Spinal Cord : Peripheral : Neurodegenerative

PrPsc converts normal PrPc into more abnormal PrPsc, amplifying the process of prion accumulation.

CJD causes vacuole formation in grey matter structures, such as the caudate nucleus and putamen, which develop into cysts without inflammation.

CJD leads to vacuolization and cyst formation, causing degradation of brain parenchyma, resulting in a 'spongy' appearance.

Dementia in CJD progresses rapidly over weeks to months.

A classic motor finding in CJD is myoclonus, which refers to sudden, involuntary muscle contractions.

Electroencephalogram (EEG) changes seen with CJD include periodic sharp wave complexes.

Huntington disease is inherited in an autosomal dominant fashion with 100% penetrance.

Huntington disease is caused by CAG trinucleotide repeat expansion on chromosome 4.

This phenomenon is termed anticipation.

The CAG copy number increases much more during spermatogenesis than during oogenesis, leading to more severe disease if the mutated allele is inherited from the father.

In Huntington's Disease, the caudate nucleus is affected more than the putamen, leading to atrophy of the striatum.

This appearance is known as hydrocephalus ex-vacuo, although the ventricles themselves are normal.

The most common biochemical change seen in Huntington's disease is the loss of the inhibitory neurotransmitter GABA.

Huntington's disease typically presents between the ages of 30-50.

Motor involvement in Huntington's disease leads to chorea, which is characterized by rapid, involuntary, or arrhythmic movements involving the face, trunk, and extremities.

Patients with Huntington's disease often experience psychobehavioral changes such as aggression, apathy, and depression years before the onset of motor symptoms.

Bradykinesia is a common feature of Parkinson Disease, characterized by slow movement.

The term for the involuntary circular movement of the fingers is 'pill-rolling' tremor.

Cogwheel rigidity refers to a ratchety pattern of resistance and relaxation during passive movement of the extremities.

Postural instability is a common feature of Parkinsonism that leads to feelings of unbalance and an increased tendency to fall.

A common feature of Parkinsonism is shuffling gait, which is due to bradykinesia and postural instability.

First-generation antipsychotics, which are D2 dopamine antagonists, may cause symptoms of Parkinsonism.

Upper motor neurons originate in the motor cortex and descend through the corticospinal tracts.

The corticospinal (pyramidal) tracts start in the motor cortex and descend through the medullary pyramids.

Most of the corticospinal tract fibers decussate (cross) at the medulla to form the lateral corticospinal tracts.

The lateral corticospinal tracts are responsible for transmitting signals from upper motor neurons to lower motor neurons, facilitating voluntary motor control of the limbs.

Corticospinal tract axons synapse with lower motor neurons at the anterior horn of the spinal cord.

The anterior horns of the spinal cord contain the cell bodies of lower motor neurons.

An upper motor neuron lesion can cause muscle weakness, spastic paralysis, clasp-knife rigidity, and hyperreflexia.

UMN lesions cause HYPERreflexia, which is an exaggerated reflex response.

UMN lesions cause spastic paralysis and clasp-knife rigidity, which is characterized by a sudden release of resistance during movement.

UMN lesions cause upgoing plantar reflexes, known as a positive Babinski sign, indicating dysfunction in the corticospinal tract.

LMN lesions cause muscle atrophy, leading to visibly thinner limbs and weakness.

LMN lesions cause flaccid paralysis and hypotonia. They also result in hyporeflexia, which is a decreased reflex response.

LMN lesions can lead to muscle fasciculations, which are involuntary muscle contractions. This is a common clinical sign observed in patients with LMN damage.

Spinal muscular atrophy (SMA) is characterized by congenital degeneration of the anterior horns, leading to muscle weakness and atrophy.

Spinal muscular atrophy (SMA), including Werdnig-Hoffman disease, follows an autosomal recessive inheritance pattern.

