Neuroscience and control
What is Alzheimer’s disease
- irreversible disorder
- leading cause of dementia
- Not the same as dementia
Hallmarks (AD)
- Brain atrophy
- Extracellular aggregates of amyloid β (Aβ) plaques
- Neurofibrillary tangles
Pathophysiology of brain atrophy (AD)
- large ventricles
- shrinked cortex and hippocampus
Pathophysiology of Amyloid-beta plaques (AD)
- Mutation gene in APP and PSEN 1/2
- APP gets cleaved by beta and gamma-secretase
- Amyloid-beta is hydrophobic, sticky and aggregates extracellularly
- Disrupt synaptic signal
- AB42 (most pathogenic form)
- Triggers neurofibrillary tangle formation
Pathophysiology of Neurofibrillary tangles (AD)
- Tau is a protein in microtubules
- kinase hyperphosphorylates Tau (due to AB plaques)
- changes form, gets sticky and clumps outside the microtubules (tangles)
Symptoms of AD
- First: mild cognitive difficulties
- Early stage: increasing impairment of learning and memory
- Middle stage: progressive deterioration (dependent)
- Late stage: complete dependence on caregivers
Biomarkers of AD
- MRI: Hippocampal decrease
- PET-scan: AB deposition levels increase
- CSF: Decrease of AB42 and increase tTau and pTau
Genetics in AD
- Autosomal dominant disease
- Faster progression
- Mutations in genes:
- - APP
- - PSEN 1 or 2
- APOE4 allele (strongest, related to LOAD)
Diagnosis of AD
- MMSE-score: in MCI, starts with plaques
- Helps differentiate types of dementia
Treatment for AD
- Antidepressants
- Antipsychotics
- Cholinesterase inhibitors
- Increasing ACh in the brain
- block certain receptors
- Ab that attack the plaques
- Behavioural therapy
What is Glaucoma and Secondary Glaucoma?
- eye conditions that damage the optic nerve due to intraocular hypertension
- isn’t always associated with elevated intraocular pressure
- irreversible vision loss
- Secondary Glaucoma:
-- prolonged use of steroids
-- severe restrict blood flow to eye
2 types of Glaucoma
- Open-angle:
-- Most common (drainage gets clogged over time)
-- Area between iris and cornea (open)
-- Decrease in peripheral vision and later decrease in central vision
-- Risk factors (Age, Myopia, Family history)
- Closed-angle:
-- Drainage gets rapidly blocked (lens pushes against iris)
-- symptoms (Severe pain, Redness, Blurry vision)
-- Risk factors (Age, Female, Hyperopia)
Hallmarks of Glaucoma
- Loss of retinal ganglia cells (degeneration of axons due to pressure)
- Thinning of retinal nerve fiber (main biomarker)
- Cupping of the optic disc (rim diameter increases, ISNT rule)
Symptoms of Glaucoma
- Tunnel vision
- optic nerve changes (increased Cup-to-Disk ratio)
Biomarkers in Glaucoma
- IOP pressure
- Cup-to-Disk ratio
Diagnosis of glaucoma
- Vision field test
- Measure of intraocular pressure
- Examination of optic nerve
- Cupping
Treatment of glaucoma
- Medication to decrease levels of Aqueous humor
- Increase outflow
- laser surgery
What is Parkinson's disease
- most common form of Parkinsonism
- characterized by rigidity, slowness, and tremor
- Dopaminergic loss in SNc (substantia nigra pars compacta)
Hallmarks of PD
- Dopaminergic neurons loss (in substantia nigra, no dopamine in basal ganglia, no initiation of movement)
- Alpha-synuclein (protein) misfolding (in substantia nigra, A-synuclein folds into alpha-synuclein, that aggregates, becomes sticky and arrogates, Oligomers -> fibrils, and becomes Lewy bodies, they travel through CNS targeting unmyelinated neurons)
What is the Braak Hypothesis
- 6 stages
- (1-2) rapid eye movement sleep disorder
- (3-4) stage of diagnose, progression to SNc, rigidity, tremor and slowness
- (5-6) progresses to cerebral cortex, cognitive impairment and hallucinations
2 central protein clearance systems in PD
- UPS (mutation in PARKS2 gene that affects the catalytic activity of UPS)
- Autophagy-lysosome pathway (mutation on GBA1 gene encodes β-glucocerebrosidase)
- Serotonin, ACh Norepinephrine system
Symptoms of PD
Motor: (Bradykinesia, Rigidity, Tremor)
Non-Motor: (Olfactory loss, Sleep disorder, Cognitive impairment)
Note: when half of neurons in substantial nigra die, motor signs and PD appear
