Objective Aging and neurodegenerative diseases Common neurodegenerative diseases Pathogenesis Treatment strategies based on basic-science

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1 Effect of Aging on Nervous System From Basic Neuroscience to Clinical Practice: Neurodegenerative Diseases Associate Professor Somsak Tiamkao Division of Neurology, Department of Medicine Faculty of Medicine, Khon Kaen University Old mens are boys again Tremulous hand and voices Stoop posture Slow Shuffling step Objective Aging and neurodegenerative diseases Common neurodegenerative diseases Pathogenesis Treatment strategies based on basic-science Collaborate Research Good Quality of Life Neurological Signs of Aging Eye signs: smaller pupil, hyperopia, dark adaptation Progressive hearing loss Diminution in the sense of smell, taste Reduced motor sign Reflex change Stance, posture, gait Cognitive function, learning, memory Physiologic and Anatomical Deterioration Age-Related Diseases Brain weight Blood flow to brain Cardiac output at rest Number of fiber in nerves Number of taste buds Power of hand grip Percentage decrease Cerebral atherosclerosis: stroke Brain tumor Infection Adverse drug reaction Falls Degenerative disease: AD 1

2 Degenerative:definition Decline from a previous level of normalcy to a lower level of function Gowers in 1902 suggested term "abiotrophy" Abiotrophy meant a lack of "vital endurance" resulting in their premature death. Degeneration refers to a more rapid process of neuronal, myelin, or tissue breakdown General Clinical Characteristics Begin insidiously, after a long period of normal nervous system function, and pursue a gradually progressive course that may continue for many years, often a decade longer. 2

3 B. Circumscribed cerebral atrophy 1. Pick disease (lobar sclerosis) 2. Mesolimbocortical dementia of non- Alzheimer type 3. Thalamic degeneration Neurodegenerative Disease Generalized degenerative disease Restricted degenerative disorder Gait and motor impairment: NPH Falls: postural reflex impairment Tremor Blepharospasm II Syndrome of progressive dementia in combination with other neurologic abnormalities A. Huntington chorea B. Other(nonhuntingtonian) types of chorea C. Cortical striatal-spinal degeneration (Jakob) and the dementia-parkinson-amyotrophic lateral sclerosis complex (Guamanian and others) D. Cortical-basal ganglionic degeneration Classification I. Syndrome of progressive dementia, other neurologic signs being absent / inconspicuous A. Diffuse cerebral atrophy 1. Alzheimer disease 2. Diffuse cerebral cortical atrophy of non-alzheimer type 3. Some cases of Lewy-body dementia E. Dentatorubropallidoluysian degeneration F. Cerebrocerebellar degeneration G. Familial dementia with spastic paraparesis or myoclonus H. Lewy-body disease I. Polyglucosan body disease 3

4 III. Syndrome of disordered posture and movement A. Parkinson disease B. Striatonigral degeneration with or autonomic failure (Shy-Drager syndrome) and olivopontocerebellar atrophy (multiple system atrophy) C. Progressive supranuclear palsy D. Dystonia musculorum deformans (torsion spasm) C. Complicated cerebellar ataxias 1. Olivopontocerebellar degeneration with or without basal ganglia degeneration (multiple system atrophy) 2. Gerstmann-StraÜssler-Scheinker disease 3. Machado-Joseph disease 4. Other late-onset, autosomal dominant and sporadic ataxias D. Paraneoplastic and alcoholic-nutritional cerebellar degenerations E. Hallervorden-Spatz disease F. Restricted dystonias including spasmodic torticollis and Meige syndrome G. Familial tremors H. Multiple tic disease I. Acanthocytic chorea V. Syndrome of slowly developing muscular weakness and atrophy (nuclear amyotrophy) A. Without sensory changes: motor system disease 1. Amyotrophic lateral sclerosis 2. Progressive spinal muscular atrophy 3. Progressive bulbar palsy 4. Primary lateral sclerosis 5. Hereditary forms of progressive muscular atrophy and spastic paraplegia IV. Syndrome of progressive ataxia A. Predominantly spinal forms of hereditary ataxia 1. Friedreich ataxia 2. Non-Friedreich ataxia(with retained reflexes,hypogonadism, or myoclonus) B. Pure cerebellar forms of hereditary ataxia 1.Holmes familial cortical cerebellar atrophy 2.Late cerebellar cortical atrophy of Marie-Foix- Alajouanine B. With sensory changes 1. Hereditary sensory neuropathies 2. Hereditary sensorimotor neuropathiesperoneal muscular atrophy (Charcot-Marie- Tooth); hypertrophic interstitial polyneuropathy (Déjerine Sottas): heredopathia atactica polyneuritiformis (Refsum); etc 4

