolar degeneration, Atrophy,neuronal loss • Biochemistry • Decreased Ach, AchE • Imaging • Atrophy • Decreased metab activity in post’r cerebral association Cortices
Senile Plaque • A hallmark pathologic lesion specific for AD is senile plaque. Plaques are composed of amyloid-beta (A-beta), which is found in soluble form in the body fluids of patients with AD. Initially, A-beta aggregates into diffuse plaques that lack definite borders. Later, it matures into compact plaques formed of A-beta fibrils that may be toxic to surrounding neurons.
Amyloid Plaques • Between Cells (extra-cellular) • Appear before Tangles do • Associated with Microglia (inflammation) • (microglia are phagocytes of the brain)
Amyloid Precursor Protein • 695-770 Amino Acids • Transmembrane protein • Beta-Amyloid is snipped out precursor protein • Beta-Amyloid- transmembrane component
Cast of Characters • Amyloid Precursor Protein (APP) • Secretases – alpha, beta, Gamma • Enzymes that cut up Amyloid Precursor Protein • Beta-Amyloid (or Aβ42) • Beta-Amyloid is the villain • Setting: The neuron cell membrane
Secretase Steps • Alpha then Gamma – OK • Beta then Gamma – yields Beta Amyloid • 40 Amino Acid fragment is OK but minority cut into toxic 42 Amino acid fragment which constitutes plaque (Aβ42)
Presenilins • Early Onset Alzheimer's • Trans-membrane Protein Cleavers • PreI: Chr 14, PreII:Chr 1 • Knockout for these proteins: No Beta Amyloid • Forms of Gamma-Secretase??
Pathogenesis of Senile Plaque • Toxic Beta Amyloid fragments build up outside the cell • E4 may be selectively removed from the extracellular space in place of beta-amyloid • Beta-Amyloid is toxic and leads to other pathology
Cutting β-Amyloid Precursor Protein • Alpha and Gamma Secretase give rise to harmless p3 protein • Beta then Gamma secretase yield either: • Harmless 40 amino acid residue of Beta-Amyloid OR • Toxic 42 Amino Acid residue of Beta Amyloid
Beta Amyloid Mediated Damage • Ca++ Deregulation • Creation of Free Radicals • Immune Aggregation
Beta Amyloid • 4.2 kD fragment, 42-43 • Abnormal cleavage of Beta Amyloid precursor protein (APP) • APP part of family of 70kD transmembrane proteins • Beta-Secretase, APP cleaving Protein • Injury, ischemia incr APP • Amyloid is neurotoxic
Mechanism of Amyloid destruction • Liberating Calcium in Cells • Damaging Mitochondria • Enhancing inflammatory (Microglial) Response
New Strategies • Beta-Amyloid Vaccine • Beta and Gamma Secretase Blockers • Zinc and Copper Chelators
Strategies to Prevent and treat Alzheimer’s • 1. Inhibition of the proteases (enzymes) that produce Aβ42 ;2. Inhibition of Aβ42 aggregation that precedes A deposition; 3. Inhibition of Aβ42 -induced neurotoxicity • Vaccine or antibody to Aβ42
Mouse Trials of Vaccine • Nasal Administration • Genetically affected mice make excessive Beta Amyloid • Mice show evidence of Dementia • 50% reduction in plaque formation • Improvement on tests • Human phase II trials begin this year
Elan Pharmaceutical trial • In PDAPP mouse (a genetically engineered mouse model with Alzheimer’s-like pathology) • AN-1792, both reduces pre-existing deposits of amyloid and inhibits accumulation
Long arm of Chromosome 10 in late onset Alzheimer ?Connected with degradation of Beta Amyloid? Insulin processing protein Rudy Tanzi Dec22,2000 Science Gene linkage
Treatment Cornerstones • Cholinesterase Inhibitors • Ancillary Symptoms • Anxiety • Agitation • Disorientation and Wandering • Sleep Disturbance • Placement • Caring for Caretaker
CSF in Alzheimer’s Disease • They found levels of CSF beta-amyloid protein were significantly lower, onaverage, in people with Alzheimer's disease than the comparison group (183pg/mL vs. 491 pg/mL). In addition, levels of CSF tau protein weresignificantly higher in Alzheimer's disease patients than in the others (587pg/mL vs. 244 pg/mL).