Dementia, Alzheimer's Disease & CJD Lecture PDF

Dementia, Alzheimer’s disease, BSC and CJD Dr F Javid Learning outcomes: On completing this lecture you should be able to: 1.Describe the symptoms of Alzheimers disease 2.Explain the basic neuropathological features which contribute to the disease progression 3. Explain the importa...

Dementia, Alzheimer’s disease, BSC and CJD Dr F Javid Learning outcomes: On completing this lecture you should be able to: 1.Describe the symptoms of Alzheimers disease 2.Explain the basic neuropathological features which contribute to the disease progression 3. Explain the importance of the deficits in cholinergic function 4.Understand the importance of cholinergic agents to the treatment of AD 5. Describe Spongiform encephalopathy  The proportion of elderly in the population is persistently increasing, at least in the developed countries, so that age-related disorders are providing an ever increasing strain on health services  In any event, normal ageing is noticeably different from dementia  Dementia Dementia is a cluster of conditions characterised by a widespread progressive decline in intellectual functions, including memory, often also emotional, personality and motor changes. Social decline and failure to live independently. Developing in middle or later life, to a point where the ability to continue normal lifestyle is seriously disrupted.  usually associated with distinctive neuropathological changes in the brain (e.g. atrophy, due to neuronal cell loss, particularly in the frontal and temporal cortex)  Some forms reflect a genetic disorder (Huntington’s disease of Creutzfeld-Jacobs disease), Mild dementia may be extremely common, possibly encompassing 5-20% of all people over 65  Alzheimer’s disease Alzheimer autopsied a woman in her 50s back in 1907. She had suffered from a progressive dementia over the preceding years and he noted unusual pathology in her brain tissue The pathology associated with Alzheimer’s disease includes :microscopic neuritic plaques and neurofibrillary tangles  Neurofibrillary tangles – seen in brains of AD patients at post mortem. Tangles are made of tau protein (microtubules, protein aggregation, tau protein within neurone). Neurofibrillary tangles are formed by hyperphosphorylation of a microtubule associated protein knows as tau, causing it to aggregate or group in an insoluble form. When tau is hyperphosphorylated, it is unable to bind and the microtubules become unstable and begin disintegrating.  Amyloid-plaque formation– degenerating nerve terminals, astrocytes etc., with centre of amyloid protein β and Ɣ-secretase enzymes act on the amyloid precursor protein (APP) and cut it into fragments. A deposits of amyloid-beta peptide and cellular material outside and around neurones are seen in AD  The disease came to bear his name and generally refer to pre-senile cases of dementia. However, similar changes are seen in cases of senile onset (older than 65).  Charlton Heston and Ronald Reagan Both developed Alzheimer's disease  Prevalence of dementia Prevalence rises with age. 6% of over 65s are affected, rising to 40% of 95 year olds. Incidence rate estimated between 0.5-2% of the population per annum. Most of these cases of dementia will be diagnosed as Alzheimer’s disease, though there is no definitive way to diagnose the disease until plaques/tangles are seen at post-mortem. The 2nd common cause of dementia is multiple- infarcts.  50-70% of all demented patients manifest the symptoms of Alzheimer’s disease The other common form, multi- infarct (or arteriosclerotic) dementia involves multiple small foci of ischaemic brain destruction  Symptoms of dementia Note that not all causes of dementia give rise to the same clinical presentation. Even within a disease such as AD, different patients will present a different spectrum of intellectual impairment. But generally… Disorientation (space & time) Memory disturbances, esp. acquired new information Concrete thinking (lack of spontaneity) Difficulty in reasoning  More symptoms… As the disease progresses, more and more functions are disturbed Patients often become: - Moody - Tearful - Delusional - Apathetic - Withdrawn - Depressed In some cases patients develop: - Motor problems - Speech difficulties - Aggression - Personality change – A distinction is made between short-term primary (or working) memory for the temporary storage of material undergoing processing and longer-term storage of processed information which is for recall on a later occasion – Working memory deficits are apparent in Alzheimer’s in both verbal and non-verbal tests  Diagnosing Alzheimer’s disease Diagnosis is not straightforward, there is no ‘definitive sign’ before death; plaques &tangles along with brain shrinkage and enlarged ventricles are definitive at post-mortem. During life diagnosis is tentative. Alzheimer’s is suggested when other causes of dementia seem unlikely Dementia due to thyroid hormone lack, vitamin B12 deficiency or alcoholism must be ruled out.  Further changes to aid diagnosis It is notable that the EEG is invariably abnormal in AD – however, most dementias cause similar changes, so this will not help differential diagnosis. CT or MRI scans show enlarged ventricles and sulci (folds on the outer surface of the brain).  