Biomarkers in PD
- PET-scan (presynaptic dopamine neuronal dysfunction)
- MRI (help differentiate from other Parkinsonism's)
- CSF (tTau, pTau and 𝛂-synuclein)
Risk factors in PD
- Age (+60)
- Environment
- Genetics (mutations in PARK genes, and GBA1 the most important)
- living in Europe or South Africa
Diagnosis of PD
- Family history (look at the symptoms)
- Physical examination
- Need to meet at least 2 of 4 supportive criteria:
-- 1. Rest tremor
-- 2. Dramatic improvement with dopaminergic therapy (e.g.,
carbidopa- levodopa)
-- 3. Presence of levodopa-induced dyskinesias
-- 4. Presence of either olfactory loss or cardiac sympathetic
denervation
treatment for PD
- Dopamine-based therapies (Levodopa)
- Cholinesterase inhibitors for cognition
- Levodopa-carbidopa (carbidopa prevents levodopa breakdown)
- DBS
Relation between AD and PD
- Increased 𝜶-synuclein expression triggers hyperphosphorylation of Tau and is also in some cases associated with amyloid-β plaques formation
What is vascular dementia
- series of minor strokes causing vascular cognitive impairment (VCI)
- complex interaction of cerebrovascular disease and risk factors that lead to changes in brain structures due to strokes and lesions
Risk factors of Vascular Dementia
- age
- hypertension
- Diabetes
- genetics
- smoking
what are microhemorrhages?
- Ruptures of small brain vessels in basal ganglia or subcortical white matter
Mechanisms of the Blood Vessel Damage Induced by Vascular Risk Factors
- Endothelial dysfunction, impairment of autoregulation, and dysfunction of neurovascular coupling
- Meditated by oxidative stress and NO deficits that lower the CBF and cause hypoxia and hypoperfusion
- EC dysfunction leads to higher BBB permeability, making plasma proteins pass (Fibrinogen)
- Fibrinogen activates CD11b and TLR, producing ROS and proinflammatory cytokines from activated microglia, astrocytes, and OPC.
- Inflammation leads to more BBB breakdown, making molecules adhere to EC, contributing to microvascular occlusion
Pathophysiology of vascular dementia
- Atherosclerosis forms in arteries (build-up of plaque in their walls)
- Parts of plaques break down and can completely block smaller arteries
- Leads to a decrease in CBF (chronic ischemia) that can lead to an ischemic stroke.
- Dead tissue liquefies (liquefactive necrosis)
- Leads to loss of mental function and a series of strokes
- Result: Dementia
Relation between AD and vascular dementia
- BBB disruption (vascular damage)
- Impairs the Aβ clearance and is followed by its accumulation in the brain and to higher vascular and neuronal toxicity (they deposit around blood vessels - amyloid angiopathy - leading to blood loss)
- This leads to NVC dysfunction
- Reduction in CBF (chronic cerebral hypoperfusion)
- This pathomechanism leads to Vascular dementia
What can cause vascular dementia
- Ischemic infarcts
- Hemorrhagic infarcts (affects multiple brain areas)
To what leads the major vascular risk factors
- endothelial dysfunction and damage (leads to reduced NO and secrete toxic factors that lead to cognitive impairment )
- Smooth muscle degeneration and dysfunction pericytes (leads to BBB breakdown)
Symptoms of Vascular dementia
- Cognitive impairment
- Motor
- Behavioral
- Hemiparesis
- Bradykinesia
- Ataxia
- Swallowing difficulties
Risk factors in Vascular dementia
- Age (+75)
- Female
- Hypertension
- Diabetes
- Mutations in APOE4 (strongest risk factor)
Biomarkers in vascular dementia
- MRI (CBF and WMH on brain)
- PET-scan (CBF changes that reflect NVC)
- Fluid (Album levels high pass BBB)
Treatment of vascular dementia
- Cholinesterase inhibitors
- Calcium channel blockers
- Adrenergic antagonists (lower blood pressure)
What is Multiple sclerosis
- Chronic, inflammatory disease of the CNS
- Most common autoimmune disease
- Myeline of neurons is damaged (disrupts signals and leads to physical, mental, and psychiatric problems)
- 2 forms:
-- Relapsing form (Isolated attacks)
-- Progressive form (building up over time)
- Caused by:
-- auto-immunity that reduces myelin production
What are the 4 types of MS?
