Neurodegenerative Diseases

• Common features of neurodegenerative diseases are studied
• The neuroanatomic distribution of neuronal loss in common neurodegenerative diseases is researched
• Knowing neuropathological features of certain diseases is paramount: Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis, Friedreich Ataxia, and Creutzfeldt-Jakob Disease

Neurodegenerative Diseases

• Alzheimer's Disease is a key neurodegenerative disease
• Synucleinopathies is a key neurodegenerative disease
• FTLD is a key neurodegenerative disease
• FTLD Tau-positive diseases include Pick disease, Progressive supranuclear palsy, and Corticobasal degeneration
• A FTLD Tau negative disease is FTLD-TDP43
• Triplet repeat disorders is a type of neurodegenerative disease

Pathogenesis

• Protein accumulation and degradation is a part of pathogenesis
• Intracellular protein accumulation and degradation involves post-translational modification in NFT in AD and Tau gene mutations in tauopathies
• Extracellular protein accumulation and degradation involves AD and Prion disease

Alzheimer's Disease (AD)

• AD is the most common neurodegenerative disease
• AD is the single most common cause of dementia
• AD has a slowly progressive course over years
• Early memory loss is a key sign of AD, especially short-term
• AD causes loss of other cortical functions language skills, judgment, abstract reasoning, and visuospatial skills
• Average survival is 5-10 years after onset of AD
• About 10% of all AD cases have a strong family history

AD Prevalence

• In 2015, 5.3 million Americans of all ages had AD
• 5.1 million Americans ≥65 years had AD
• Two-thirds of AD patients are women

Genetics of AD

• Pathology of autosomal dominant AD is similar to sporadic AD
• 50-70% of late-onset sporadic AD cases have a genetic component
• APOE4 increases deposition of Aβ in AD
• AD risk is increased 3x with 1 allele and 15X with 2 alleles

AD Gross Findings

• Key gross findings: Granulovacuolar degeneration, Hirano bodies, Neuritic plaques

Neuritic Plaques

• Extracellular Amyloid-ß, abnormal neurites , and reactive microglia are key signs of neuritic plaques
• The most important feature to diagnose AD is neuritic plaques
• Multiple neurons contribute neurites to each plaque
• There is a decreased number of synapses within plaques

Amyloid-β Peptide (Aβ)

• Aβ is a key component of plaques and is found in vessels
• Aβ is derived from Amyloid Precursor Protein (APP), a normal transmembrane protein, via abnormal cleavage by β-,y-secretases
• Peptides of varying lengths exist, with Aβ42 being more toxic than Aβ40
• Smaller oligomers of Aβ are more toxic than larger aggregates

Neurofibrillary Tangles (NFT)

• Neurofibrillary tangles (NFT) and threads are a classic feature of AD
• Intracytoplasmic neuronal inclusions are a classic feature of AD
• "Ghost tangles" remain after the cell dies

Tau

• Tau: a microtubule-associated protein, is a key component in AD
• Hyperphosphorylation causes tau dissociation from microtubules and self-aggregation of tau into paired helical filaments (PHF)
• Tau mutations cause non-AD neurodegenerative diseases

Microtubule Functions

• Key functions of microtubules: Mitotic spindles, Organization of cytoplasm, Growth of cell processes, Transport along axons and dendrites
• The amino-terminal region of tau may affect microtubule interactions with the cell membrane and other organelles

Diagnosis of Alzheimer

• Diagnosis of Alzheimer disease uses the ABC method through the National Institute of Aging – Alzheimer's Association (NIA-AA) system
• Aβ receives the A score
• NFTs (Braak score) get the B score
• Neuritic plaques (CERAD rating) get the C score
• These areas can be reported as “Alzheimer-related neuropathology (A_, B_, C_)”

Aβ Distribution Assessment

• Aβ distribution assessment uses the Thal score
• Any evidence of diffuse or neuritic plaques by Aβ immunohistochemistry (or Hirano silver stain) is key
• A0: no amyloid
• A1: neocortex, hippocampus, entorhinal cortex
• A2: thalamus and striatum
• A3: brainstem and cerebellum