What happens in the brain? Structurally: Neurochemically: Changes in areas Decrease in ACh associated with transmission from the learning and basal forebrain memory first: plaques and Decrease in tangles appear in pyramidal cells (thus, the hippocampus reduced glutamate) and associated In time, many neuro- cortex transmitters are Cell degeneration reduced, but Ach & in these areas glut change earliest  Neurochemical pathology There is a major finding of a significant decrease in choline acetlytransferase, indicating a decline in cholinergic function also loss of cells in the nucleus basalis of Meynert from where major cholinergic projections go to the cortex and hippocampus  The degeneration in forebrain cholinergic systems has provided the single most important hypothesis of Alzheimer’s disease  cholinergic degeneration underlies the memory impairments associated with dementia However, it should be noted that there are other neurotransmitter changes in dementia/Alzheimer’s disease  Current treatment: Works to replace decreased Ach levels (as AD destroys cholinergic neurones): Drugs used are cholinesterase inhibitors Block breakdown of Ach in the synapse, thus ACh that is released acts on receptors for longer, and transmission is increased Only current therapy – alleviates cognitive decline to some extent in some AD patients, but side effects are unpleasant and is not very effective. E.g. drugs – Aricept, tacrine…  Potential novel therapies? Some researchers are investigating an abnormal processing of the -amyloid plaques from families. If drugs can stop amyloid plaques from depositing in the brain, they may slow/stop AD. Other researchers are looking at an enzyme called ApoE, since this has been identified as the product of the mutation in the genetic familial cases of AD. However, these researchers rely on familial AD mutations, and only 20% of AD cases are familial cases ( and these are usually atypical [early onset] cases) - will work to translate to all AD cases?  Novel symptomatic therapy Since ACh is depleted in the AD brain, ACh- increasing therapy has been used However, glutamate is also depleted, and no therapies targeting this problem have yet been designed Glutamatergic drugs are potentially dangerous (excitotoxic), but it may be possible to work on neurotransmitters that modulate glutamate transmission It is hypothesised that 5-HT1A antagonists may provide an alternative…  Pharmacological models Attempts have been made to reproduce some of the symptoms of dementia in animals by: Disrupting the cholinergic system with lesions of the NBM or by administering scopolamine to block cholinergic function Disrupting the brain vascular system  Performance of animals before and after such manipulations in a variety of behavioural tasks in the T-maze, radial maze, passive avoidance and many other tasks, has allowed the testing of potential ‘anti- dementia’ drugs  At the present time there are no clinically useful drugs for the treatment of dementia but research continues at an enormous pace Ideally we require knowledge as to how neurones die and how to prevent such changes In the meantime, existing therapies can be described as follows;  (1) Cholinergic drugs Cholinergic drugs have been developed in an attempt to replace declining cholinergic function Agents with a direct agonist effect on the muscarinic receptor (e.g. arecoline) or compounds inhibiting acetylcholinesterase (e.g. eserine) have all been tried  Tacrine, a cholinesterase inhibitor, the first drug approved for treating AD, Trials showed modest improvements in tests of memory and cognition in about 40% of AD patients, but no improvement in other functional measures that affect quality of life. Should be given four times daily and produces cholinergic side effects such as nausea and abdominal cramps, as well as hepatotoxicity in some patients  For mild to moderate disease: Donepezil, Galantamine are reversible inhibitor of acetylcholinestrase Rivastigmine, is a reversible non- competitive inhibitor of acetylcholinestrase  For moderate to severe : Memantine, is a NMDA-receptor antagonist that affects glutamate transmission for treating moderate to severe Alzheimer’s disease.  Another approach to enhance cholinergic function is to provide abundant amounts of precursor substances lecithin and choline, but with modest if any success  (2) Cerebral vasodilators Trials showed to produce little if any cognitive improvement  (4) Nootropics (Piracetam et al.) Piracetam, oxiracetam, aniracetam and many others improve memory in animal tests, possibly by enhancing glutamate release, but are probably ineffective in AD.  (5) Neuropeptides Vasopressin has some effects in some animal models on memory consolidation, but inconsistent effects have been obtained in man It may improve attention  (6) 5-HT receptor antagonists Ondansetron and other 5-HT3 receptor antagonists have been shown in animal models at Bradford to increase cognitive performance 5-HT1A antagonist studies Primates training on a learning task Given a drug that blocks glutamate transmission (MK- 801) Learning is impaired If 5-HT1A antagonist also administered, learning is restored to normal levels (WAY)  (7) Mixed drug regimes and ‘SMART’ drugs Many of the drugs listed in 1 to 5 have been used together in an attempt to treat memory impairment or dementia However, they have also been used by normal people in an attempt to improve cognition An interesting , if not worrying trend  (8) Drugs which impair cognition Anticholinergics and benzodiazepines are well known examples  An increased risk in Down Syndrome patients An increased risk of dementia in patients with Down Syndrome Down syndrome is caused by the presence of an extra copy of chromosome 21. And APP