Neuroscience Week 4: Neurodegenerative Disorders Flashcards
the common theme of neurodegenerative diseases
- abnormal aggregation of proteins
- aggregates are resistant to proteases
- neuronal death and propagation of abnormal proteins
Disease table
Temporal progress of Alzheimer’s
Alzheimer’s Stages: Mild cognitive impairment duration
7 years
Alzheimer’s Stages: Mild cognitive impairment disease is found in?
medial temporal lobe
Alzheimer’s Stages: Mild cognitive impairment symptoms
- short-term memory loss
- Forgetfulness
Alzheimer’s Stages: Mild Alzheimer’s duration
2 years
Alzheimer’s Stages: Mild Alzheimer’s Disease is found in
medial temporal lobe and spreads to lateral temporal and parietal lobes
Alzheimer’s Stages: Mild Alzheimer’s symptoms
6 listed
- reading problems
- poor object recognition
- poor direction sense
- language deficits
- math deficits
- motor skill loss
Alzheimer’s Stages: Moderate Alzheimer’s duration
2 years
Alzheimer’s Stages: Moderate Alzheimer’s disease is found in?
spreads to frontal lobe
Alzheimer’s Stages: Moderate Alzheimer’s Symptoms
6 listed
- poor judgment
- impulsivity
- Short attention
- language deficits
- math deficits
- motor skill loss
Alzheimer’s Stages: Severe Alzheimer’s duration
3 years
Alzheimer’s Stages: Severe Alzheimer’s disease is found in?
spreads to occipital lobe
Alzheimer’s Stages: Severe Alzheimer’s Symptoms
3 listed
- visual problems
- Hallucinations
- Mutism
The most common cause of dementia in the elderly?
Alzheimer’s disease
Second most common cause of dementia?
Vascular dementia caused by hypertension, atherosclerosis or vasculitis
Alzheimer’s common age of onset?
Rarely present before age 50 (if it does think familial secondary to mutations in presenilin-1 and 2, part of γ-secretase complex, 5-10% are familial)
about ~50% incidence in >/= 84 years of age
Alzheimer’s Timeline
5-10 years to mutism, immobility, and hallucinations
Down syndrome and Alzheimer’s Disease
Down’s syndrome patients have increased incidence because gene for amyloid precursor protein is in chromosome 21 and down syndrome is chromosome 21
Alzheimer’s Disease Pathophysiology
- Amyloid precursor protein is normally cleaved by α and γ secretases producing a harmless soluble protein
- If the protein is cleaved by β secretase and then cleaved by γ secretase which generates large Aβ peptide (pathologic)
- β-amyloid deposition could be one of the triggers for Alzheimer’s Disease and lead to kinase activation which can phosphorylate Tau leading to microtubule disassembly
- Tau when hyperphosphorylated dissociates from microtubules and translocates from axons to the soma
- The clinical symptoms of Alzheimer’s disease correlate with Tau rather than β -amyloid
- Tau becomes sequestered causing neurofibrillary tangles
- Degeneration of cholinergic neurons in nucleus basalis of Meynert
Alzheimer’s Disease Treatment lecture
- Donepezil acetylcholinesterase inhibitor to increase cholinergic levels
- Memantine NMDA antagonist to prevent cell death
Alzheimer’s Disease forms
Sporadic form is the most common
APoE-2 reduces risk
ApoE-3 intermediate risk
ApoE-4 increases risk
Alzheimer’s Disease Risk Factors
APoE-2 reduces risk
ApoE-3 intermediate risk
ApoE-4 increases risk
These are cholesterol transporting proteins the relation to Alzheimer’s disease is not fully understood
The clinical symptoms of Alzheimer’s disease correlate with?
Tau burden rather than β-amyloid
CTE AKA
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy also presents with?
Neurofibrillary tangles
Tau when hyperphosphorylated dissociates from?