- Clinically isolated syndrome (CIS)
The first neurological attack caused by inflammation (demyelination). Not fulfill MS criteria
- Relapsing-remitting MS (RRMS)
Most common MS. Unpredictable relapses followed by months or years of remission. The attacks leave problems. Weakness, Altered sensations, impaired vision during the relapse. Remitte is where remyelination happens.
- Primary progressive MS (PPMS)
10-20% of patients. No remission. Progressive disability. Around 40 years age.
- Secondary progressive MS (SPMS)
Progressive neurological decline. 65% of those who had RRMS in approx 19 years. Persistent inflammation and neurodegeneration of mitochondrial dysfunction and consequent axonal damage
Mechanism of inflammation in MS
- Caused by Th1 and Th17 cells
- MMPs disrupt BBB and let T-cells pass and attack myelin and reduce neuronal transmission
- Th1 (IL1, IFN-𝛄, TNF-𝜶) Th17 (IL17)
- Cytokines stop neurotransmission and disrupt more BBB
- letting more T-cells enter CNS and recruiting macrophages and B-cells
- B-cells produce Ab-myelin and pro-inflammatory cytokines
- macrophages destroy oligodendrocytes
- without myelin, leaves behind areas of scar tissue (plaques/sclera)
- afterward, Treg inhibits immune cells and reduces inflammation and the remyelination happens
- Over time remyelination stops (irreversible axonal loss)
How do T-cells pass the BBB in MS?
- Tethering (Lymphocytes interact with molecules on EC P-selectin)
- Rolling (rolling beside the vessel wall–a transient, reversible process)
- Adhesion (after coupling with the EC, lymphocytes pass BBB by paracellular, T-cells alter occludin and claudin in TJ to pass, or transcellular, they alter the inflamed BBB and make a pore)
what are the symptoms of MS?
- double vision
- Dysarthria
- Dysphagia
- Ataxia
Risk factors of MS
- Toxins
- Genetics
- Infection
- living in the north (lack of Vit D)
- Increased risk after giving birth
Biomarkers in MS
- MRI (T1 active inflammation, T2 lesion load)
- DIR
- CSF (increased IgG, IgM OCBs)
Genetics in MS
- ID2 and 4 (negative regulators are highly expressed, and OPCs can't differentiate)
- APOE4 (high risk)
- HLA DR2 (genes in chromosome 6 for MHC in macrophages, DC, and B-cells that exaggerate IR)
Diagnosis of MS
- signs and symptoms
- McDonald criteria (most used. MRI)
- CSF (inflammatory products)
Treatment of MS
Goal: returning function after an attack, preventing new attacks, and preventing disability
- Physical therapy
- Occupational therapy
Pharmacology (recommended when more than 2 lesions are seen in MRI)
- IV Corticosteroids (during acute symptomatic attacks)
- Monoclonal Ab therapies (for PPMS)
Pathophysiology of Autoimmune encephalitis (surface proteins)
NMDAR encephalitis (IgG1)
-- IgG Ab anti-GluN1 subunit of NMDAR
-- Receptor cross-linking and internalization
-- Reversible, but untreated causes permanent destruction
-- Affects Hippocampus
-- Average 21 years, female dominant, 58% have ovarian teratoma
-- Symptoms: insomnia, seizures, dyskinetic movement, Psychiatric, hallucinations.