is located in chromosome 21. Hence down syndrome patients will have an extra copy of APP  Summary on the pathology of Alzheimer's Disease Accumulation of Senile (amyloid) plaques and neurofibrillary tangles, Tau protein, Loss of cortical cholinergic neurons, Neurotransmitter losses such as Acetylcholine, Norepinephrine, serotonin, glutamate, GABAs and prevalence of Inflammatory responses ß-amyloid is generated by two enzymes which cut APP (Amyloid precursor protein) at two different positions, producing Aβ and APPsβ:  Potential treatment strategies for Alzheimer’s 1. Acetylcholinesterase inhibitors Eg. Donepezil, Rivastigmine , Galantamine AD patients have lower levels of Acetylcholine. Ach helps to send messages between nerve less. Ach esterase inhibitors prevent acetylcholineserase. Increased Ach helps in communication between nerve cells, may alleviate symptoms of AD Adverse effects: nausea, vomiting, diarrhoea, anorexia, tremors, bradycardia, Myalgia due to enhanced cholinergic neurotransmission (muscle cramps)  Potential treatment strategies 2. NMDA-glutamate receptor antagonist: Physically blocks NMDA receptor-associated ion channels, limiting Ca2+ influx into the neuron, inhibiting overstimulation by glutamate Adverse effects: confusion, agitation, restlessness Eg. Memantine 3. Antipsychotics: Modestly useful in reducing aggression and psychosis Eg. Risperidone  Conclusions Although cognition enhancing drugs are prescribed - but they generally remain of little, if any, benefit  Directed study: Tabulate the drugs currently prescribed to patients with the disease, consider their mode of action, adverse effects and interactions with other medications Reviews their dosing regime and intervals  CJD/BSE/other spongiform encephalopathies… From mad cows and cannibals to should we eat beef?  Spongiform encephalopathy The brain tissue seen in a range of species after a range of different disease processes bears a startling resemblance to a sponge We see this in cows dying from BSE, sheep dying from an old disease called scrapie, cannibalistic tribes people from Papua New Guinea, and victims of ‘new variant’ (or old variant!) CJD…  Scrapie “Dementing illness of middle-aged sheep” Causes behavioural/motor impairment, starting with an ‘awkward’ gait and ending in death Describing by farmers for centuries – written reports exist from the 17th century.  CJD/GSS/FFI and other initials Creutzfeldt-Jakob disease (CJD): Affects approx. 1 in a million people Also some families with specific mutation have 50% of passing CJD onto their offspring Last, but not least, some people get CJD through an iatrogenic route – due to operative procedures (or possibly due to BSE-infected material?) Gerstmann- Straubler- Scheinker (GSS) -Similar to CJD, occurs in specific families with particular mutation  Fatal Familial Insomnia (FFI) Very unusual spongiform encephalopathy. Inherited. Symptoms slightly different to the mainly motor symptoms of CJD &GSS. FFI has some motor effects, but main effect is on sleep patterns. Each of these disorders is invariably fatal. None of these disorders are ‘new’ (except for the iatrogenic forms).  Kuru In the 1950s, Australian doctors working in Papua New Guinea described a disease seen in the Foré tribes people. The disease resembled CJD, at the time an obscure disorder, seen very rarely worldwide. The people of the Foré tribe were developing motor impairments that led onto dementia and death. Bizarrely, women and children were most affected.  The pattern didn’t fit a genetic explanation, it took some time before the disease could be understood Endo-cannibalism was practiced by the Foré , i.e. when someone died, funerary ritual involved preparation, cooking and eating of the body by family members A spontaneous case of CJD probably started the disease – family members then ate the body and the disease was passed on.  Women and children were preferentially affected because men tended to get the ‘choice’ muscle, and women and children ate the internal organs, more loaded with infective material Kuru has almost totally died out in Papua New Guinea. The Australian government made cannibalism illegal and the practice began to die out in the 1950s. The few cases that still occur every year show just how long incubation time for spongiform encephalopathies can be!  BSE (Bovine Spongiform Encephalopathy) Intensive farming methods involve the use of rendered meat from sheep carcasses to produce a foodstuff used for cattle In the early 1980s, a subtle change in the rendering process led to a ‘new’ disease, BSE (mad cow disease) in which sheep scrapie somehow crossed the species barrier into cattle.  BSE & new variant CJD It is interesting to note that an obscure and rare disease (CJD) is now well known by the general public because of a particular rise in cases Bear in mind that the usual pattern for CJD involves onset in the patients’ late 40s (at the earliest) and the disease progression to death takes an average of 6-8 years. Shortly after the BSE crisis, unusual cases of CJD were seen. These cases have not been numerous, but are notably ‘atypical’ – normal CJD pathology but with younger onset and a typical diagnosis to death time of only 12-24 months.  A relationship to BSE is likely, but this does not tell us how many new variant cases are likely to occur, now or in the future. Incubation periods are hard to estimate – look at Kuru, where some people still fall victim in old age, having not practiced cannibalism since their early childhood.