- Microtubules
- when Tau is phosphorylated it dissociates and the microtubules become unstable and disassemble
- Tau becomes sequestered in neurofibrillary tangles
Alzheimer’s Disease Macroscopic pathology
- Cortical atrophy (narrowing of the gyri, widening of the sulci) in advanced AD
- Cortical atrophy and hydrocephalus ex vacuo (dilation of ventricles) in AD from the loss of neural tissue surrounding them
Normal brain comparison to Alzheimer’s Brain
Alzheimer’s Disease Microscopic pathology
- plaques contain a central core of amyloid and a surrounding region of dystrophic neurites
- stain is Bielschowsky Silver stain
- or antibodies specific for Tau
- intracellular filamentous inclusions composed of hyperphosphorylated Tau
Neuritic Plaque & Neurofibrillary tangles
(Extracellular) Aβ deposits with Tau paired helical filaments in Alzheimer’s disease
Tangles are typically intracellular
Cerebral Amyloid Angiopathy
- β-amyloid can also deposit around blood vessels
- can be a source of intraparenchymal hemorrhage
Frontotemporal Dementia AKA
Pick’s Disease
Pick’s Disease AKA
Frontotemporal Dementia
Frontotemporal Dementia Classification
includes a spectrum of disorders that preferentially affect the frontal and/or temporal lobes
Frontotemporal Dementia Description and clinical presentation
characterized by progressive deterioration of language (primary/progressive aphasia: deficits in word finding, word usage, word comprehension, or sentence contruction-damage to frontal and/or temporal lobes) and changes in personality (behavioral variant: disinhibition, hyperorality, apathy, loss of empathy, compulsive behaviors- damage to frontal lobes predominates)
Frontotemporal Dementia vs Alzheimer’s Disease
- behavioral and language problems precede memory disturbances
- occurs at younger ages from Alzheimer’s Disease
Frontotemporal Dementia pathological subgroups
2 listed
Frontotemporal Dementia-tau = Pick’s disease, which is associated with smooth, round inclusions known as Pick bodies
Frontotemporal Dementia-TDP43
Frontotemporal Dementia-tau
= Pick’s disease, which is associated with smooth, round inclusions known as Pick bodies
Frontotemporal Dementia-TDP43
- TDP43 neuronal inclusion are also found in a large proportion of cases of Amyotrophic lateral sclerosis
- this overlap is manifest clinically, as many individuals with ALS also show evidence of frontotemporal dementia
Frontotemporal Dementia vs ALS
- Frontotemporal Dementia TDP43 neuronal inclusions are also found in a large proportion of cases of Amyotrophic lateral sclerosis
- this overlap is manifest clinically, as many individuals with ALS also show evidence of frontotemporal dementia
Frontotemporal Dementia Pathological Features
Atrophy of the temporal lobe w/ or w/o atrophy of the frontal lobe
severe neuronal loss and gliosis in the region of atrophy
FTLD-tau cytoplasmic inclusions seen in loss of normal nuclear immunoreactivity
and TDP43 intranuclear inclusions
Frontotemporal Dementia PAthological features what kind of bodies and cells and macropathology
- Pick bodies
- Pick Cells (balloned neurons)
- Knife-like Gyri
Parkinson’s disease Description
Parkinson’s disease is a hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra.
