Neurodegenerative demyelinating diseases (Gianani) Flashcards
Dementia (loss of mental power) is a generic term, not a disease entity. Any pathology that causes significant brain damage, at any age, can cause dementia. The causes of dementia include:
Stroke and ischemic encephalopathy (multi-infarct or vascular dementia)
Hippocampal sclerosis
Head trauma (subdural hematomas, diffuse axonal injury, chronic traumatic encephalopathy)
Hydrocephalus
CNS infections (HIV encephalitis, Creutzfeldt-Jakob disease)
Metabolic CNS disorders (lysosomal storage and peroxisomal diseases)
Demyelinative diseases (multiple sclerosis)
Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, diffuse Lewy body dementia, Huntington’s disease, and others)
Neuropsychiatric disorders
Severe medical illness or organ failure
The effects of medications
Cortical -
- Alzheimer’s disease
- Frontotemporal dementias ,Pick’s disease
- Diffuse Lewy body disease
- Corticobasal degeneration
Midbrain
- ** Parkinson’s disease
- Idiopathic
- Post-infectious
- Toxic (Meperidine analog MTPT)
- Parkinsonian dementia complex of Guam
- Multiple system atrophy (Striatonigral degeneration; Olivoponto- cerebellar degeneration; Shy Drager S.)
- Progressive supranuclear palsy (PSP)
Caudate nucleus
Huntington’s disease
Spinocerebellar degenerations
(CAG repeat syndromes)
- Spinocerebellar ataxias
- Friedreich’s ataxia
Motor system
(Upper cerebral cortex and lower motor neurons in brain stem and spinal cord )- Amyotrophic lateral sclerosis
- Spinomuscular atrophy
Mechanisms of cellular damage
Free radicals with oxidative injury
DNA damage & repair
Excitotoxicity
Blood brain barrier dysfunction
Mitochondrial dysfunction with energy depletion
*** Protein truncation with dysfunction/misfolding and/or accumulation
Liver: α1-Antitrypsin Deficiency
Just a reminder…..another disease caused by protein misfolding
This is not apoptosis! This is the actual misfolded protein in the cytoplasm. This leads to apoptosis…inflammation…cirrhosis..
Protein Misfolding and Aggregation (mainly know the list of proteins)
Common feature of several neurodegenerative conditions:
Beta-Amyloid: Alzheimer Disease (AD), *Cerebral Amyloid Angiopathy
Tau (tauopathies): AD*, Frontotemporal Lobar Degeneration (FTLD), Picks Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration
TDP43: Frontotemporal Lobar Degeneration (FTLD), some forms of ALS
Synuclein (synucleinopathies): Parkinson’s *Disease, Dementia with Lewy Bodies Disease, Multiple System Atrophy
Huntingtin: Huntington Disease
Prion protein( PrP ): CJD, vCJD, GSS, FFI
Prions or prion type of behavior of proteins in
neurodegenerative disorders
“This capacity for a protein in an abnormal conformation to induce similar structural change in other molecules as a self-propagating process has recently been demonstrated for many of the aggregating proteins associated with traditional neurodegenerative diseases. The suggestion that, at least within an individual, there may be cell-to-cell spread of disease-associated protein aggregates provides a link between prion diseases and other disorders such as Alzheimer disease and Parkinson disease.”
Alzheimer Disease
Tau and β-amyloid
Most common dementia (~85%) Onset >65 years of age Slowly progressive memory dysfunction Dysphasia, dyspraxia Progression to akynetic mutism Most are sporadic A minority are familial (earlier onset) Down syndrome
alzheimer’s Signs and Symptoms
Progressive memory loss Poor planning and problem solving Confusion with time and place Problems with word finding Misplacing objects Decreasing judgment Social withdrawal Mood/personality changes
Genetics of Familial AD
Familial: Mutations of……..