NFTs Assessment

• For NFTs Assessment use Braak score
• Tangles begin in the mesial temporal lobe and spread throughout the hemisphere
• Braak score reflects distribution (not numbers) of tangles
• 1 - entorhinal cortex
• 2 - hippocampus
• 3 – inferior temporal
• 4 – association cortex (MFG, SMTG, IP)
• 5 – occipital area 18
• 6 – occipital area 17

Neuritic Plaques Assessment

• For assessment for neuritic plaques, use the CERAD rating
• Ratings use 3 standard sections and rate how common the neuritic plaques are in the worst area of worst slide

CERAD Ratings

• CERAD ratings used an age-adjusted plaque score for NIA-AA scores: CO, C1, C2, or C3

Parkinson Disease (PD)

• PD is the second most common neurodegenerative disease
• 1% of the population over 65 has PD
• Usual onset for PD is at 55-65 years of age
• PD has a slight male predominance
• The key signs of PD can be remembered through “TRAP”: Resting Tremor, Rigidity, Bradykinesia, Postural instability
• Visible microscopic findings of PD is a Loss of pigmented dopaminergic neurons in substantia nigra, Lewy bodies, Lewy neurites

Causes of PD

• Inherited PD is rare and has <5% disease-causing mutations
• Genetic factors influence PD
• Having a first-degree relative with PD increases risk 2-3 fold

Parkinson Symptoms

• Parkinson disease and dementia can occur along with Co-existing disorders, particularly Alzheimer disease
• Severe, end-stage PD itself (Parkinson disease dementia) is a major cause
• Dementia with Lewy bodies is also a cause for PD (dementia develops first or within one year of a diagnosis of PD)

Huntington Disease (HD)

• HD was described by Huntington in 1872
• Symptoms of HD: Chorea, Memory deficit, Personality changes, Depression, Bulbar dysfunction
• Onset is mid-life (mean=35-45, ranges from 2-80) with death 10-15 years post onset
• Prevalence is 7-10/100,000

HD Description

• HD is a HTT- subtelomeric gene on 4p
• Huntingtin protein is widely expressed in fetal and adult tissues but its function is unknown
• HD can be identified by a CAG repeat sequence at N-terminus
• A normal gene has 9-37 CAG repeats
• Huntington Disease has 37-100 repeats or more
• Visible HD signs include: Atrophy of striatum (especially caudate nucleus), Corresponding dilation of ventricles, Cortical atrophy appears later
• Neuronal loss and reactive astrocytosis is visible
• Intranuclear inclusions: huntingtin is visible

HD Neuron loss

• There is a loss of 50% of striatal (spiny) neurons during onset of Huntington's disease
• Similar inclusions exist in other polyglutamine diseases
• Neostriatal degeneration moves in Caudorostral, Dorsoventral, and Mediolateral
• Grade of striatal disease correlates with other brain regions

Ataxia Description

• Cerebellar Ataxia: disease of cerebellum and/or afferent/efferent tracts leading to failure of cerebellar cortical function
• Sensory Ataxia: disease of peripheral nerves, dorsal root ganglia, or ascending tracts in the spinal cord

Ataxia Etiology

• Ataxia is caused by Acquired toxic, nutritional, metabolic, inflammatory, infective, ischemic, and paraneoplastic issues
• Hereditary issues cause Ataxia – Non-hereditary issues cause Ataxia

Friedreich Ataxia (FRDA)

• FDRA was first described by Friedreich in 1863 as a spinal cord abnormality
• The disease is the most common inherited ataxia with 1 in 50,000 being affected
• Symptoms generally begin to affect people at ~10 to before 25 years of age
• Key signs of FRDA: Progressive gait ataxia, Upper motor dyscoordination, Tremors, Pes cavus, distal muscle wasting, cardiomyopathy

