Common causes of dementia

Transcription

1 Common causes of dementia Alzheimer s disease vascular (multi-infarct etc.) dementia dementia of Parkinsonism Huntington s disease Pick s disease Creutzfeldt-Jacob disease etc.

2 DEGENERATIVE DEMENTIA Pick s - bodies FRONTOTHEM- PORAL DEMENTIA VASCULAR DEMENTIA Non-specific histological changes (D. Knopman, 1999) ALZHEIMER S DISEASE LEWY S BODIES Dementia in Parkin s disease

3 PLAQUES AND TANGLES beta-amyloid plaques are amorphous extracellular deposist of beta-amyloid protein intra- neuronal - neurofibrillary tangles = comprising filaments of a phosphorylated form of microtuble-associated protein (Tau) Beta-amyloid plaques Neurofibrillary tangles

4 Neurons have inner supporting structure partly formed by microtubules. Tau protein helps to stabilisate the microtubules. In Alzheimer s disease, tau is more phosphorylated, this tau does not bind on microtubules and the microtubules are colapsing. Neurofibrillar tangles

5 Alzheimer s disease (AD) in 50-60% pacients with dementia; women are affected twice as often as men after the age of 70 years damage of neurons particularly in hippocampus and parietal lobe multigenetic factor (extracellular placks of agregated betaamyloidu increased influx of Ca2+ into the neurons mechanisms of neurotoxicity) the cholinergic activity is affected the most most important for cognitive and memory functions.

6 BRAIN NORMAL ALZHEIMER S DISEASE

7 Pet Scan of normal brain Pet Scan of the brain in Alzheimer s disease

8 (OLD) AGE GENETICS ENVIRONMENT, SOCIETY β-amyloid PHOSPHORYLATION of TAU OXYGEN FREE RADICALS FAILURE of TAU GENETICS NERVOUS CELL DISORDER DEMENTIA

9 Signs of AD progressive global memory loss parietal lobe functional abnotmalities of spatial orientation deteriorating social skills, loss of drive, initiative and intelect depression, anxiety, aggression, emotional lability, unconcern, agitation sleep disorders

10 Drugs in Alzheimer s disease Cognitive drugs: inhibitors of acetylcholinesterse (donepezil, rivastigmin, galantamin; fysostigmine) inhibitor of NMDA glutamate receptors (memantin) Prekursors of acetylcholine (ACH) (lecitin); Improvement of utilising of the precursors of ACH (acetyl-lkarnitin); Agonists of cholinergic receptors (pilokarpin, arekolin, milamelin, xanomelin) Nootropics: piracetam meklofenoxate pyritinol Brain vasodiatators (dihydroergotamin, flunarizin, cinnarizin) Further: Neurotropic growth factors Antiflogistics Inhibitors of Ca2+ chanells Antioxidants Atypical neuroleptics (risperidon, tiaprid)

11 AChEI even if the mechanisms of effect are different, the effctiveness is comparable donepezil AChEI non-competitive, reversible 4-6 week step (5, 10) rivastigmine AChEI, BuChEI noncompetitive, reversible 2 week steps (1.5, 3, 4.5, 6) galantamine AChEI competitive, reversible; nachr allosteric modulation 4 week steps (4, 8, 12)

12 EFFECTS AND METABOLISM OF ACETYLCHOLINE Presynaptic nervous ending RECEPTORS Astroglia ACh N = nicotinic M = muscarinic BuChE ACh = acetylcholinergic BuChE M receptor N receptor RIVASTIGMINE AChE ACh AChE GALANTAMINE Postsynaptic nervous ending

13 MECHANISM OF MEMANTIN EFFECT non-competetive inhibitor of NMDA receptors with low up to middle affinity, fast kinetic, dependent on membrane potential it blocks abnormal effects of glutamate activity, which could lead to neuronal cells damage and cognitive dysfunctions it keeps the physiological activation of NMDA receptors necessary for learning and memory Source: Danysz W, et al. Neurotoxicity Res. 2000;2:85-87.

14 PATHOLOGICAL ACTIAVTION OF NMDA RECEPTORS Abnormal quiet state Disturbance of impuls transfer Chronic neurodegeneration Buzz Signal Buzz Signal not registered Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist a review of preclinical data, pages , copyright 1999, with permission from Elsevier. Glutamate Magnesium Calcium

15 MEMANTINE BLOCKS PATHOLOGICAL ACIVATION OF NMDA RECEPTORS Abnormal quiet state Memantine blocks pathological activation Memantine improves signal registration Ca 2+ M Ca 2+ Buzz Buzz M Signal Buzz Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist a review of preclinical data, pages , copyright 1999, with permission from Elsevier. M Glutamate Magnesium Calcium Memantine

16 SAFETY and TOLERANCE of MEMANTINE no clinically important differences between memantine x placebo groups in: adverse effects physiological parameters laboratory results EKG Memantine in dosis 20 mg/day is comparably safe with placebo well tolerated for treatment of Alzheimer s disease memantine is well tolerated in combination with inhibitors of ACHE

17 Average change in SIB from the initial degree Memantine+Donepezil in severe and very severe Alzheimer s disease P=.06 P=.03 P<.001 P=.006 *P<.001 P<.001 Memantine+Donepezil Placebo+Donepezil End n = n = weeks *OC analysis. LOCF analysis. Adapted from Tariot P, et al. JAMA. 2004;291: Improvement Impairment

18 ANTI-AMYLOID S DRUGS this approach - more promising than really effective by now LY inhibitor of -sekretasis, danger of inhibition of Notch signal, short life-time R-flurbiprofen selective inhibitor of - sekretasis, which dicreases the amyloid A - 42 tramiprosate inhibits the binding of A and heparine, which induces the aggregation into fibrils, lowers soluble A and plaques

19 Phases of dementia MILD MODERATE SEVERE TERMINAL I N D E P E N D E N C E MEMORY PERSONALITY SPATIAL DISORIENTATION APHASIA APRAXIA CONFUSION AGITATION INSOMNIA RESISTIVENESS INCONTINENCE EATING DIFFICULTIES MOTOR IMPAIRMENT BEDFAST MUTE DYSPHAGIA INTERCURRENT INFECTIONS TIME

20 THE AIMS OF TREATMENT OF DEMENTION I N D E P E N D E N C E QUALITY OF LIFE DIGNITY WELL BEING TIME

21 Huntington s disease hyperkinetic disorder abnormal momevements of some muscle groups (chorea) neuropatological changes are most remarkable in basal ganglia; the worse neurodegeneration in cholinergic and GABA-ergic neurons; dopaminergic activity is increased (due to GABA disinhibition) the movement disorders are combined with demetia; most common in the age of years; genetics - autosomal dominant gene (protein huntingtin helps to the processes of excitotoxicity a apoptosis)

22 Drugs in Huntington s disease Neuroleptics (antidopaminergics on specific receptors) but dementia is not touched using this treatment (dementia probably through affected cortical neurons) Depletion of dopamine: (BUT serious adverse effects! - depression, hypotension) Reserpine Meserpine Tetrabenazine Central muscle relaxants decreasing of motoric symptoms: Baclofen Drugs decreasing excitotoxicity slow the progression of dementia