ALZHEIMER'S AND STROKE TREATMENT OF BRAIN DAMAGE IN THE ELDERLY ALZHEIMER'S DISEASE THE DISEASE: First described by the German Neuropathologist Alzheimer in 1907 Described as specific NEUROANATOMICAL abnormalities in post-mortem brain of a sub- set of DEMENTIAS + Dementia meaning simply a dense, general deterioration of the mental faculties, especially memory for self and situation + In practice, most dementias have an insidious onset and a progressive downward course + Can result from a host of causes, including paresis, chronic severe epileptic attacks, viral infection, certain genetic disorders, and Alzheimer's On a behavioral basis, dementia of the elderly had been known for at least 4,000 years Epidemiology There is a rare sub-set of early-onset Alzheimer's, with a strong genetic component Typically afflicts the elderly 1/5th of those over 85 have the disease + Over 4 million cases in the USA + 30-40% of the elderly in nursing homes are afflicted As always, there appears to be a genetic predisposition Otherwise, no sex bias (except that most of the elderly are women!), no racial or geographic biases Some odd facts: + Cigarette smoking is slightly protective + High levels of anti-inflammatories such as aspirin are protective, substantially so! + Early-onset Alzheimer's is invariant in early middle age in Down's syndrome + Some environmental agents are suspected in Alzheimer's-like dementias, from Cycads in Guam to aluminum compounds + But a recent study of elderly nuns could predict Alzheimer's from the content of autobiographies written in their early twenties, with eventual victims showing restricted imagination and fluency THE CLINICAL PICTURE: Of course no two diseases are the same! Typically insidious onset Memory loss is characteristic: Begins with loss of memory for recent events Progresses to total loss of memory for virtually everything, as patients enter a persistant "vegetative" state Symptoms in the social sphere Gradual withdrawal from active engagement with life Lessening of mental alertness Thoughts and activities become self-centered and childish In a sizable sub-set of patients, delusions and aggression also occur, causing severe management problems Symptoms in the motor sphere: Hyperactivity is common + Hyperactivity combined with memory loss causes a sub-set of patients to simply vanish! As is loss of sphincter control Ultimately rigidity and near-paralysis THE NEUROANATOMY OF ALZHEIMER'S To date, a positive diagnosis still requires pm examination of the brain for the symptoms first described by Alzheimer A triad of symptoms is seen: 1. Neurofibrillary tangles - surviving neurons show dense tangles of the previously-ordered neurofibrils 2. Senile "plaques", enriched in -amyloid, are seen in brain and in cerebral vasculature 3. Substantial neuronal cell death, resulting in the usual sulcal and ventricular enlargement and in vacuoles or holes where cells used to be All of the above correlate with behavioral symptoms Regional changes in the brain: Cortex is more affected than are subcortical regions, and prefrontal cortex perhaps most The "limbic" system, especially the hippocampus and amygdala are also hard- hit, accounting in part for the memory and social deficits THE NEUROCHEMISTRY OF ALZHEIMER'S Acetylcholine-containing neurons are especially damaged Nucleus Basalis: a sheet of Ach neurons at the base of the forebrain, projecting widely to cortex, is hard-hit As are Ach projections from septum to hippocampus BOTH systems are important for memory Ach abnormalities impair memory, and Ach agonists improve memory Other neurotransmitters are also hit, if less hard. These include serotonin and norepi but not dopamine, to any substantial degree. Glutamate is also down CAUSE(S) OF ALZHEIMER'S DISEASE (AD) -AMYLOID ABNORMALITIES: All known types of AD involve formation of -amyloid senile plaques Downs' syndrome All other known GENETIC abnormalities confer abnormalities in -amyloid Transgenic mice programmed for increased -amyloid develop Alzheimer's as they age Understanding -amyloid: -amyloids(BAPs) are peptide chains of varying length, from 39 to 44 amino acids BAPs are made from beta-amyloid precursor proteins or BAPPs (called APP in text): these have several isoforms, only one of which is restricted to neurons BAPPs seem to play a variety of roles in the normal brain and body. In neuronal cell culture, they PROMOTE neuron survival, protect against excitotoxic or ischemic insult, regulate intracellular calcium, and promote neurite outgrowth However, BAPP knockouts do just fine! Formation of BAPs from BAPP is a normal physiological process The common form of BAP has 40 amino acids But this process is greatly accelerated in AD Especially of the pathological 42 or 43 amino- acid varieties It is this longer-chain peptide that clumps and forms plaques High concentrations of BAP are neurotoxic, increasing cell death and inflamation This toxicity is enhanced towards Ach neurons! Other compounds encouraging BAP plaque formation include ApoE, a protein involved in normal lipid metabolism NEUROFIBRILLARY TANGLES Incidence and spread of these tangles is actually MORE predictive of the behavioral course of AD than are the BAP plaques The tangles appear to result from excessive phosphorylation of the tau protein, an essential element of all microtubules The relationship between tau and BAP is uncertain CEREBRAL INFLAMMATION IN AD AD is accompanied by low-level signs of general inflammation, including: Senile Plaques are surrounded by astrocytes and microglia, the glial components of the defensive systems of the brain This is a normal response to brain damage! But these glial cells can kill neurons Other indications of inflammation include: Enhanced levels of major histocompatibility class II antigens Increased levels of inflammatory cytokines IL-1 and IL-6 Neurotoxic components of the classical complement pathway BAP and inflammation Microglia can increase BAP production And BAP can cause glial proliferation and neurotoxicity As well as activation of cytokines and complement PHARMACOLOGICAL APPROACHES TO TREATING AD: To date, nothing has worked well Acetylcholine: MUCH frustrating effort has been expended on drugs which enhance Ach, with effects best described as marginal Anti-inflammatory treatment looks better! People given high levels of such compounds show a 50% reduction in Alzheimers But these drugs have many side effects, and treatment would have to begin BEFORE AD onset Vast sums are being spent on the search for drugs which normalize BAPs TREATMENT OF DISRUPTIVE BEHAVIOR: This is a major problem in nursing homes Such disorders are sometimes accompanied by delusions or paranoia Providing a (weak) justification for use of psychotropic drugs with sedative side-effects including: Neuroleptics Benzodiazepines