FRDA Genetics

• FRDA is autosomal recessive
• The FRDA gene in centromeric region of 9q
• Frataxin- mitochondrial membrane protein is a key feature
• The commonest mutation is expansion of a GAA triplet repeat in intron that ranges from 200-1700 – Normal number of repeats: 6-34
• Repeat expansion results in reduced transcription and loss of expression of frataxin

Describing FRDA

• The brain in patients with FRDA is grossly unremarkable
• Spinal cords and dorsal roots are atrophic
• There is degeneration and astrocytosis of the posterior columns and spinocerebellar and corticospinal tracts
• Cerebellum: white matter with astrocytic gliosis, cortex normal, severe cell loss in dentate and marked atrophy of superior cerebellar peduncle
• In FRDA the Cerebral cortex has no specific pathologic changes, functional imaging showed cortical atrophy and reduced metabolism
• Peripheral nerves loss dorsal root ganglion cells with severe depletion of large myelinated axons from posterior roots and sensory nerves

Amyotrophic Lateral Sclerosis (ALS)

• ALS is regarded as “Motor neuron disease”
• Both upper and lower motor neurons (spinal cord, medulla) are affected
• People aged 40-60 years are affected, with male > female
• Causes progressive weakness and atrophy, and affects respiratory muscles
• The usual duration is of 3-5 years; 10% of patients live > 10 years
• There is a 5-10% familial chance in catching the disease
• Key gross findings in ALS: Atrophy of ventral roots, Rarely, atrophy of motor cortex
• Key microscopic findings in ALS: Loss of myelinated axons in corticospinal tract, Loss of myelinated axons in ventral roots and motor nerves, Loss of motor neurons
• ALS has Neuronal inclusions containing Ubiquitin and TDP-43

Prion Disease Description

• Sporadic Creutzfeldt-Jakob disease: 85-90% of cases
• Inherited: Familial Creutzfeldt-Jakob disease can also be a cause
• Gerstmann-Sträussler-Scheinker syndrome, and Fatal familial insomnia are other causes
• Acquired: latrogenic Creutzfeldt-Jakob disease, variant CJD, and Kuru are other causes of the disease
• Cellular PrP is a normal membrane-associated protein
• Disease occurs when PrPc undergoes conformational change to a β-pleated sheet configuration that is resistant to degradation by proteinase K
• Polymorphism at codon 129 acts as a susceptibility factor
• It codes for either methionine or valine

Key details for Sporadic CJD

• Its Etiology is unknown
• Incidence 1-2/ million/year
• Most cases homozygous for M or V at codon 129
• Rapid progressive dementia, myoclonus, ataxia, typical EEG, + 14-3-3 CSF

CJD Assessment

• the brain may be normal or show atrophy, including, the caudate, thalamus, and cerebellar folia
• Key microscopic findings include: Spongiform change, Loss of synapses, Astrocytic gliosis, Activation of microglia, Hyperphosphorylation of Tau, Accumulation of abnormal PrP
• Cerbral cortex and cerebellum contain amyloid plaques surrounded by vacuoles which are known as "florid plaques"
• it is more common that all patients are MM at codon 129 and there is Accumulation of PrPSc in lymphoreticular tissue
• it can be caused by latrogenic: Pituitary extracts, dural grafts, corneal transplants, depth electrodes
• Oral transmission: Kuru and vCJD
• Aerosolization: Scrapie
• Not proven: maternal-fetal, blood products, occupational

CJD Infectivity of organs

• High infectivity: Brain, spinal cord, pituitary, dura, eye
• Medium infectivity: Lymphoid tissue (including bowel), placenta, CSF
• Low infectivity: Peripheral nerve, bone marrow, pancreas, lung, liver, thymus
• Non- detectable areas: Muscle, kidney, fat, bone, blood, saliva, urine, feces, semen, milk
• Infectivity depends on route of inoculation such as Intracerebral > intravenous > intraperitoneal > subcutaneous
• There is a 10,000-fold difference between intracerebral and subcutaneous routes