Neurodegenerative Disorders Flashcards by sami sh

Identify examples of Neurodegenerative disorders.

Parkinson’s disease
Alzheimer’s disease
Huntington’s disease
Motorneurone diseases
Spinocerebellar degenerations
Spongiform encephalopathies
FTD, other dementias
Progressive MS
Others

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Identify possible factors which contribute to neurodegeneration.

Protein handling disorders
Activation of cell death pathways
Mitochondrial dysfunction
Lack of growth factors
Oxidative stress
Ionic dysequilibrium
Excito- toxicity
Immune attack
Toxins

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Identify genes associated with ALS.

Superoxide Dismutase 1
TAR DNA Binding Protein (TDP-43)
Fused in Sarcoma (FUS)
C9orf72 (most common)

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Identify possible mechanisms of neuronal death in neurodegenerative disorders.

1) Excitotoxicity (through glutamate, and calcium overload)
2) Oxidative Stress (result of excessive production of reactive oxygen species)
3) Apoptosis (Many different signalling pathways can result in apoptosis, but in all cases the final pathway resulting in cell death is the activation of a family of proteases (caspases), which inactivate various intracellular proteins)

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Identify the main examples of motorneuron diseases.

Amyotrophic Lateral Sclerosis
Progressive Muscular Atrophy (LMN)
Primary Lateral Sclerosis (UMN)
Spinal Muscular Atrophy (groups of spinal nerves degenerate at different times, relatively slowly)
Lou Gehrig’s disease

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Does ALS have upper, or lower motor neuron signs ?

Both (brisk reflexes in muscles that are fasciculating)

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Identify a treatment used for ALS, describing its mode of action. How long does it prolong life ?

RILUZOLE

Blocks TTX Na channels
Reduces Glutamate release (Calcium block)
Increases astrocyte glutamate uptake
Enhances GABA activity
Enhances BDNF action

Prolongs life by about 3 months

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Identify the main features of dementia.

1. Neuropsychological deficits
Amnesia (memory)
Aphasia (speech) 
Agnosia (recognising things) 
Apraxia (complex movements)

Neuropsychiatric features
(Behavioural and psychological symptoms, BPSD)
Psychiatric symptoms
Behavioural disturbances
Activities of daily living
Instrumental
Basic

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Describe the cognitive assessment for a patient with possible dementia.

1) Frontal lobes – sequencing and fluency
• Luria hand sequencing task (repeat this sequence of movements)
• Verbal fluency 1 minute words F,A, S, animals

2) Temporal lobes – memory, speech (L)
• Address test
• Object recall
• Serial 7s

3) Parietal lobes – Spatial awareness (R), Language (L)
• Clock face (draw clockface)
• Naming objects
• Drawing cube, interlocking infinity
• Agnosia

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Identify specific tool for dementia screening.

MMSE

ACE-R Psychometrics (more sensitive, more specific)

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Describe diagnosis of dementia.

Dementia is conventionally diagnosed when progressive cognitive decline has occurred, and this has had noticeable impacts upon a person’s ability to carry out important everyday activities.
The pathological changes in the brain that will eventually lead to the symptoms of dementia are likely to have commenced well in advance (15-30 years) of the time at which the person’s symptoms would first have been noticed

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Define mild cognitive impairment.

• MCI requires subjective memory impairment and cognitive impairment not meeting dementia diagnostic criteria (in particular with no impairment in core ADLs)

Can be reversible (conversion by n omeans inevitable, even for MCI up to 25% in some studies show subsequent recovery of normal cognitive function)

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Describe the main presentation of Alzheimer’s disease.

• Presents with early memory disturbance, progressing to dyspraxia and dysphasia, eventually immobile and mute

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Identify the main histological processes of AD.

1) Neurofibrillary tangles
• predominantly composed of tau
• normal tau stabilises microtubules
• tau is hyperphosphorylated in NFTs and forms paired helical filaments

2) Amyloid plaques
• Extracellular proteinaceous deposits
• Largely composed of Aβ peptides that aggregate together to form fibrils–either diffuse or neuritic (surrounded by dystrophic neurites)

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What are the main CSF markers investigated for the diagnosis and management of AD, almost all immunoassay ?

