Pathology of the Central and Peripheral Nervous system

What is the #1 cause of dementia (> 60%)?

Alzheimer disease

What percentage of Alzheimer disease cases are sporadic versus inherited?

Most cases are sporadic; less than 2% are inherited

What mutations are associated with Alzheimer’s disease?

• Mutation APOE gene

• Presenelin 1 and 2

• Amyloid precursor protein (Chr. 21)

At what age are most Alzheimer disease patients diagnosed?

Over 65 years of age

What are the four signs and symptoms of early-stage (mild) Alzheimer disease?

1. Short-term memory loss

2. Difficulty finding correct words and names

3. Difficulty performing familiar and common tasks

4. Difficulty in planning and organizing

What are the symptoms and signs seen in middle-stage (moderate) Alzheimer disease?

• Increasing impairment of learning/memory

• Agnosia (defects in perception)

• Apraxia (defects in movement)

• Loss of vocabulary and language fluency

• Fading long-term memories

• Sundowning

What does the term "sundowning" refer to in Alzheimer disease?

Restlessness, confusion, and agitation that worsen at dusk

What are the main manifestations of late-stage (severe) Alzheimer disease?

• Worsening memory and cognitive skills

• Susceptibility to infections (e.g., pneumonia)

Which brain region shows prominent atrophy in Alzheimer disease that leads to difficulty in learning new things or forming new memories?

The hippocampus

What ventricular change is observed in Alzheimer disease pathology?

Enlargement of the ventricles

What are neurofibrillary tangles composed of and what do they do?

Collections of tau protein in the cytoskeleton that block synaptic communication of neurons

What are senile (amyloid) plaques in Alzheimer disease composed of and where are they located?

Extracellular amyloid deposits between neurons that hinder communication

What clinical evaluation tool is used in the diagnosis of Alzheimer disease?

MMSE (Mini Mental Status Evaluation)

What findings on lumbar puncture support an Alzheimer disease diagnosis?

Elevated Amyloid Beta 42 and p-Tau in CSF

What plasma biomarker can be evaluated for Alzheimer disease?

Plasma p-tau-217

Which imaging modalities are used to evaluate Alzheimer disease?

CAT scan, MRI, and FDG-PET

Which cholinesterase inhibitors are used in the treatment of Alzheimer disease?

Aricept (donepezil, rivastigmine, and galantamine)

Which NMDA antagonist is used to treat Alzheimer disease?

Memantine

Which amyloid-directed monoclonal antibodies are used for Alzheimer disease?

Donanemab and lecanemab

Can Alzheimer disease medications reverse memory loss?

No, they do not reverse memory loss and they may slow it down

What is Parkinson disease primarily classified as?

A long-term neurodegenerative disease mostly affecting motor function

What environmental and physical factors are associated with the risk of Parkinson disease?

Head trauma and exposure to pesticides

What is the typical age of onset for Parkinson disease, and when does early-onset PD occur?

• Most patients are over 60

• Early-onset: before age 50

Which gender is more commonly affected by Parkinson disease?

Males

What does the acronym 'TRAPS' stand for in Parkinson disease?

Tremor, Rigidity, Akinesia, Posture (postural instability)

Describe the resting tremor seen in Parkinson disease.

Usually starts in one hand or leg, and can affect the jaws and tongue

What motor symptoms in Parkinson disease cause a shuffling gait and increased risk for falls and fractures?

Bradykinesia/akinesia (shuffling gait) and postural instability (falls and bone fractures)

What are the non-motor signs and symptoms of Parkinson disease?

• Cognitive deficits (thinking, judgment, planning)

• Slow or infrequent blinking ("serpentine stare")

• Hallucinations and psychosis (paranoia)

What is the core cellular pathology in Parkinson disease?

Depletion of dopamine-producing neurons in the substantia nigra of the basal ganglia. (Reduce dopamine)

How does Parkinson disease affect basal ganglia pathways?

It stimulate indirect neural pathway and acts as a hypokinetic basal ganglia disease.

What microscopic structures accumulate in Parkinson disease and what is their effect?

• Lewy bodies (accumulation of atypical proteins)

• Disrupt dopamine production → affects mental capacities and behavior

What is the surgical procedure of choice for Parkinson disease?

Deep brain stimulation (DBS)

What are the advantages of deep brain stimulation (DBS) in Parkinson disease?

