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Neurodegenerative Disease (Alzheimers Disease (Experimental treatments for…
Neurodegenerative Disease
Dementia-
Loss of Mental power,
Generic term not a disease
Other forms of dementia
Vascular dementia (associated with stroke)
Frontotemporal dementia
Reversible causes-thyroid problems, vitamin deficiencies
Chronic traumatic encephalopathy-repeated traumatic brain injury
Dementia with lewy bodies
Down Syndrome Duplication of genome -Duplication of genome 21
Huntingtin Disease (HD)
Initially quick movements of feet or hands / Emotional ,cognitive and movement disturbance Dyskinesia involuntary movement -clumsiness
Brain regions- Primary neurons of striatum (caudate nucleus and putamen) , Also a deep layer cortical neurons , thalamus,white matter changes, larger ventricles
Genetic disease autosomal dominant transmission.Caused by the mutation of the HTT gene, Normal HTT involved in brain development intracellular vesicular trafficking, mitochondrial function, but exact roles remain unknown.
Very large gene with 67 exons and large protein >3000 amino acids
Normal HTT fewer than 36 glutamine encoding
CAG
trinucleotide protein
Mutant greater than 36 CAG repeat in exons ,Association shows that length of CAG =year you will develop it and longer COG shows an earlier death
Current Treatments Only mask symptoms
Tetrabenazine
(FDA approved) symptomatic treatment of hyperkinetic movement -Likely depletion of dopamine, serotonin and noradrenaline, however, there are many sides effects
Antipsychotics-
Haliperoid suppress movement may worsen involuntary contracts and muscle rigidty
Antidepressants
-protzac
Psychotherapy,speech
therapy,physical therapy assitive devices
Clinical Trials
IONIS HTTRX-a
ntisense oligonucleotide (ASO)
drug to decrease the production of huntingtin protein, binds to HTT MRNA stimulating degradation. Injection into CSF lumbar puncture, Randomized, placebo controlled dose-escalation study-intrathecal injection into CSF
Alzheimers Disease
APOE (apolipoprotein E) lipoprotein metabolism
APOE - three isoforms (e2,e2,e4)
E4 gene polymorphism most significant risk of developing AD
IN familial diseases; Rare dominantly inherited mutations- Eg. Presenlin
Experimental treatments for AD
No disease modifying drug avaliable
Recent trials of antibodies against amyloid Beta. Solanezumab Phase 1 trial showed well tolerated, no evidence, no clinical benefit minor changes. Future direction detect changes before they get the disease.
Mild Cognitive impairment -Identification before they have dementia. Reversible, possible linked with traumatic brain injury and other environmental factors. Controlling cardiovascular says disease (HBP), mental stimulating task, social engagement.
Parkinson Disease
Brain regions and changes involved in PD: Substantia nigra pars compacta (SNpc) dopaminergic nuerons loss, Indirect control of fine movements and initiation of movement SNPC dopamine release to nueron of striatum.
Characteristics intracellular LEWY bodies alpha synucelin protein
Alpha-Synuclein
synaptic and nuclear protein, primarily expressed in brain comprises up to 1% of all neuronal proteins
Envionmental causes of PD
MPTP 1methyl 4 pehny 1236 tetraphydoriline used in animals to model PD. It has the same chemical compound as herbicide paraquat one of most commonly used herbicide.
Disrupts electron transport chain of mitochondria, in plants but also in animals,Exposure 2* increased risk of PD (meta-analysis)
Treatment of PD
Dopamine replacement Levadopa, Block doapmine breakdown- MA)-B inhibitors (eg.selegiline) ,Blocks glutatmate allowing increased dopamine release ,dopamine mimics ,releieve symptoms but only temporary and does not prevent disease progression
Deep brain stimulation Electrode in brain can improve tremors,rigidity, reversible
Injection of fetal neural grafts for P, inject into the substantia niagra of PD patients but pathology spread from patients to patients
Spreading of Pathology in PD
Potential general mechanism in neurodegenerative diseases,Antibodies are used to target pathology spread antibodies against alpha synuclein in current phase 1/2 trial
FTD Frontal temporal dementia
Three Subtype of FTD
Behavioural- 60% of FTD disinhibition, apathy, loss of empathy, mood change
Semantic dementia -ability to speak preserved but meaning lost
Progressive non-fluent aphasia (PNFA) -Aphasia deterioration of language
Progressive, personality, behaviour and or language disturbance
FTD genetics
Most common genetic form is mutation in the
C90RF72 gene
Altered RNA -> Accumulate in neurons, abnormal translation of repeat resulting in accumulation of GA-,GP-,GR-,PA-,PR- deptide protein.These protein form pathological inclusion in nuerons.
FTD pathology
TAU protein -Similar to AD pathology but without anyloid beta
FUS
TDP-43 -similar to MND but primary in the brain
Motor Nueron disease
Upper-increased toned brisk reflexes
Lower-weakness, wasting ,fasciculations
Spinal onset- arm and leg , bulbar onset- 25%(speech and swallowing, faster progression)
Leads to paralyis
Only one approved drug -riluzole
Only extends life but no benefit in individual quality of life
Death through respirattion
Primary culprit is TDP-43 - ubiquitous nuclear RNA /DNA-binding protein
TDP43
Forms inclusion
UBiquintiated
Becomes cytoplasmic
Phosphorylated
Cleaved
Design better MND mouse models, Doxycycline- suppresiible neuronal specific cytoplasmic-targeted (NLS mutant)
htDP-43
RNLS mice
Brain spinal cord expression
High level of cytoplasimic TPD-43
Accumulation of phopho TDP43
Nuerodegeneration
Development of disease phenotype