– amyloid-β42 (Aβ42)
– Total tau (t-tau)
– Phosphorylated tau (p-tau)
(but no CSF marker can reliably predict development of AD in healthy individuals)

Real Time Quake-Induced Conversion (RT QuIC) is a new way of looking for levels of Aβ42, one of the components of APP, in spinal fluid of patient which are going on to develop AD.

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Identify neurochemical changes in AD.

Marked loss of ACh, related to neuronal loss from nucleus basalis of Meynert
Loss of GABA from cortex secondary to neuronal loss
Serotonin (5HT) input from dorsal raphe nuclei reduced
Noradrenaline input from locus ceruleus reduced

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Describe treatment for dementia.

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Essentially, block breakdown of ACh, increase amount of ACh released, or of glutamate released:

Acetylcholinesterase inhibitors (block breakdown of ACh); donepezil, galantamine, rivastigmine used in mild to moderate dementia.
NMDA receptor (glutamate receptor) antagonists e.g. memantine used in moderate to severe DAT.

Identify a screening tool for AD.

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ADAS-cog

Out of 70
Measure of cognitive performance
FLAWED
Widely used primary outcome measure in clinical trials
Some modifications have been made by adding components, but these do not overcome the key problems

Describe the main features of fronto-temporal dementia (Pick’s disease)

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Inappropriate behavior
Early loss of personal awareness and social awareness
Early signs of disinhibition
Mental rigidity
Hyperoralism (eat things inappripriately)
Specific syndrome
May have memory problems

What is the objective in MS treatment ?

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Reduce number of relapses

Identify older drugs which can be used for degeneration, and describe the effect of each.

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Statins (may have positive effects on neurodegeneration)
Na channel blockers (e.g. Lamotrigine, amiloride)
Anti-glutamate (reducing excitotoxicity)
Free radical scavengers (e.g. beetroot juice)
Metformin

What is the average life expectancy of MND ?

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About 3 years

Are there any agents which are proven to slow clinical deterioration for AD, PD, or MND ?

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Nothing that is proven to slow clinical deterioration for AD or PD, one treatment for MND.

What is the most important cause of disability over age 60 ?

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Neurodegenerative disorders

DEMENTIA - Is it a diagnosis ? - What is the diagnostic test for it ?

DEMENTIA - Syndrome, NOT specific diagnosis - Only definitive diagnostic test is pathology, usually post-morterm, no single diagnostic test, no reliable biomarker

Identify an ethical problem associated with dementia.

If we don’t have anything to alter the course of the disease, does early diagnosis help anyone?

Which group of patients with mild cognitive impairment has the highest conversion rate into dementia ?

Conversion rates are probably highest for amnestic MCI in which the prominent impairment is one of memory (amnestic MCIs have Aβ42 levels which are lowered significantly ~10 years before clinical symptoms of AD manifes)

What proportion of all cases of dementia are made up by AD ?

70%

What is the prevalence of AD at 65 ? 90 ?

Prevalence of AD 1% at 65, 40% at 90 (doubles every 5 years)

Which of men or women are more affected by AD ? What proportion of AD is familial ?

Female predominance 10 familial

Describe neuroimaging of AD.

• Structural and Functional • CT, MRI • Perfusion SPECT (Single Photon Emission Computed Tomography) – usually Tc99-HMPAO - images variations in regional cerebral blood flow which display charactersitic abnormalities in early AD - widely available now in many DGHs • FDG-PET – (F18 - Fluoro-deoxyglucose – Positron Emission Tomography) - Uptake of FDG proportional to cerebral glucose metabolism, thus thought to be indicator of cerebral metabolism • Amyloid Imaging

Identify possible neuroimaging findings in AD.