• Doesn’t destroy brain tissue

• Reversible

• Can be adjusted

• Bilateral procedures → without significant increase in adverse events

What is Parkinsonism and how does its etiology differ from Parkinson disease?

A group of neurological problems sharing PD features that is NOT caused by primary nerve cell degeneration as in PD.

What is the 2nd most common cause of dementia after Alzheimer disease?

Dementia with Lewy bodies

How is Huntington disease inherited and what gene is mutated?

• Autosomal dominant

• Mutation in the Huntingtin gene (leading to abnormal huntingtin protein)

At what stage of life does Huntington disease typically begin?

Middle age

What are the motor symptoms of Huntington disease?

Motor: chorea (jerky, uncontrolled movements), difficulty chewing and swallowing

What specific brain structure atrophies in Huntington disease?

The caudate nucleus in the basal ganglia (with loss of neurons)

Which neurotransmitter's secretion is reduced in Huntington disease?

Gamma-aminobutyric acid (GABA)

Is Huntington disease a hypokinetic or hyperkinetic basal ganglia disease?

Hyperkinetic basal ganglia disease (compared to Parkinson disease, which is hypokinetic)

What parts of the nervous system degenerate in Amyotrophic Lateral Sclerosis (ALS)?

Corticospinal tracts (upper motor neurons and lower motor neurons)

What do the terms "amyotrophic" and "sclerosis" refer to in ALS?

Amyotrophic: weak muscles → lack of nerve stimulation

Sclerosis: degeneration → scarring in the nerves

What gene mutation is linked to hereditary Amyotrophic Lateral Sclerosis (ALS)?

SOD1 mutation

What is the typical age of onset and gender predilection for ALS?

• Mostly 40s to 60s

• Mostly males

What are the characteristic motor signs and symptoms of ALS?

• Asymmetric limb weakness (arms and legs)

• Fasciculations, clonus

• Hyperreflexia

• Weakness in muscles of mastication

What functions are specifically spared in Amyotrophic Lateral Sclerosis (ALS)?

Bowel, bladder, and sensory functions

What is the typical life expectancy after diagnosis in ALS?

Death usually occurs in 2 to 6 years

What is the primary underlying pathology in Multiple Sclerosis (MS)?

Immune-mediated destruction of myelin sheaths in the CNS by T-cells, replaced by numerous glial plaques or scars (sclerotic tissue)

Why do axons fail to function properly in Multiple Sclerosis?

They fail to conduct nerve impulses because of demyelination

What is the typical demographic for Multiple Sclerosis (age and gender)?

• Young adults

• More common in females

What are common signs and symptoms of Multiple Sclerosis?

• Difficulty speaking and swallowing

• Facial pain

• Ataxia (difficulty walking/balance)

• Nystagmus

• Sensation of pins and needles

• Optic neuritis

What are the four clinical classifications of Multiple Sclerosis?

1. Relapsing-remitting MS (RRMS)

2. Secondary progressive MS (SPMS) - gets worse w/ second event

3. Primary progressive MS (PPMS) - gets worse and no second event

4. Progressive-relapsing MS (PRMS)

What is the imaging procedure of choice for confirming and monitoring Multiple Sclerosis?

Magnetic Resonance Imaging (MRI)

What diagnostic tests can be performed for Multiple Sclerosis besides MRI?

• Evoked potentials (identifies subclinical lesions)

• Lumbar puncture (evaluates CSF for oligoclonal bands and intrathecal IgG production)

What medication is used to hasten recovery from an acute exacerbation of MS?

Methylprednisolone (Solu-Medrol)

What short-term treatment can be used for severe MS attacks if steroids are contraindicated or ineffective?

Plasma exchange (plasmapheresis)

Which steroid is commonly used for acute transverse myelitis and acute disseminated encephalitis?

Dexamethasone

Name the interferon disease-modifying therapies (DMTs) used for Multiple Sclerosis.

• IFN beta-1a

• IFN beta-1b

• Peginterferon beta-1a

Name the S1P receptor modulators used for Multiple Sclerosis.

Siponimod, fingolimod, and ozanimod

What are used as disease-modifying therapies for Multiple Sclerosis?

Monoclonal antibodies

What are used in the treatment of Multiple Sclerosis?

Miscellaneous immunomodulators

What is hydrocephalus?

An increase in cerebrospinal fluid (CSF) within the brain ventricles

What are four common causes of hydrocephalus?