Parkinson’s Disease pathophysiology
- Abnormal protein and organelle clearance due to defects in autophagy and lysosomal degradation have a pathogenic role in the disease
- The Lewy Body is a characteristic inclusion in Parkinson’s Disease and Lewy Body Dementia
Lewy Body
- The Lewy Body is a characteristic inclusion in Parkinson’s Disease and Lewy Body Dementia
- Is a characteristic inclusion containing
α- synuclein, a protein involved in synaptic transmission
- Most cases of PD are sporadic but point mutations in the
α-synuclein gene causes autosomal dominant PD
- α-Synuclein aggregates are cleared by autophagy and several mutations associated with PD are in genes whose products (LRRK2, Parkin, others) are involved in endosomal trafficking pathways implicated in autophagy
Most cases of PD are sporadic but point mutations in the
α-synuclein gene causes
autosomal dominant Parkinson’s Disease
α-Synuclein aggregates are cleared by
autophagy and several mutations associated with PD are in genes whose products (LRRK2, Parkin, others) are involved in endosomal trafficking pathways implicated in autophagy
Gaucher Disease and Parkinson’s Disease
It also has been demonstrated that heterozygosity for the Gaucherdisease–causing mutation in glucocerebrosidase (a lysosomal enzyme involved in lysosomal degradation) is a risk factor for PD
Parkinson’s Disease Morphology
Study A, B, and C
α-Synuclein Inclusion AKA
Lewy body
Lewy Body Dementia Description
3 listed
- Lewy body dementia is a sporadic neurodegenerative disease
- It combines the neurological manifestations of dementia and parkinsonism.
- Patients present with fluctuating attention and cognition and visual hallucinations. Motor parkinsonian manifestations (bradykinesia, rigidity, and less frequently tremor) vary in severity and may appear later. Patients also have depression, sleep disorder, and autonomic dysfunction
Lewy Body Dementia Clinical Presentation
- It combines the neurological manifestations of dementia and parkinsonism.
- Patients present with fluctuating attention and cognition and visual hallucinations.
- Motor parkinsonian manifestations (bradykinesia, rigidity, and less frequently resting tremor) vary in severity and may appear later.
- Patients also have depression, sleep disorder and autonomic dysfunction
Lewy Body Dementia Pathologic Hallmark
- The pathologic hallmark is the presence of eosinophilic intracytoplasmic inclusions (Lewy bodies), which contain aggregated α-synuclein, in the deep cortical layers throughout the brain, especially in anterior frontal and temporal lobes, cingulate gyrus, and insula
Lewy Body Dementia Vs Parkinson’s Disease
- The differentiation of Parkinson disease dementia (PDD) and Dementia with Lewy bodies (DLB) is somewhat arbitrary.
- In PDD, dementia occurs in the setting of well-established parkinsonism, while in DLB, dementia usually occurs concomitantly with or before the development of parkinsonian signs.
- If parkinsonism is present for more than one year before the onset of dementia, it is officially classified as PDD.
Basically if parkinsonism is present 1 year or more before the onset of dementia then it is Parkinson’s Disease
Other neurodegenerative diseases with Parkinson-like symptoms
- Progressive Supranuclear palsy
- Multiple system atrophy (α-synucleinopathy)
- Corticobasal degeneration (tauopathy)
Huntington’s Disease Etiology
- Trinucleotide expansion of the HTT (Huntingtin) gene on chromosome 4p
- This adds a polyglutamine segment to huntingtin. This protein is widely expressed throughout the brain. It is thought that the CAG-expanded huntingtin has a toxic function. However, huntingtin is a key cellular protein involved in cellular transport and is important for cell viability. Therefore, loss of huntingtin function may also contribute to the pathogenesis of HD
Huntingtons Disease pathophysiology
- The CAG triplet expansion is probably due to malfunction of cellular processes that repair strand breaks and remove mispaired bases from DNA.
- The expanded huntingtin, conjugated with ubiquitin, forms aggregates (inclusions) in the nuclei cytoplasm and dendrites of affected neurons.
- These inclusions can be detected by immunohistochemistry using antibodies to huntingtin.
- These findings suggest that there is an error in the proteolytic degradation of the expanded huntingtin.
- Impairment of this process apparently causes huntingtin-ubiquitin complexes to be translocated into the nuclei
Huntington’s Disease # of repeats
- Adult-onset patients have 40-50 repeats.
- A high number of repeats is associated with early onset and more rapidly progressing disease.
- The expanded CAG repeat is unstable and may increase in size in successive generations.
- This causes the disease to appear at a younger age and more severe form, a phenomenon is known as anticipation.
- Anticipation occurs more commonly if the mutated allele is inherited from the father.