β amyloid precursor protein (21q21)
In the Down syndrome region
Early onset: mutations of... Presenilin 1 (14q24.3) Presenilin 2 (1q31-q42)
Mutation of any of the above genes leads to increased β- amyloid precursor protein
Apolipoprotein E gene (19q13.2) (ε4 isoform) increases risk about 25% for late onset AD
(This apoE isoform promotes β-amyloid precursor protein formation)
Tau (17q21.1)
main things to know about alzheimer’s
Tau
neurofibrillary tangles
High levels of tau protein in the CSF linked to poor recovery after head trauma
Inflammatory reaction to amyloid plaques and Tau tangles, with subsequent gliosis leads to grey matter loss.
CEREBRAL AMYLOID ANGIOPATHY
This is not Alzheimer Disease but when AD is present this condition is almost always present !
The ischemic lesions of CAA cause dementia.
Can cause ischemic or hemorrhagic lesions….vessel lumen can obliterate…vessel wall becomes weak and can break.
PICK’S DISEASE
Described almost 2 decades before AD.
Pick’s disease has long been the prototype of FTLDs.
It presents between 45-65 years with confusion and FTLD
symptoms and has a progressive course lasting 2-5 years, sometimes more.
In advanced stages it cannot be distinguished clinically from AD.
- The brain shows atrophy of frontal and temporal lobes,
** Pick bodies (tau-positive spherical cytoplasmic neuronal inclusions)
AD: plaques composed of
dystrophic neurites
beta amyloid
tau
AD: tangles composed of
tau
both intracellular and extracellular
Progressive supranuclear palsy
(not important)
PSP is a tauopathy in that affected individuals commonly develop progressive truncal rigidity, disequilibrium with frequent falls and difficulty with voluntary eye movements.
Other symptoms that are frequently observed include nuchal dystonia, pseudobulbar palsy and a mild progressive dementia.
The onset is usually between the fifth and seventh decades, with males affected approximately twice as frequently as females.
The disease is often fatal within 5 to 7 years of onset.
Parkinson Disease (PD)
Presents as a hypokinetic movement disorder caused by loss of dopaminergic neurons from the substantia nigra (nigrostriatal system)
Progresses as a global neurodegenerative disease to involve the cerebral cortex frequently leading to cognitive impairment… “Dementia with Lewy Bodies”.
The dopaminergic neurons of the substantia nigra project to the striatum and results in depletion of striatal dopamine.
The severity of the motor syndrome is proportional to the dopamine deficiency.
Etiology of Parkinson Disease
IDIOPATHIC form……..Unknown
MPTP PARKINSONISM
GUAM PARKINSON-DEMENTIA (GPD)
- toxic amino acid in the seed of a cycad plant which is used to make flour and is a staple in the local diet
Aluminum
- Aluminum can disrupt the neuronal cytoskeleton and cause neurofibrillary pathology.
Parkinsonian syndromes may also develop in the course of other conditions that damage the SN, e.g., striatonigral degeneration, postencephalitic parkinsonism, manganese poisoning, carbon monoxide poisoning, hypoxic-ischemic encephalopathy, traumatic brain injury, and stroke.
basal ganglia info
Virtually all inputs to the basal ganglia arrive via the striatum (caudate, putamen, and nucleus accumbens). Outputs leave the basal ganglia via the internal segment of the globus pallidus and the closely related substantia nigra pars reticulata and compacta.
The presumptive diagnosis of PD
can be based on the presence of the central triad of parkinsonism—tremor, rigidity, and bradykinesia—in the absence of a toxic or other known underlying etiology.
The clinical syndrome of parkinsonism combines:
diminished facial expression (often termed masked facies)
stooped posture
slowing of voluntary movement
festinating gait (progressively shortened, accelerated steps)
rigidity
“pill-rolling” tremor
This impression is confirmed by symptomatic response to l-DOPA replacement therapy.
Deep brain stimulation (DBS
In DBS, electrodes implanted into the subthalamic nucleus or inner part of the globus pallidus provide electrical stimulation to these and surrounding structures. This stimulation induces physiological and chemical changes that ameliorate some of the motor symptoms of PD by a poorly understood mechanism. Unilateral tremor and rigidity may also respond to stereotactic ablation of the contralateral globus pallidus, ventrolateral thalamus, or subthalamic nucleus.
