Neurodegenerative disorders Flashcards
How does the European brain disorder burden look compared to the rest of the world?
In Europe its estimated that 35% of all disease burden is attributable to CNS disorders
Was 4000 billion Euros a decade ago (X2 the cost of cancer !)
Depression was the biggest contributor to “days lost to a brain disorder
What is the definition of Neurodegenerative Diseases and can you give examples of them?
Neurodegenerative Diseases - “Ensemble of conditions primarily affecting the neurons in the human brain, which frequently culminate in neuronal cell death”
Examples;
Common Dementias;
- Alzheimer’s disease
- Vascular dementia
- Frontotemporal demential (FTD)
- Other dementias (Lewy body and HIV dementia)
Dementia can also be seen in;
- Parkinsons disease
- Huntingtons disease
Other Neurodegenerative Diseases;
- Motoneurone disease (Amyotrophic lateral sclerosis ALS), Progressive bulbar atrophy; primary lateral sclerosis; spinal muscular atrophy etc)
- Spinocerebellar degenerations
- Spongiform encephalopathies
- Progressive MS
- Other chronic traumatic encephalopathy - prion disease, BSE, neurosyphilis
How big of an issue are Neurodegenerative Diseases in the UK versus the world?
Neurodegenerative Diseases are a big problem for humanity
Biggest growing demographic group > 80 years in UK
Old age is a risk factor for most neurodegenerative disease
50 million with dementia now -> in 2050 140 million world wide and 900,000 in the UK (1.3% of population)
What ages and risks are there for people developing Alzheimer’s and Parkinson’s disease ?
Alzheimers disease risk and age is about 1% in 65 year olds and 50% in 95+ year olds (its more common in women as live longer)
Parkisons disease is more common in men than women and majorly affects both groups after the age of 60 years old
- Around 145,000 people with Parkinsons in UK
There’s a couple of drugs proven to slow down clinical deterioration for AD and one of them treats PD (temporarily) and one treatment for MND (motor neurons disease).
What are the features of Motor Neurons Disease (MND)?
Motor Neurons Disease (MND) average life expectancy is about 3 years - there is one treatment for it right now
Describe Dementia?
Dementia is a clinical entity (“brain failure” syndrome - syndrome not a specific diagnosis)
Dementia is congenitally diagnosed when progressive cognitive decline (brain failure) has occurred, and this has had noticeable impacts upon a person’s ability to carry out important everyday activities (usually irreversible deterioration)
The pathological changes in the brain that will eventually lead to the symptoms of dementia are often likely to have commenced well in advance (15-30 years) of the time at which the person’s symptoms would first have been noticed
Diagnosis is clinical where as imaging tests are usually used to identify treatable causes
There is a lack of single diagnostic test in life and post mortem pathology is the only definitive diagnostic
We do have some reliable biomarkers (improvement here, blood test for pTau)
What is the definition of cognition ?
Cognition is the mental action or process of acquiring knowledge and understanding through thought, experience and the senses
5 Domains of cognition;
- Learning and memory
- Language
- Visuo-spatial function
- Executive function
- Psychomotor abilities
What are the 3 main categories and their sub-categories that dementia can be broken down into ?
The syndrome of dementia
1). Neuropsychological deficits
- Amnesia (a partial or total loss of memory)
- Aphasia (inability to understand or produce speech)
- Agnosia (inability to interpret sensations)
- Apraxia (inability to perform certain purposeful actions)
2). Neuropsychiatric features (behavioural and psychological symptoms)
- Psychiatric symptoms
- Behavioural symptoms
3). Activities of daily living;
- Instrumental (activities that allow an individual to live independently in a community, etc)
- Basic
What is the treatment for dementia ?
Treatment is supportive (there is no curative or reversing treatments)
Cholinesterase inhibitors can sometimes temporarily improve cognitive function - Slows down degeneration but does not cure!
What do you look for/to test in cognitive assessments ?
Frontal lobes - sequencing and fluency;
- Luria hand sequencing task (palm, fist, edge hand)
- Verbal fluency 1 minute words F, A, S animals
Temporal lobes - memory, speech (L);
- Address tests
- Object recall
- Serial 7’s
Parietal lobes - spatial awareness (R), Language (L);
- Clock face
- Naming objects
- Drawing cube, interlocking infinity
- Agnosia
Asssments for these are the following cognitive profiling tests;
1). Mini-Mental State Examination (MMSE) - not the best as have to be very demented
- Dementia relatively advanced in order to score poorly
- Copyright issues affecting use
2). Addenbroke’s Cognitive Examination III (ACE-III). The original ACE was developed to help detect mild dementia and differentiate between Alzheimers disease and frontotemporal dementia
(score of 82-88 is suspected, below 82 is serious)
Also a mobile version for ACE which does auto-scoring and reporting, can compare score to see deterioration
What is Mild cognitive impairment ?
MCI is defined, in part, by the decline in function or 1 or more off the 5 cognitive domains
MCI requires subjective memory impairment and cognitive impairment not meeting dementia diagnostic criteria (in particular with no impairment in core ADL’s - activities of daily living)
Conversion rates to Alzheimers Disease are probably highest for amniotic MCI in which the prominent impairment is one of memory - these range from 10 - 15% pr year in clinic-based studies with lower rates (5-10%) seen in longitudinal population-based studies
Conversion is by no means inevitable, even for MCI up to 25% in some studies show subsequent recovery of normal cognitive function
Have memory or cognitive impairment which is greater than would detect for age but less than dementia, affecting daily life. 50% go on to develop dementia within 3 years. (sometimes can regress as well!)