Atrophy of brain, but that happens with ageing anyway (i.e. nothing very specific to AD)

Describe the way amyloid imaging works.

• Beta-amyloid (Aβ) is 39-43 amino acid metalloprotein and is a normal product of cell metabolism in the brain • It is believed that a combination of overproduction of Aβ and impaired clearance of Aβ in Alzheimers disease is responsible for the accumulation of extra-cellular placques of Aβ • C11-PiB PET (Carbon11 – Pittsburgh compound B Positron Emission Tomography). PiB crosses the blood-brain barrier easily and binds strongly to Aβ allowing quantitative imaging of Aβ burden. In combination with CSF Aβ and tau measurement, probably the best antecedent biomarkers for AD at the preclinical and prodromal phases. However in established dementia Aβ burden on PiB-PET does not correlate well with level of cognitive impairment • PiB PET has also been used to monitor treatment response to amyloid- clearing therapies

Describe any efforts to develop immunisations against AD.

1) Active immunisation (AN1792) against amyloid-β42 BUT a lot of patient developed meningo-encephalitis as a result. Amyloid was removed BUT neurodegeneration continued (which suggests that may not be amyloid, but possibly Tau) 2) Bapineuzumab (aab-001), immunisation against amyloid-β42 passive transfer in phase III ineffective, some inflammation 3) New trials using anti-Tau and anti-Ab

Identify some components of the ADAS-cog.

- Word Recall - Commands - Naming objects and fingers - Orientation - Word recognition

Describe some of the main shortcomings of ADAS-cog.

- Population does not start responding until quite demented - NOT sensitive - Scale's best place of measurement (sweet spot) is at 35 (halfway to being demented) (MMSE equivalent of 14, which is quite demented), which means this is no good for early testing of performance

How much do Cholinesterase inhibitors improve patients on the ADAS-cog scale ?

Improve them by around 2 points after 6 months

Describe timeline of multiple sclerosis.

1) Episodes of relapses (relapsing-remitting), characterised by: - Frequent inflammation - Demyelination - Axonal transection - Plasticity and re-myelination 2) After number of years, more progressive disease (secondary progression), characterised by: - Infrequent inflammation - Chronic axonal degeneration - Gliosis Initial episodes of inflammation start attacking nerve cells so gradual loss of nerve cells as number of episodes of relapse decreases.

Does cannabis have any therapeutic value for MS ? Identify possible problems with designing such a study.

Unclear but beneficial from patient's perspective (esp helps muscle spasticity and pain). Endogenous cannabinoid (2AG) MAY be neuroprotective after brain injury (i.e. prevents nerve cell death, may also have anti-inflammatory, anti-oxidant, anti-apoptotic properties) DIFFICULTIES - difficult to identify objective assessment of benefit - Despite double blind design, patients can tell what they are taking due to side effects, so possibly subjective response

Identify primary outcome measures for neurodegeneration. Identify any limitations of these.

Physician-based EDSS (expanded disability status scale): Time to EDSS progression of at least 1 point from a baseline EDSS of 4.0, 4.5 or 5.0 or at least 0.5 points from a baseline EDSS ≥5.5. Once identified, confirm deterioration at next scheduled six monthly visit Patient-based MSIS-29 physical impact scale: Overall mean change from baseline to end of study. LIMITATIONS - People not very willing to continue to be monitored over years - EDSS poor scale (disproportionate, difference between 0 and 1 not much but between 9 and 10 is life and death)

Describe the findings of a study researching effects of cannabinoids on neurodegeneration. Identify possible explanations for this.

-EDSS showed no major difference in progression of scale over three year period (most people started 6-6.5, and over the years started pretty stable), but for those with earlier EDSS, progressing more rapidly there was a difference (with 2AG) POSSIBLE EXPLANATIONS - Drug doesn't work - Population not changing so won't see effect - Measurement instruments inadequate - Higher level disability beyond help - Differential effects at different levels (e.g. anti-spacticity effects)

Neurodegenerative Disorders Flashcards

(41 cards)