-- Diagnosis: MRI (shows FLAIR), CSF (Ab)
LGI1 (IgG4)
-- alter protein-protein interaction
-- affects the voltage-gated potassium channels
Anti-mGluR1
-- G-protein coupled glutamate receptor
-- Reduce basal neuronal activity
-- Block induction of LTD in Purkinje cells
-- Activate EC in BBB
-- Kill neurons with excitotoxicity, apoptosis, and/or complement fixation
-- Ataxic behavior
-- Affects cerebellum
Pathophysiology of Autoimmune encephalitis (intracellular)
- associated with underlying malignancy
- T-cell mediated encephalitis (not Ab-mediated)
- Decreased response to immunomodulatory therapy
Anti-Hun (most common)
Symptoms of AE
- change in behavior
- psychosis
- seizures
- memory and cognitive deficits
- dysautonomia
risk factors of AE
- Women
- Younger age
- Viral infection (herpes simplex can trigger anti-NMDAR)
- Teratoma (paraneoplastic syndrome)
- Genetics
-- not appear to run in family
-- Anti-LGI1 (HLA class II genes)
Treatment of AE
- corticosteroids
- Immunosuppressant
- Acute Immunotherapy
- Surgery (remove tumor)
- Plasma exchange
Pathogenesis of AChR in MG
2 mechanisms:
1.
- IgG1 and IgG3
- They cross-link AChR and internalize and degrade them
-- AChR degradation (Antigenic modulation )
2.
- IgG1 and IgG3 bind to C1q
- activates classical pathway of complement system
- Formation of MAC (membrane attack complex)
- Dense clustering of AChRs allows interaction of IgGs Fc regions (hexamers of IgG)
- C3a and C5a attract monocytes and neutrophils, blocking synaptic transmission (facilitates antigenic modulation)
Thymus has an important role in AChR-MG
- Mature T-cells with MHC leave the thymus
- AIRE (autoimmune regulator) initiates transcription of self-antigens
- can develop thymoma (50% develop AChR-MG) common in age +50
Pathogenesis of MuSK and LRP4 in MG
MuSK-MG:
- IgG4 (Bispecific, but monovalent)
- Fab-arm exchange reaction
-- don't induce dimerization of MuSK
-- They block MuSK and LRP4 interaction (loss of AChR)
- don't activate complement system
LRP4-MG
- IgG1
- inhibit interaction between LRP4 and agrin
- this reduces the AChR clustering
- and damages NMJ
Symptoms of MG
- ptosis
- diplopia
- generalized weakness
- impairment speaking (dysarthria)
Risk factors of MG
- women develop earlier (20-30)
- Smoking
- Age, obesity, low omega-3
- Genetics (possibly one of HLA genes)
treatment of MG
- corticosteroids (most effective)
- ACh (esterase inhibitor) they don't pass BBB
- Thymectomy (remove thymus
- Exchange plasma (myasthenic crisis)
- High dose IV Ig (myasthenic crisis)
What are Muscular Dystrophies?
- inherited genetic disorders (mutation in one of two genes)
- progressive weakness and degeneration of skeletal muscles
- autosomal dominant inheritance
Duchenne myotonic dystrophy (DMD)
- Most common form of Muscle dystrophy
- X-linked disorders
- Common in man
- predominant in children
- Characterized as the absence of dystrophin (stabilize and protect muscle fibers)
what are Myotonic dystrophies?
- Most common of MD in adults
- autosomal dominant
- 2 mutations:
-- DMPK gene (chromosome 19) - DM1
-- CNBP gene (chromosome 3) - DM2 (milder)
Myotonic Dystrophy type 1 (DM1)
- Most frequent MD in adults
- Multisystemic disorder
- Symptoms:
-- Slowly progressive muscle weakness(start in distal M)
-- Myotonia
-- Delay in muscle relaxation
- Mutation in DMPK gene (chromosome 19)
- Expansion of CTG repeat in the gene for DMPK enzyme in an untranslated region. It's made into mRNA but not protein! (>50 repeats)
- earlier age of onset in generations ("anticipation")
- Pathways
-- Haploinsufficiency
-- Alteration of neighboring genes
-- RNA-induce toxicity (Main mechanism)
Myotonic Dystrophy type 2 (DM2)
- Caused by CCTG repeat in the first intron
- Less severe
- symptoms: (Slowly progressive muscle weakness, starting proximal muscles. Myotonia)
Treatment for Muscular dystrophy
- genetic → antisense oligoclonal
- Corticosteroids (DMD)
- Antibiotics
- Physical therapy
- Gene therapy:
-- Admin of adenovirus (arrives to nucleus and can produce dystrophin or integrate chromosome and produce it)
-- Antisense oligonucleotides (ASO’s) - targets mRNA, or CRISPR-Cas9