Birth defects, brain tumors, meningitis, and subarachnoid hemorrhage

What is the most common cause of brain surgery in children?

Hydrocephalus

What is the mechanism and primary symptoms of hydrocephalus?

• Arachnoid villi cannot absorb CSF

• CSF can’t be removed in circulatory system

What is the surgical management for hydrocephalus?

A shunt that drains excess CSF into the peritoneum (ventriculoperitoneal shunt)

What are Neural Tube Defects (NTDs) and when do they occur during development?

Congenital defects resulting from failure of neural tube closure. Occurring during the first month of pregnancy.

What are three risk factors for Neural Tube Defects?

Maternal obesity, low folic acid intake, and diabetes mellitus

How are Neural Tube Defects prevented?

Sufficient folic acid intake during pregnancy

What is the most important neural tube defect?

Spina bifida

What is Spina bifida?

When the spinal cord fail to close.

What is a meningocele?

A type of spina bifida where the meninges herniate/protrude through the vertebral defect, but the spinal cord does not

What is a myelomeningocele (meningomyelocele) and its clinical consequence?

• A spina bifida defect where BOTH meninges and the spinal cord herniate

• Causes at least some paralysis of the legs

What is the surgical timing for repairing a spina bifida defect?

Surgery within 2 days of birth

What is Cerebral Palsy (CP) and is it progressive?

A heterogeneous group of disorders affecting movement and posture that is NON-PROGRESSIVE (does not worsen with age)

When do brain injuries causing Cerebral Palsy typically occur?

During pregnancy (75%)

What is the most common type of Cerebral Palsy?

Spastic CP (accounting for 80% of cases)

What are the physical and oral findings associated with Spastic Cerebral Palsy?

• Stiff muscles and awkward movement

• Small bones (including maxillae and mandible)

• Increased risk for dental caries and periodontitis

• Cognitive defects, seizures may occur

What causes an epileptic seizure?

Massive, abnormal electrical discharge of neurons in the brain

What are causes of brain damage leading to epilepsy?

• Head trauma

• Infections (encephalitis or meningitis)

• Tumors

• Arteriosclerosis or ischemia

What occurs during generalized seizures (tonic-clonic / grand mal)?

Massive bursts of electrical activity sweep through the entire brain at once.

Leads to: convulsions, loss of consciousness, falls, and massive muscle spasms

What is a partial seizure, and how does it compare in frequency to generalized seizures?

• An electrical disturbance localized to one area of the brain

• More common than generalized seizures

What is an absence (petit mal) seizure and what is an aura?

Absence: a partial/generalized episode characterized by staring into space

Aura: a focal sensory/motor sensation that warns of a larger seizure to come

What is used to treat epilepsy?

Anticonvulsant medication

What is meningitis?

Inflammation of the meninges surrounding the brain or spinal cord

What are classic signs and symptoms of meningitis?

Headache, fever, and stiff neck.

What complications occur in severe cases of brain edema in meningitis?

Brain herniation through meningeal compartments, loss of consciousness, and damage to the trigeminal nerve.

What is poliomyelitis and how is poliovirus transmitted?

• An enterovirus infection targeting the CNS

• Transmission: fecal-oral route

What is the only natural host for poliovirus?

Humans

Are most poliomyelitis cases asymptomatic?

Yes (most of it, 70%)

What is a clinical manifestation of paralytic polio (1% of cases)?

Marked atrophy of muscles

What is the specific CNS pathology in poliomyelitis?

Poliovirus destroys motor neurons in the anterior horn cells of the spinal cord

What is Post-Polio Syndrome?

A condition occurring decades after initial recovery from polio (characterized by new pain, weakness, and atrophy in muscles that may or may not have been originally involved)

What kind of vaccines are used against Poliomyelitis?

Inactivated vaccines (very effective)

What cellular components make up a neurofibroma?

Neurons, fibroblasts, Schwann cells, and mucin

What are the clinical characteristics of a solitary neurofibroma?

Painless, slowly growing, flaccid or rubbery, benign

What is the difference between plexiform neurofibroma and solitary neurofibroma?

Plexiform can be painful and become malignant.

Where do neurofibromas most commonly occur in the oral cavity?

The tongue, palate, and buccal mucosa (occasionally central within the mandible)

What is the genetic defect in Neurofibromatosis Type 1 (NF-1)?

Mutation/defect of the NF-1 tumor suppressor gene located on chromosome 17