In spinal muscular atrophy (SMA), the involvement of the anterior horns is bilateral, leading to lower motor neuron (LMN) symptoms that are also present bilaterally, affecting both sides of the body.

Infantile spinal muscular atrophy (SMA) is known as Werdnig-Hoffman disease and typically presents before the age of 6 months.

Poliomyelitis, caused by the poliovirus, targets the anterior horn cells, leading to lower motor neuron (LMN) degeneration and resulting in symptoms similar to those seen in spinal muscular atrophy (SMA).

Polio leads to asymmetric weakness/paralysis.

ALS, also known as Lou Gehrig's Disease, is a progressive neurodegenerative disease that affects motor neurons.

ALS causes both upper motor neuron (UMN) and lower motor neuron (LMN) lesions.

ALS affects the bilateral lateral corticospinal tracts, leading to atrophy and sclerosis.

ALS causes asymmetric distal extremity weakness and atrophy.

ALS is associated with mild cognitive impairment, specifically frontotemporal dementia.

Mutations in the superoxide dismutase type 1 (SOD1) gene are frequently found in ALS.

Riluzole improves survival in ALS by decreasing glutamate-induced excitotoxicity within neurons.

Friedreich's ataxia is due to an autosomal recessive loss-of-function mutation in the frataxin (FXN) gene on chromosome 9.

Friedreich's ataxia is caused by an expanded GAA repeat in the frataxin gene.

A loss-of-function mutation in the FXN gene leads to decreased frataxin levels.

Frataxin is involved in iron homeostasis in the mitochondria.

Decreased frataxin leads to mitochondrial iron accumulation, which causes oxidative stress and ultimately results in cell death, affecting multiple neural tracts and peripheral nerves.

The degeneration of spinocerebellar tracts and dentate nuclei disrupts coordination and balance, leading to gait ataxia in individuals with Friedreich ataxia.

Dorsal column degeneration in Friedreich ataxia results in loss of proprioception and vibration sensation, impairing the individual's ability to sense body position and movement.

Lower extremity weakness in Friedreich ataxia is caused by degeneration of the lateral corticospinal tract, which affects motor control and strength in the legs.

Motor neuropathy in Friedreich ataxia causes foot abnormalities such as pes cavus (high arched foot) and hammer toes.

Friedreich ataxia is associated with kyphoscoliosis, which is an abnormal curvature of the spine.

Friedreich ataxia is associated with hypertrophic cardiomyopathy, which can lead to arrhythmias and heart failure, the most common cause of death in affected individuals.

Individuals with Friedreich ataxia often experience insulin resistance and diabetes.

Guillain-Barré syndrome (GBS) is an immune-mediated demyelinating disorder of the peripheral nervous system, also known as acute inflammatory demyelinating polyradiculoneuropathy.

Myelin sheaths in the peripheral nervous system are crucial for insulating nerve fibers, which enhances the speed and efficiency of electrical signal transmission between neurons.

GBS may be caused by an inappropriate immune response to a preceding infection, where the antigen of the pathogen cross-reacts with components of the peripheral nerves (a phenomenon known as molecular mimicry).

In GBS, Schwann cells are targeted by the autoimmune response, which damages the myelin sheath they produce for peripheral nerves.

The most common precipitating organism in GBS is Campylobacter jejuni, an S-shaped enteric gram-negative bacterium that can cause bloody diarrhea in children and spreads through fecal/oral transmission or ingestion of undercooked meat.

GBS can be precipitated by viral infections, including upper respiratory infections, HIV, EBV, and CMV.

In GBS, helper T cells play a crucial role in the cellular immune response by recruiting macrophages, which contribute to the damage of the myelin sheath.

The HUMORAL immune response in GBS may involve autoantibody-mediated destruction of Schwann cells or myelin antigens.

The COMPLEMENT cascade may be activated locally in GBS as a result of antibody binding, contributing to the disease process.

Histology of GBS shows an endoneurial inflammatory infiltrate with abundant small cells and prominent blue nuclei around peripheral myelin.