5 VI. Syndrome of spastic paraplegia without amyotrophy A. Hereditary spastic paraplegia B. Primary lateral sclerosis The prevalence of dementia in elderly was 9.8 VII. Syndrome of progressive blindness or ophthalmoplegia with or without other neurologic disorders A. Hereditary optic neuropathy (Leber) B. Pigmentary degeneration of retina (retinitis pigmentosa) C. Stargardt disease D. Progressive external ophthalmoplegia with or without deafness or other system atrophies (Kearns-Sayre syndrome) D E M E N T I A D : Degenerative (AD), drugs E : Endocrine M : Metabolic E : Epilepsy N : Neoplasm, nutrition D E M E N T I A T : Toxic, trauma I : Infection, inflammation, infarction A : Atherosclerosis, alcohol VIII. Syndrome characterized by neurosensory deafness A. Pure neurosensory deafness B. Hereditary hearing loss with retinal disease C. Hereditary hearing loss with system atrophies of the nervous system Differential diagnosis; 2D 4A D epression D elirium A phasia A gnosia A nxiety A mnesia 5

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7 ก ก (3 ) 3 ก ก (1)... (1)... (1) Vascular Dementia White matter disease Lacuna infarction B Neuroimaging helps differentiate AD AD + CVD VaD VaD and AD PET scan in Vascular Dementia VaD AD+CVD AD Many patients have overlap of AD and significant CVD The clinical overlap is referred to AD+CVD Healthy Brain Predominance of Large Infarcts Images courtesy of Michael Mega, UCLA. 7

8 Projecting cholinergic systems in the brain An important characteristic of the cholinergic neurons of the basal forebrain is their dependence on nerve growth factor (NGF). They synthesize the nerve growth factor receptor (TrkA receptor) and transport it to their terminals in the cerebral cortex Effect of NGF and pro-ngf on cell survival Cholinergic regions in basal forebrain AChE staining Normal Cellular and Molecular Neurobiology 2006; Aug 31 Epub ahead of print Cholinergic depletion and amyloidogenesis may be 2 interactive processes in AD ACh increases NGF production by cortical neurons Cerebral cholinergic projections from human basal forebrain Selden et al. Brain (1998) NGF then binds to TrkA receptors and is transported retrogradely to the cell bodies of NBM where it exerts a neurotrophic effects. NGF increases nonamyloidogenic processing Aβ42 interfere with NGF signaling. 8

9 Target for ChEIs treatment Volumetric MRI Effect of Nicotinic Stimulation on Working Memory MCI MRI results Galantamine Placebo Rate of Brain Atrophy (%/y) * Total Population* Males Females *p = p < p = *Placebo (n=142), galantamine (n=127), p= Placebo (n=59), galantamine (n=70), p< Placebo (n=83), galantamine (n=57), p= Neuroprotective effects of galantamine Trophic factor dependency of cholinergic neurons Pro-NGF increase, NGF decrease in AD Pro-NGF is cleaved to NGF by tpa, plasminogen and Timp1 which are decreased in AD NGF binds with TrKA receptors which is expressed in basal forebrain cholinergic neurons (trophic effect) Atrophy of nucleus basalis of Meynert (NBM) in AD Bruno & Cuello PNAS 2006 Brain Res Bull 2005;64:

10 Cholinergic Circadian Rhythm High nocturnal ACh sleep-related AEs wakefulness 1 nightmares 2 sleep medication 3 memory consolidation AChE inhibition therapies should support cholinergic circadian rhythm AChE = acetylcholinesterase; AE = adverse event 1. Saint-Mleux B, et al. J Neurosci. 2004;24: Pagel JF. Hum Psychopharmacol. 2003;18: Stahl SM, et al. J Clin Psychiatry. 2003;64: Fig. Structure of mitochondrion The Galantamine ER - Pellet Based ER Capusle 25% as Immediate release Rate controlling membrane 75% as Extended release Sugar sphere Fig. The ubiquitin proteasome system Galantamine PRC: Low nocturnal ACh Proteins that have a function in major neurodegenerative diseases with mitochondrial involvement 80 0,6 Drug concentration (ng/ml) Donepezil 10 mg/d GAL PRC 24 mg/d GAL IR 2 x 12 mg/d ACh release Low levels needed 8 AM 11 AM 2 PM 5 PM 8 PM 11 PM 2 AM 5 AM Clock time 0,4 0,2 0 ACh release (pmol/min) Davis B, Sadik K. Dement Geriatr Cogn Disord. 2006;21:

11 Mitochondrial involvement in less common neurodegenerative disease Parkinson s Disease Substantia Nigra Parkinson s Disease Aetiology of Parkinson's disease Environmental or endogenous toxins Aetiology Single or multiple genes Pathogenesis free mitochondrial iron oxidative protein radicals dysfunction stress aggregation Parkinson's disease(s) 11

12 A. Normal Motor Circuit B. Motor Circuit in PD C. Motor Circuit In PD with Levodopainduced Dyskinesia CORTEX CORTEX CORTEX PUTAMEN PUTAMEN PUTAMEN SNc SNc Implanted Components DA DA SNc GPe GPe GPe VL VL STN STN VL STN GPi GPi GPi SNr SNr SNr PPN PPN PPN Excitatory Inhibitory C W Olanow, J A Obeso et al. TINS Supplement Surgery in Parkinson s disease Substantia nigra axial Instruments T2W FSE coronal Deep Brain Stimulation Off On 12

13 Amyotrophic Lateral Sclerosis 13

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15 Thank you The Kynurenine pathway 15