What is the continuum off cognitive impairments ?
Age-associated memory impairment;
- Refers to changes in cognition with ageing
- Older people have a relative deficiency in recall, particularly in speed of recall
- However the earliest manifestations of dementia are very similar
Mild cognitive impairment (MCI);
- Greater memory loss than age-associated memory impairment; memory and sometimes other cognitive functions are worse in patients with this disorder than in age-mismatched controls
- Up too 50% of patients with mild cognitive impairment develop dementia within 3 years
Dementia;
5 “domains” of cognition;
1). learning and memory
2). Language
3). Visuospatial function
4). Executive function
5). Psychomtor abilities
MCI is defined in part by the decline in function of 1 or more of these domains
Dementia on the there hand is diagnosed by the decline in at least 2 domains. Diagnosis of either syndrome entails subjective and objective data from the medical history, mental status examination and relevant neuropsychological testing
What are the features of the Addenbroke’s Cognitive Examination III (ACE-III)?
Addenbroke’s Cognitive Examination III (ACE-III);
The original ACE was developed to help detect mild dementia and differentiate between Alzheimers disease and frontotemporal dementia
(score of 82-88 is suspected, below 82 is serious)
Also a mobile version for ACE which does auto-scoring and reporting, can compare score to see deterioration
Is useful for discriminating between dementia, MCI and controls
ACE-III is not reliable for discriminating between dementia subtypes
ACE-III should then be combined with other tools to identify dementia subtypes
What are the risk factors and preventions of dementia ?
Risk factors and preventions of dementia;
- Less education
- Hypertension
- Hearing impairment
- Smoking
- Obesity
- Depression
- Physical inactivity
- Diabetes
- Infrequent social contact
Specific recommended actions;
- Maintain BP 130mm Hg or less (> 40 years)
- Recommend use of hearing aids and reduce noise induced hearing los
- Reduce exposure to air pollution and second hand tobacco smoke
- Prevent or reduce head injury
- Limit alcohol use and in particular > 21 units per week
- Avoid smoking uptake and support smoking cessation
- Ensure and provide primary and secondary education
What are the features of Alzheimer’s?
Alzheimer’s disease;
- 70% all cases of dementia
- Prevalence of AD 1% at 65, 40% at 90 doubles every 5 years)
- Female predominance
- Most sporadic (10% familial)
- Presents with early memory disturbance, progressing to dyspraxia and dysphasia, eventually immobile and mute
What are the signature proteins found in Alzheimers disease ?
Proteins called aggregates are found in Alzheimers Disease;
Amyloid plaques - are extracellular proteinaceous deposits largely composed of AB peptides
Neurofibrillary Tangles - are intracellular fibrils, predominantly composed of Tau which is a microtubule stabilising protein. Tau tangles in hyperphosphorylated + forms paired helical filaments
Enlarged endosomes called Lipoid granules have also ben found in these patients and a close study showed that many of the genes in genetic cases are associated with sporadic Alzheimers disease affect the endosomsal trafficking !
What are the features of Amyloid Precursor Peptide ?
Amyloid Precursor Peptide cleavage pattern determines plaque formation;
- Its membrane protein is processed in secreter pathway
- Cleaved by secretases
- If beta secretase acts Abeta fragments with 38-42 amino acids generate
- Less soluble and aggregate extracellularly to make fibrils/plaques
How does Endosomal malfunction affect Alzheimer’s disease?
Endosome enlargement occurs earlier than Tau or Amyloid
Key components of remoter are depressed in hippocampus of AD patients
Deficient sorting complex called retromer diverts APP and secrets to same compartment with production of AB and increases in Tau too !
Now genes for every component of retromer complex has been found associated with Alzheimer’s
Lucocq lab investigates novel modulators of retromeer as a therapeutic target in AD and PD
What drugs affect Acetylcholine turnover ?
Drugs affect Acetylcholine turnover;
- Galantamine
- Donepezil
- Rivastigmine
Just slows down Ach loss which slows neuron loss (used in mild AD)
What drugs reduce excitoxicity ?
Drugs reduce excitoxicity;
Memantine - Used in moderate to severe AD and blocks current flow through channels of Glutamate receptors
Excitotoxicity refers to neuronal death caused by the over activation of excitatory amino acid receptors (causes calcium overload)
- Release of glutamate from astrocytes
- On extra-synaptic NMDA (glutamate receptors)
- Driving apoptosis (red pathway right)
- Antagonizes normal Glutamate driven survival pathways (green light)
What are the NICE approved treatments of Alzheimers dementia ?
NICE approved treatments of Alzheimers dementia;
- Actylcholinesterase inhibitors - donepezil, galantamine and riastigmine used in mild to moderate dementia
- NMDA receptor antagonists (e.g Memantine used in moderate to severe DAT (dementia of Alzheimers type)
What occurs at a cellular level in Parkinson’s disease ?
a-synuclein accumulation (“toxic” aggregates)
Signature change in substantia nigra (and other neurones)
Lewy body’s
Genes associated - functions associated with endoscopes (e.g VPS35) retromer components - links a-synuclein aggregation
What are the mechanisms of Riluzole Action?
Mechanisms of Riluzole Action;
- Reduces glutamte releasee (calcium block ?)
- Increases astrocyte glutamate uptake
- Decreases glutamate levels
- Mechanism was unknown but recent data - riluzole inhibits TDP43 metabolism via CK1 inhibition