Segmental demyelination throughout peripheral nerves in GBS impairs nerve conduction, leading to the clinical symptoms of the disease.

GBS characteristically presents with symmetric ascending muscle paralysis.

GBS characteristically presents with decreased or absent deep tendon reflexes (DTRs).

GBS may present with bilateral facial paralysis (Bell's palsy) if paralysis ascends high enough to involve cranial nerve VII (CN VII).

GBS may present with respiratory failure due to paralysis of motor neurons innervating the diaphragm and accessory respiratory muscles.

In GBS, the CSF displays Albumino-Cytologic dissociation, characterized by a high protein level but a normal cell count. This is due to increased capillary permeability at the blood-nerve barrier.

Charcot-Marie-Tooth (CMT) disease is a group of disorders affecting the development of peripheral nerve axons or their myelin sheath, classified as hereditary motor sensory neuropathy.

CMT is most commonly inherited in an autosomal dominant pattern.

CMT is caused by defective production of proteins involved in the structure and function of peripheral nerves and myelin, leading to demyelination and axonal dysfunction of peripheral nerves.

CMT presents with progressive lower extremity weakness and atrophy within the first two decades of life.

Foot drop is characterized by weakness in foot dorsiflexion due to lesions in the common fibular nerve, which is a common presentation in CMT.

CMT eventually leads to a high-arched foot deformity known as pes cavus, caused by atrophy of nerves and muscles of the foot.

CMT can lead to thoracic kyphoscoliosis, which is a curvature of the spine in both coronal and sagittal planes due to weakness of trunk muscles.

CMT can present with sensory loss, particularly in the following areas:

• Proprioception
• Vibration
• Discriminate touch

These senses are normally carried on large, myelinated fibers.

The most common central nervous system demyelinating disorder is Multiple Sclerosis (MS), which is caused by the autoimmune destruction of oligodendrocytes.

Oligodendrocytes are glial cells that form myelin sheaths around axons in the CNS. They contain cellular projections that apply myelin to enhance the speed of electrical impulses along the axons.

Multiple Sclerosis (MS) most commonly affects women, with onset typically occurring in early adulthood, particularly in the 20s to 30s age range.

The HLA-DR2 genotype is associated with an increased susceptibility to developing Multiple Sclerosis (MS).

Viral infections may contribute to the development of Multiple Sclerosis (MS), suggesting a potential environmental trigger for the disease.

MS is more common further from the equator.

Autoreactive helper T cells inappropriately respond to antigens in myelin, leading to the release of inflammatory cytokines.

Active plaques are localized areas of inflammation in the white matter of the brain or spinal cord, characteristic of MS.

Active plaques contain abundant macrophages that phagocytose myelin debris as part of an inflammatory infiltrate.

Active plaques contain abundant CD8+ cytotoxic T cells as part of an inflammatory infiltrate.

Active plaques are surrounded by proliferating astrocytes, a reaction known as active gliosis.

In an active plaque, a small proportion of neuronal axons may be lost, although the majority remain uninjured.

Acute active plaques eventually progress to a chronic inactive phase where axons are completely demyelinated, macrophages disappear, and axons and oligodendrocytes are lost, with astrocytes filling the lesion with a glial scar.

Plaques commonly form near the ventricles, although they can form anywhere in the CNS.

MS characteristically presents with neurologic signs and symptoms that cannot be explained by a single lesion.

MS characteristically presents with a relapsing-remitting pattern of symptom progression.

MS frequently presents with fatigue, particularly after hot showers or strenuous activity in hot environments.

Multiple Sclerosis (MS) is the most common cause of optic neuritis (inflammation of the optic nerve).

Optic neuritis presents with unilateral eye pain (aggravated by ocular movements) and vision loss, primarily affecting central vision (central scotoma).

In optic neuritis, there is a relative afferent pupillary defect where shining light in the affected eye causes bilateral pupils to constrict less than normal, resulting in them staying slightly dilated.

