[10.04c] Neurodegenerative, Genetic, Metabolic, Toxic, and Acquired Diseases V2.2.pdf

Progressive loss of particular groups of neurons that often share functions

What is the definition of neurodegenerative diseases?

Accumulation of protein aggregates or proteinopathies

What is the common pathologic process across neurodegenerative diseases?

Adaptive response to sequester small toxic proteins into larger inclusions

What is the current theory regarding the formation of large protein aggregates?

Protein aggregates recognized histologically

What are inclusions?

Anatomic/Symptomatic and Pathologic

What are the two different approaches used to classify neurodegenerative diseases?

Type of inclusions or abnormal structures observed

On what is the pathologic classification of neurodegenerative diseases based?

Prion protein aggregation and intracellular spread

What causes rapidly progressive prion diseases?

Creutzfeldt-Jakob Disease or CJD

What is the most common prion disease?

Spongiform change

What is the characteristic morphologic feature of prion disease in the brain?

Intracellular vacuoles in neurons and glia

What causes the spongiform change seen in prion diseases?

Alpha-helical PrPc

What is the normal cellular form of the prion protein?

Beta-sheet PrPsc

What is the pathogenic, misfolded conformation of the prion protein?

Physical interaction

How does PrPsc convert normal PrPc into the pathogenic form?

Propagation of misfolded proteins

What accounts for the transmissible nature of prion diseases?

Seventh decade

When is the peak incidence for sporadic Creutzfeldt-Jakob Disease?

Average survival of 7 months

How rapidly fatal is Creutzfeldt-Jakob Disease?

Iatrogenic transmission

Corneal or dural transplantation and contaminated human growth hormone are examples of what in CJD?

Variant CJD or vCJD

Which prion disease is linked to exposure to bovine spongiform encephalopathy?

Young adults

Which age group is primarily affected by Variant CJD?

Kuru plaques

What are the aggregates of prion protein stained with periodic acid Schiff in the cerebral cortex called?

Alzheimer Disease

What is the most common cause of dementia in older adults?

Accumulation of Amyloid beta and tau

What is the fundamental abnormality in Alzheimer Disease?

Amyloid plaques

What are the extracellular deposits of aggregated beta-amyloid peptides in the neuropil?

Neurofibrillary tangles

What are the intracellular aggregates of the microtubule-binding protein tau?

Generation of beta-amyloid or Abeta

What is the critical initiating event for the development of Alzheimer Disease?

Alpha-secretase and gamma-secretase

Which enzymes cleave Amyloid Precursor Protein into harmless soluble peptides?

BACE and gamma-secretase

Which enzymes cleave Amyloid Precursor Protein into pathogenic Abeta peptides?

Chromosome 21

On which chromosome is the gene encoding Amyloid Precursor Protein located?

Down Syndrome

Which condition is associated with nearly universal development of Alzheimer Disease due to APP gene dosage?

Apolipoprotein E or ApoE

Which genetic locus on chromosome 19 has a strong influence on the risk of developing Alzheimer Disease?

Tau protein aggregates

What triggers a stress response and loss of microtubule stability in Alzheimer neurons?

Number of neurofibrillary tangles

Which pathologic marker correlates best with the degree of dementia in Alzheimer Disease?

18F-labeled amyloid-binding compounds

What imaging method is used to demonstrate beta-amyloid deposition in the brain?

Increased phosphorylated tau and reduced Abeta

What are the characteristic biomarker changes in the CSF of Alzheimer patients?

Frontal, temporal, and parietal lobes

Which lobes show the most pronounced cortical atrophy in Alzheimer Disease?

Gyral narrowing and sulcal widening

How is cortical atrophy grossly characterized?

Silver stain

Which histological stain highlights neurofibrillary tangles within the neuronal cytoplasm?

Braak Staging

What is the system used to stage Alzheimer Disease based on the spread of neurofibrillary tangles?

Hippocampus

Where is neurofibrillary tangle involvement confined in Braak Stages 1 and 2?

Forgetfulness and memory disturbances

What are the initial symptoms of Alzheimer Disease?

Intercurrent disease such as pneumonia

What is usually the terminal event in Alzheimer Disease?

Frontotemporal Lobar Degeneration or FTLD

What is the group of disorders associated with focal degeneration of frontal and/or temporal lobes?

Personality, behavior, and language alterations precede memory loss

How is FTLD clinically distinguished from Alzheimer Disease?

FTLD-tau and FTLD-TDP

What are the two most common pathologic patterns of Frontotemporal Lobar Degeneration?

Pick bodies

What are the smooth contoured, 3R tau-containing inclusions found in some forms of FTLD-tau?

TDP-43

Which RNA-binding protein is found in inclusions of the most common genetic form of FTLD?

C9orf72

Which gene expansion is the most common genetic form of both FTLD and ALS?

Parkinson Disease

What is the neurodegenerative disease marked by a prominent hypokinetic movement disorder?

Loss of dopaminergic neurons from the substantia nigra

What causes the motor symptoms in Parkinson Disease?

Tremor, rigidity, and bradykinesia

What is the central triad of parkinsonism?

Masked facies

What is the term for diminished facial expression in Parkinson patients?