Huntington’s Disease Anticipation
The expanded CAG repeat is unstable and may increase in size in successive generations. This causes the disease to appear at a younger age and more severe form, a phenomenon known as anticipation. Anticipation occurs more commonly if the mutated allele is inherited from the father.
Biochemical analysis of Huntington’s disease and symptoms
- Biochemical analysis of the striatum in HD shows loss of GABA and other transmitters.
- The decrease of GABA and unbalanced dopamine activity result in chorea
- Dementia and depression (including suicide) are common in advanced stages
Huntington’s Disease Morphology
- atrophy of the striatum and ventricular dilation
- an intranuclear inclusion in a cortical neuron is strongly immunoreactive for Ubiquitin
- Microscopic examination reveals severe loss of neurons from affected regions of the striatum along with gliosis. There is excitotoxicity-mediated cell death of medium-sized, spiny neurons that GABA.
Spinocerebellar Ataxias Description
- Spinocerebellar ataxias (SCAs) are a heterogeneous group of several dozen diseases with clinical findings that include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy.
- These disorders affect, to a variable degree, the cerebellar cortex, spinal cord, other brain regions, and peripheral nerve
As with Huntington’s disease, several forms of?
Spinocerebellar Ataxias are caused by CAG repeat expansions encoding polyglutamine tracts in various genes
Alzheimer’s Familial Mutations
Rarely present before age 50 (if it does think familial secondary to mutations in presenilin-1 and 2, part of the γ-secretase complex, 5-10% are familial)
Spinocerebellar Ataxias Pathologic Features
- Spinocerebellar ataxias (SCAs) are a heterogeneous group of several dozen diseases with clinical findings that include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy. These disorders affect, to a variable degree, the cerebellar cortex, spinal cord, other brain regions, and peripheral nerve
- Degeneration of neurons, often without other distinctive histopathologic changes, occurs in the affected areas and is associated with mild gliosis
Amyotrophic Lateral Sclerosis Protein Inclusions
- Superoxide Dismutase (SOD1)
- TDP43
Amyotrophic Lateral Sclerosis has ________ similar to __________
- TDP-43
- Frontotemporal lobar Degeneration
ALS Overview
ALS Morphology
Prion Diseases Description
- Prion diseases are a group of infectious diseases in which the causative agent is an abnormal form of a cellular protein.
- These include sporadic, familial, iatrogenic, and variant forms of Creutzfeldt-Jakob disease (CJD), as well as animal diseases such as scrapie in sheep and bovine spongiform encephalopathy in cattle (“mad cow disease”)
Prion Diseases Etiology
- The prion protein (PrP) undergoes a conformational change from its normal shape (PrPc) to an abnormal conformation called PrPsc(scforscrapie). PrPsc has a high content of β-sheets, a characteristic that makes it resistant to proteolysis
- Also, binds to normal proteins and changes their conformation to PrPsc
Creutzfeldt-Jakob Disease Clinical Presentation
- CJD is characterized by dementia that progresses rapidly (weeks to months; death in less than 1 year)
- associated with ataxia and startle myoclonus.
- Periodic sharp waves are seen on EEG.
- Increase in 14-3-3 protein in CSF
Creutzfeldt-Jakob Disease Diagnostic Test Findings
2 listed
- Periodic sharp waves are seen on EEG.
- Increase in 14-3-3 protein in CSF
Variant Creutzfeldt-Jakob Disease is related to?
- bovine spongiform encephalopathy
- “ingesting contaminated tissues”
Iatrogenic Creutzfeldt-Jakob Disease (iCJD) causes
6 listed
- iatrogenic CJD (iCJD)has been caused by injection of growth hormone and gonadotrophin extracted from cadaveric pituitaries, contaminated dural grafts, corneal transplants, and contaminated surgical instruments
Creutzfeldt Jakob Disease Morphology
- Spongiform encephalopathy neurons with vacuoles, brain looks like a sponge
- Variant CJD has amyloid plaques