A relative afferent pupillary defect in optic neuritis can be demonstrated by shining light into the normal eye and then into the affected eye; the subtle defect from the affected side becomes more obvious during this test.

Multiple Sclerosis (MS) can present with internuclear ophthalmoplegia, which is caused by a lesion in the Medial Longitudinal Fasciculus (MLF) that coordinates horizontal eye movement.

A lesion in the MLF, such as on the right side, results in the right eye being unable to adduct when the left eye abducts, leading to a lack of coordinated eye movement.

Internuclear ophthalmoplegia can cause horizontal nystagmus in the unaffected eye, which may shake despite an injury in the other eye.

Multiple Sclerosis commonly presents with sensory symptoms, which may include sensations of numbness or tingling.

Multiple Sclerosis can present with hyperreflexia, indicating an upper motor neuron defect, which results in exaggerated reflex responses.

'Clasp knife rigidity' is a type of muscle spasticity associated with upper motor neuron defects, commonly seen in Multiple Sclerosis (MS). It is characterized by a sudden release of resistance during passive movement of a joint, resembling the action of a clasp knife.

Lhermitte sign is characterized by an electric shock sensation running down the spine when the neck is flexed. It is a common symptom in Multiple Sclerosis (MS) indicating involvement of the cervical spinal cord.

Multiple Sclerosis (MS) can lead to bowel and bladder dysfunction due to autonomic nervous system involvement, resulting in issues such as incontinence or difficulty in urination.

Intention tremors are involuntary shaking movements that occur during purposeful movement, often seen in Multiple Sclerosis (MS) due to cerebellar involvement. They can affect the ability to perform coordinated tasks.

'Scanning speech' refers to a speech pattern characterized by staccato, disjointed sentences. It is a symptom of Multiple Sclerosis (MS) that results from neurological impairment affecting speech production.

MRI is used to diagnose MS, revealing areas of demyelinated plaques.

In MS, protein electrophoresis of CSF reveals oligoclonal bands representing IgG antibodies due to the production of large amounts of IgG by multiple B cell lines.

A lumbar puncture is performed to collect CSF for diagnosing MS.

Creutzfeldt-Jakob Disease (CJD) is a spongiform encephalopathy that is technically classified as an infectious disease. It is associated with the consumption of beef tainted with bovine spongiform encephalopathy (BSE), commonly referred to as 'mad cow disease'.

CJD is caused by the accumulation of misfolded prion protein (PrP). The normal form of the protein (PrPc) transforms into a misfolded form (PrPsc) characterized by beta-pleated sheets instead of the normal alpha-helix conformation.

In Wilson's disease, accumulation of copper in the striatum and direct binding of dopamine by free copper can lead to Parkinsonism due to a copper metabolism defect that results in cirrhosis.

Parkinson's disease is caused by a loss of dopaminergic neurons in the substantia nigra (pars compacta), leading to low dopamine levels.

In Parkinson's disease, the dopaminergic neurons of the substantia nigra contain dark pigmented neuromelanin, and there is a pale appearance of the substantia nigra due to the loss of neurons.

Lewy bodies are round eosinophilic, cytoplasmic inclusions composed of aggregates of alpha synuclein. They are typically found in the substantia nigra.

Deep brain stimulation is sometimes used to inhibit the subthalamic nucleus and improve symptoms in Parkinson's Disease.

Dementia is a chronic neurocognitive disorder that causes progressive decline in at least one area of executive cognitive ability, such as memory, speech, or attention, while maintaining clear consciousness. In contrast, delirium involves an acute alteration of cognition.

The most significant risk factor for Alzheimer's disease is age, with 50% of individuals over 85 years old being affected.

Down syndrome is associated with early-onset Alzheimer's disease, often occurring by age 40.

Trisomy 21 may increase the production of amyloid precursor protein (APP), which is the precursor to amyloid beta, leading to early-onset Alzheimer's disease.

