General Neurology Conditions

Alzheimer's Disease - Overview

- 25% of AD is familial (3 or more family members being affected)

- most prevalent type of dementia

- characterized by progressive impairment of behavioral and cognitive function

- estimated risk by age 65

- male: 11.6%

- female: 21.1%

- Late onset AD (LOAD) -> 95%

- Early onset AD (EOAD) ->5%

- Accumulation of beta-amyloid plaques & neurofibrillary tangles

Alzheimer's Disease - Symptoms

Initial & common symptoms

- short term memory loss, problem solving & executive functioning difficulty

- language disorder & visuospatial skill loss

- driving, financial management, & activity planning problems

Moderate-late stage

- apathy, social withdrawal, agitation, psychosis, wandering

Late stage

- dyspraxia, olfactory dysfunction, sleep disturbances, dystonia, & Parkinsonian Sx

- leads to total dependence

Death

- 8-10 years after Sx onset

- malnutrition & pneumonia leading causes

Alzheimer's Disease - Late Onset Genes

APOE (e2, e3, e4)

- Significant risk factor for early & late AD

- Homozygous APOE e4/e4 -> 15-fold increased risk

- Heterozygous APOE e3/e4 -> 3x increased risk

- e2 is protective against LOAD

TREM2 p.Arg47His

- statistically significant for LOAD

- heterozygous Odds Ration of ~3.0

Alzheimer's Disease - Early Onset Genes

APP, Chr. 21

- 10-15% of cases

- onset often in 40-50s

- Thought why Trisomy 21 has Alzheimer's in 50%

PSEN1, Chr. 14

- 20-70% of cases

- Onset 40-50s with rapid progression over 6-7 years

- associated with seizures, myoclonus, language deficits

PSEN2

- ~5% of cases

- Onset 40-75

- 11 year duration with reduced penetrance

Unknown -> 20-40% of cases

Alzheimer's Disease - Diagnosis

- Clinically diagnosed

- slowly progressive dementia and neuroimaging findings of gross motor cortical atrophy

- Use MRI, PET scan, CSF

- can do molecular testing but not always diagnostic

Alzheimer's Disease - Treatment

- Cholinesterase inhibitors

- Partial N-methyl D-aspartate antagonists

- Amyloid targeting immunotherapy (reduce plaques)

Amyotrophic Lateral Sclerosis - Overview

- Progressive, paralytic, neurodegenerative disease affecting upper and lower motor neurons

- wide variability in onset, symptoms, & progression

- most common of motor neuron disease

- 5-10% of cases are familial (2 or more people affected)

Amyotrophic Lateral Sclerosis - Symptoms

Common Symptoms

- muscle weakness/cramps, twitching

- stiff muscles (spasticity), bulbar weakness

Other Symptoms

- cognitive impairment (30-50%)

- frontotemporal dementia (15-20%)

- behavioral impairment

Common Course

- atrophy & weakness spread from initial sites leading to eventual paralysis

- death 3-5 years after symptom onset (respiratory failure, pneumonia, pulmonary embolism, cardiac arrhythmia)

Amyotrophic Lateral Sclerosis - Genes

- 10-15% have genetic ALS

C9orf72 -> 39-45%

- AD Inheritance

- Hexanucleotide GGGGCC expansion (>60)

- associated with frontotemporal dementia

SOD1 -> 15-20%

- AD & AR Inheritance

- p.Ala4Val common in NA populations (associated with death 12-18 months after symptom onset)

- p.Ile113Thr (reduced penetrance, later onset, longer survival)

Also FUS (Parkinsonism, later onset, longer survival) & TARDBP (p.Gly298Ser earlier onset & 24 month survival)

Amyotrophic Lateral Sclerosis - Diagnosis

- EMG (90%)

- molecular testing -> not always diagnostic but done because of treatment

Amyotrophic Lateral Sclerosis - Management & Treatment

- Prevent weight loss

- assistive technologies -> walking, talking

- Riluzole -> slows progression

- Edaravone -> treat early stages ALS

- Tofersen -> SOD1 specific ALS treatment (why do genetics)

Frontotemporal Dementia - Overview

- broad term that describes a group of neurodegenerative diseases

- 10% of all diagnosed dementia

- leading cause of early onset dementia

- 15-20% genetic & 40% familial

Frontotemporal Dementia - Symptoms

- characterized by: alterations in behavior, language, and executive function, and motor function

- each gene is associated with a different presentation

Frontotemporal Dementia - Genes

C9orf72 -> 5-20%

- Onset avg. 58

- age-related penetrance

- Heterozygous GGGGCC repeat expansion

- Normal: 2-24 | VUS: 24-60 | PV: 61-4,000+

- Associated with TDP-43 aggregation

- Associated with behavioral & movement FTD

GRN -> 5-10%

- Onset avg. 65

- 90% penetrant by age 75

- Associated with TDP-43 aggregation

- associated with behavioral & speech FTD & rarely corticobasal syndrome

MAPT -> 5-10%

- Onset avg. 58

- 100% penetrant

- associated with abnormal Tau protein aggregation

- associated with behavioral & sometimes Parkinsonism & progressive supranuclear palsy

Frontotemporal Dementia - Diagnosis

- neuropsych exam

- brain imaging

- definitive diagnosis only made with genetic testing and/or post-mortem autopsy of brain

Frontotemporal Dementia - Treatment

- Symptom management & support

- SSRIs

- selective dopaminergic antagonists

- antipsychotics

Parkinson Disease - Overview

- Degeneration of dopaminergic neurons in substantia nigra

- Accumulation of alpha-synuclein within Lewy Bodies

- 10% are genetic

- Diagnosis made clinically

Parkinson Disease - Symptoms

- Presentation begins with asymmetric motor features

- Nonmotor symptoms (GI motility issues, constipation, rapid eye movement sleep disorder, depression, cognitive decline)

- Motor symptoms (bradykinesia, resting tremor, rigidity) presents asymmetrically

- Motor symptoms become bilateral (postural instability, functional impairment, loss of independence)

Parkinson Disease - Genes

LRRK2 -> 1-2% of adult PD

- AD inheritance

- AJ ancestry: 13-30%

- African Berber ancestry: 41%

PINK1 (3.7%) & PRKN (1-15%) -> early onset adult PD

- AR Inheritance

GBA1 - possible monogenic PD

- Individuals with Gaucher disease have increased risk or are predisposed to developing PD

- Penetrance 10-15% by age 80

Parkinson Disease - Treatment

- Symptomatic

- Oral levodopa

- If poor response, the diagnosis is likely incorrect

- deep brain stimulation

Charcot-Marie Tooth Hereditary Neuropathy - Symptoms

- symmetric & slowly progressive distal motor neuropathy of the arms and legs

- typically onset in 1st to 3rd decade

- results in weakness and atrophy in feet and/or hands

- distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed tendon reflexes, and pes cavus (high arched foot but may collapse)

- SNHL

- typically "painless" but can be described as painful

Charcot-Marie Tooth Hereditary Neuropathy - Genes

- PMP22 accounts for ~50% of cases

- 1st tier testing is PMP22 del/dup analysis

- Also GDAP1, MFN2, MPZ, HINT1, SH3TC2, GJB1 (XL)

Charcot-Marie Tooth Hereditary Neuropathy - Diagnosis & Treatment

- Diagnosis made with peripheral neuropathy on medical history and exam

- Symptomatic treatment -> shoes with support, walking/ambulatory aids, surgery (foot)