Festinating gait

What is the term for the progressively shortened, accelerated steps seen in Parkinson Disease?

Pill-rolling tremor

What is the characteristic resting tremor of Parkinson Disease?

Response to L-Dopa replacement therapy

What clinical test helps confirm a presumptive diagnosis of Parkinson Disease?

Alpha-synuclein

What is the major component of the Lewy body?

Lewy body

What is the diagnostic hallmark of Parkinson Disease?

SNCA

Which gene encoding alpha-synuclein was the first mutation identified in autosomal dominant Parkinson Disease?

DJ-1, PINK1, and Parkin

Mutations in which three genes are associated with mitochondrial dysfunction in autosomal recessive Parkinson Disease?

Glucocerebrosidase

Heterozygous mutations in which lysosomal enzyme are the most important risk factor for Parkinson Disease?

LRRK2

Which gene mutation is a common cause of autosomal dominant and some sporadic late-onset Parkinson Disease?

Pallor of the substantia nigra and locus coeruleus

What is the characteristic gross finding in the Parkinsonian brainstem?

Eosinophilic, round to elongated inclusions with a dense core and pale halo

What is the microscopic appearance of a Lewy body?

Dementia with Lewy Bodies

What condition may represent advanced Parkinson Disease where protein aggregates spread to the cerebral cortex?

Progressive Supranuclear Palsy or PSP

Which tauopathy is characterized by truncal rigidity, disequilibrium, and difficulty with voluntary eye movements?

4R tau

What type of tau is found in the inclusions of Progressive Supranuclear Palsy?

Corticobasal Degeneration or CBD

Which progressive tauopathy involves tufted astrocytes, coiled bodies, and ballooned neurons?

Neuronal achromasia

What is the term for the ballooned neurons seen in Corticobasal Degeneration?

Multiple System Atrophy or MSA

Which sporadic disorder involves alpha-synuclein inclusions in oligodendrocytes?

Striatonigral, olivopontocerebellar, and autonomic circuits

What are the three neuroanatomic circuits involved in Multiple System Atrophy?

Orthostatic hypotension

What is a prominent autonomic symptom of Multiple System Atrophy?

Glial cytoplasmic inclusions

What is the primary pathologic hallmark of Multiple System Atrophy?

Huntington Disease

What is the autosomal dominant disease characterized by progressive chorea and dementia?

Degeneration of striatal neurons

What causes the movement disorders in Huntington Disease?

CAG

Which trinucleotide repeat is expanded in the HTT gene in Huntington Disease?

Chromosome 4p16.3

Where is the HTT gene located?

Anticipation

What is the phenomenon where paternal transmission of Huntington Disease leads to earlier onset in the next generation?

Intranuclear inclusions containing huntingtin

What is the pathologic hallmark of Huntington Disease?

Striatum (Caudate nucleus and putamen)

Which brain structures show striking atrophy in Huntington Disease?

Ventricular dilation

What gross change occurs in the brain secondary to striatal atrophy in Huntington Disease?

Spinocerebellar Ataxias or SCA

What is the heterogeneous group of autosomal dominant diseases causing progressive ataxia?

Friedreich Ataxia

Which autosomal recessive disease is caused by a GAA trinucleotide repeat expansion?

Frataxin

Which protein is affected in Friedreich Ataxia?

Cardiomyopathy

What is a common non-neurological feature of Friedreich Ataxia?

Ataxia-Telangiectasia

Which disease involves an ataxic-dyskinetic syndrome, conjunctival telangiectasias, and immunodeficiency?

ATM gene

Which gene mutation on chromosome 11 causes Ataxia-Telangiectasia?

Amyotrophic Lateral Sclerosis or ALS

Which disease involves the loss of both upper and lower motor neurons?

Denervation of muscles producing profound weakness

What is the result of motor neuron loss in ALS?

SOD1 on chromosome 21

One of the first discovered hereditary forms of ALS involves mutations in which gene?

Thinning of the anterior roots of the spinal cord

What is a characteristic gross morphology of the spinal cord in ALS?

Asymmetric weakness of the hands

What is a common early symptom of ALS?

Fasciculations

What are the involuntary contractions of individual motor units seen as ALS progresses?

Kennedy Disease

What is the X-linked polyglutamine repeat disease characterized by distal limb amyotrophy and bulbar signs?

Androgen receptor

Which receptor gene is affected in Kennedy Disease?

Spinal Muscular Atrophy or SMA

What is the group of childhood disorders characterized by marked loss of lower motor neurons?

SMN1

Disruption of which gene is associated with all forms of Spinal Muscular Atrophy?

Werdnig-Hoffman disease or SMA Type 1

What is the most severe form of Spinal Muscular Atrophy?

Neuronal Storage Diseases

Which autosomal recessive disorders are caused by deficiencies in enzymes required for sphingolipid or mucopolysaccharide catabolism?

Leukodystrophies

Which disorders are caused by mutations in genes involved in the generation or maintenance of myelin?

Insidious and progressive loss of cerebral function at a young age

How do leukodystrophies typically present?

Krabbe Disease

Which leukodystrophy results from a deficiency of galactocerebroside beta-galactosidase?