Mutations in presenilin 1, located on chromosome 14, may promote the production of amyloid beta, contributing to early-onset Alzheimer's disease.

Mutations in presenilin 2, located on chromosome 1, may promote the production of amyloid beta, which is associated with early-onset Alzheimer's disease.

Homozygosity of the ApoE4 allele on chromosome 19 is a risk factor for late-onset Alzheimer's disease, increasing the risk by 10 times.

Amyloid beta proteins, derived from APP, are misfolded proteins that aggregate to form neuritic (senile) plaques in the brain, which are associated with Alzheimer's disease.

Accumulations of amyloid beta form extracellular plaques primarily in the medial temporal lobe (including the hippocampus and amygdala), leading to neuronal dysfunction and apoptosis, contributing to Alzheimer's disease.

Hyperphosphorylated tau protein accumulates intracellularly to form neurofibrillary tangles, particularly in the medial temporal lobe, which is a hallmark of Alzheimer's disease.

Neurodegeneration in Alzheimer's disease leads to loss of cortical mass, resulting in ventricles that appear enlarged on imaging, a condition known as hydrocephalus ex vacuo.

Brain atrophy in Alzheimer's disease is most prominent in the hippocampus and can be seen on MRI early in the disease.

Alzheimer's disease is associated with low levels of acetylcholine.

Low acetylcholine levels in Alzheimer's disease are caused by decreased activity of choline acetyltransferase (ChAT).

The nucleus basalis of Meynert is responsible for memory and cognition and is especially prone to low acetylcholine levels and dysfunction in AD.

The predominant feature of Alzheimer's Disease is memory dysfunction, particularly with recent events.

Executive cognitive dysfunction in Alzheimer's Disease is characterized by difficulty planning or organizing.

Visuospatial impairment is a feature of Alzheimer's Disease, commonly presenting as getting lost in familiar surroundings.

Frontotemporal dementia causes preferential degeneration of the frontal and temporal lobes.

Up to 25% of cases of frontotemporal dementia are inherited in an autosomal dominant fashion.

The onset of frontotemporal dementia is typically in the fifth and sixth decades, opposed to the eighth decade in Alzheimer's disease.

Histologically, FTLD-tau (Pick disease) displays Pick bodies, which are hyperphosphorylated tau protein forming intracellular inclusion bodies in neurons.

A common subtype of frontotemporal dementia is caused by the accumulation of abnormally ubiquitinated TDP-43 RNA binding protein.

The behavioral variant of FTD leads to early personality and behavior changes such as inappropriate behavior, apathy, hyperorality, and compulsivity.

The primary progressive aphasia variant of FTD causes early, progressive language dysfunction characterized by paucity of speech, repeated phrases, and word-finding difficulty.

FTD is associated with ALS, as most patients with ALS show TDP-43 intracellular neuronal inclusions.

DLB is caused by the accumulation of alpha-synuclein, which forms round, eosinophilic intracellular inclusions.

Patients with DLB typically develop Parkinsonism, which includes symptoms such as bradykinesia, cogwheel rigidity, and resting tremor. Lewy bodies are also seen in patients with Parkinson's Disease.

DLB commonly causes visual hallucinations early in the course of the disease.

Vascular dementia is characterized by a stepwise decline in cognition, where stable cognitive function is punctuated by periods of acute, permanent decline.

Cerebrovascular events, such as strokes, lead to a stepwise decline in cognition in vascular dementia, with infarcts of varying age observable on MRI.

In patients with advanced HIV-AIDS, particularly those with CD4 counts <200, cognitive decline and dementia may occur.

In HIV-associated dementia, inflammatory activation of microglia and macrophages occurs, contributing to cognitive decline.

Activated macrophages and microglial cells in HIV dementia release cytokines, leading to inflammation, formation of microglial nodules, necrosis, and multinucleated giant cells.