Molecular and Genetic Basis for Dementing Disorders

1. Molecular and Genetic Basis for Dementing Disorders Mitra Assadi, M.D. Associate Professor of Neurology UMDNJ/RWJ

2. Dementia • Deterioration in intellectual abilities resulting in a decline in function • Memory • Attention • Reasoning • Language and arithmetic's • Visual and Spatial orientation • Abstract and problem solving

3. Diagnosis • Hx • Neuropsychological eval • Brain imaging • Screening for treatable causes • LP

4. AD-Clinical Features • The most common cause of dementia • age #65 • global intellectual impairment • Initial manifestations: memory & attention • Depression v/s pseudo-depression

5. AD Pathology • Intra-neuronal inclusions: Tangles, Tau positive • Extra-neuronal inclusions: Plaques, Amyloid positive • Cholinergic Deficiency

6. Other Factors • Mitochondrial bioenergetic decline • Trace element deposition (iron, copper) • Oxidative stress

7. Oxidative Stress • Cumulative effect of free radical oxidation • Lipid peroxidation damage neuronal membranes and myelin • Protein peroxidation • DNA peroxidation, impaired protein synthesis

8. AD-Genetics • 30% have a family history • AD • Late onset cases are sporadic • Genes responsible for familial AD: • APP • PS1 • PS2

9. AD-Molecular Basis • Conversion of APP to AB40 and AB42 • Increase activity in beta and gamma secretase • APP mutations alter the splice sites for the secretase enzyme • Aggregation of beta amyloid is neuro-toxic

10. APO E Protein • Susceptibility gene • Gene polymorphism includes: E2, E3, E4 • Stronger risk factor in late onset AD

11. AD Treatment • Vitamin E 1000 mg/d • Fish oil • Cholinestrase inhibitors • Anti-psychotics • Anti-depressants

12. FRONTOTEMPORAL DEMENTIAS • Characterized by lobar brain atrophy • Includes a spectrum of degenerative syndromes: Frontal Variant Temporal Variant Progressive Aphasia CBD

13. FTD-FRONTAL VARIANT • Prominent behavioral manifestations: disinhibition, apathy, executive dysfunction, stereotype/ritual behavior • Memory is preserved

14. FTD-TEMPORAL VARIANT • Semantic dementia • Progressive decline in receptive language • Memory is preserved

15. FTD-PROGRESSIVE APHASIA • Perisylvian atrophy • Marked decline in verbal fluency, stuttering • No behavioral issues • Memory is preserved

16. FTD-CBD • Parietal lobe atrophy • Parkinsonian features • dystonic posturing

17. FTD-PATHOLOGY • Pick’s bodies, Tau positive • Ballooned neurons • Spongiosis in the cortex • No cholinergic deficiency • Serotonergic deficiency

18. FTD-GENETIC ASPECTS • Dominant inheritance • Early onset; 45-65 years of age • Gene alteration on chromosome 17 • Tau protein gene, contains 14 exons • Exons 9,10,11 and 12 code for microtubule binding sites

19. FTD-MOLECULAR BASIS • M-RNA is subjected to post transcription splicing • Alternative splicing of exons 2, 3 and 10 results in 6 different Tau isoforms • Mutations cause increase incorporation of exon 10: 4 repeat Tau • Aggregation of 4 repeat tau causes neurotoxicity and apoptosis

20. FTD, genetic causes cont. • Progranulin, chromosom 17 seen in 13% of cases • Vasolin Containing Protein (VCP) • Charged Multi-vesicular Body Protein (CHMP2B)

21. PARKINSON DISEASE • Decrease in motor agility/speed • resting tremor • rigidity

22. PD-PATHOLOGY • Substantia nigra inclusion bodies: Lewy bodies, positive for alpha-synuclein • Neurochemistry: Dopaminergic Deficiency

23. PD-GENETIC CONSIDERATIONS • Park 1 gene; chromosome 4, codes for Alpha-synuclein • Park 2 gene; chromosome 6:Parkin gene

24. MISELANEOUS DEMENTING DISORDES • PSP: Taupathy • MSA: Alpha-synucleinopathy • DLBD: Alpha-synucleinopathy

25. TREATMENT STRATEGIES • Decrease gene expression • decrease protein aggregation • Free radical scavenger • Anti-inflammatory medications • Nerve growth factors • Gene therapy

26. Case one 45 y/o woman Looks depressed no longer takes interest in reading the paper or doing the cross word puzzles Is irritable and anxious Paces and night Makes frequent errors at work, decreased efficiency Has to double check her work repeatedly and needs reminders

27. Case 1 • What is the best way of managing this patient? • Psychiatric eval for depression • Neuropsych eval • Start an anti-depressant agent • Spinal tap to r/o herpes encephalitis

28. Exam • MMS score is 30 • Flat affect, abulic and indifferent • Deceased verbal fluency • Obsessing over thoughts • Normal CN and motor exam

29. Case 1, cont You sent the patient for a neuropsych eval. What is your prediction about the results? • Global intellectual dysfunction • Frontal lobe dysfunction • Anxiety and depression • Conversion disorder

30. Case 1, cont • How would you treat this patient? • With a memory enhancer • With a SSRI • With a sleeping agent • With an anti psychotic

31. Case 2 • A 40 year old woman c/o poor memory and concentration • Education back ground: 10th grade, “average student” • Employed on and off • Makes frequent errors and needs reminders • Feels very anxious and depressed • Unable to sleep at night • Has a normal exam

32. Case 2, cont • what is the best way of managing this case: • MRI of brain • Neuropsych eval • LP • None of the above

33. Case 3 • A 58 y/o man c/o decreased memory • Has trouble finding his way when driving • Feels depressed and worried • Has lost 10 lbs in a year

34. Case 3, cont • Physical exam • MMS score is 27, recall 0/3 • Normal language • Normal CN and motor

35. Case 3, cont • What is the best way of managing this case? • MRI of brain • Neuropsych eval • EEG • LP

36. Case 3, cont • What would you prescribe for this patient? • A memory enhancer • An anti-depressant • Namenda • All of the above