Alzheimer described a presenile dementing illness characterized pathologically by neurofibrillary accumulation in the neurons as well as senile plaques containing substantial amounts of beta amyloid configured proteins. Since the pathologic changes are identical in most cases of old-age dementia (occurring over the age of 65), we use the term Alzheimer disease to include this common form of dementia, which affects approximately 5-10% of adults over 65 and possibly as many as 40% of individuals over 85. The disease has a familial tendency in some families and is associated with mutations in the beta amyloid gene. Also, risk of Alzheimer disease is higher in individuals with the epsilon 4 version of apolipoprotein. This risk is particularly high in individuals who are homozygous for this.
The pathologic changes in persons with Alzheimer's disease are most severe in the hippocampi. This is the reason that loss of recent memory (i.e., learning new material) is an early clinical feature. The posterior temporo-parietal association area is often affected early, as well. Therefore, mild anomia (trouble finding nouns) and constructional apraxia are also common early signs. There is early loss of cholinergic neurons in the nucleus basalis (of Meynert) and drugs that inhibit central nervous system acetylcholinesterase (increasing the amount of acetylcholine available in the brain) improve symptoms of the condition modestly. As the illness progresses it involves more of the cortex, with more severe cognitive loss and eventually frontal lobe disturbances become prominent. However, paresis, sensory loss, or visual field defects are not seen. Despite trouble finding the right words, repetition of even complex phrases is preserved (a transcortical aphasia).
Alzheimer disease is the most common cause of dementia of age. Older persons with dementia are often diagnosed as having "cerebral arteriosclerosis" when, in fact, they have Alzheimer disease. Vascular dementia does occur in association with Alzheimer's disease but is frequently associated with clear findings indicative of prior strokes (spasticity, paresis, pseudobulbar palsies, aphasia, etc). Amyloid also collects in arterial walls in Alzheimer disease patients and may contribute to a coexisting vascular dementia (amyloid angiopathy).
Unfortunately, there is no definitive diagnostic test for Alzheimer disease. Pathologic diagnosis is still the only way to definitively diagnose the condition. Imaging is insensitive (although is often useful to rule out other conditions that can cause dementia). Some functional imaging studies have shown promise at defining abnormalities in function of the temporal and posterior parietal lobes, however this has not been widely applied in clinical practice. Investigators have been looking at certain components in the CSF (particularly tau proteins and beta amyloid) as a possible diagnostic test. However there are still many questions about the utility of these tools. Obviously, methods for definitive diagnosis will be more important if a specific therapy is proven effective.
Recent data suggest that accumulation of amyloid deposits in the characteristic Alzheimer's plaques is the active pathology of the disease. There are animal models of the condition that are improved by vaccination against amyloid in an attempt to stimulate the immune system to help clear away amyloid. However, this approach has yet to produce an effective human treatment. Epidemiologic and a few prospective studies suggest that there may be some element of inflammation in the condition and some have suggested excess oxidation as a contributing factor. Despite some limited therapeutic trials, there are no proven methods for arresting the progression of the condition.
Pick's disease (also known as frontotemporal dementia) is a rare condition that can run in families and results in degeneration of the frontal and temporal lobes of the brain. This can be severe in some cases, permitting reasonably accurate diagnosis on the basis of imaging. However, most cases are not so easy to diagnose, especially at the onset. This condition tends to present in one of two ways. Firstly, it may present as disordered behavior (usually either with disinhibited behavior or with apathy). The disinhibited behaviors include agitation, socially inappropriate behavior or impulsivity. There is usually a lack on insight into their condition and a lack of empathy. The second presentation is dominated by language problems, usually accompanied by behavioral problems. Despite these deficits, memory and spatial skills remain intact. Pathology does not show the changes of Alzheimer disease, but rather shows the presence of intraneuronal "Pick bodies". There is no effective therapy for Pick's disease other than, perhaps, psychotropic medications and behavior modification to control the worst of the behavioral issues. This condition tends to be more aggressive than Alzheimer disease, usually resulting in death in 2-10 years.
Collectively, these conditions result in non-inflammatory degeneration of muscles
This is the most common type and is a sex-linked recessive trait. It affects young boys, in whom pseudohypertrophy of the calves and weakness of the hip and shoulder girdles progress from early childhood. Levels of serum muscle enzymes (CPK and aldolase) are extremely high. The children are usually confined to a wheelchair by the age of 10, and they usually die in the second to third decade. It is due to a mutation in the gene for an inappropriately-named normal protein named dystrophin. A less severe mutation in this same gene is responsible for a somewhat later onset dystrophy, Becker dystrophy. No effective therapy is known, although steroids may slightly prolong the course.
This is a heterogeneous group of conditions that usually appear in adolescence or adult life with proximal limb weakness. The weakness usually progresses slowly, but it may arrest spontaneously. There are at least 15 different mutations that contribute to this presentation and some are passed on recessively while others have dominant inheritance.
This condition also can be recessive or dominant and appears to have at least several different genetic abnormalities producing this phenotypically distinct pattern of weakness and wasting. Symptoms usually appear in adolescence or very early adult life with weakness of face muscles and of muscles attached to the scapula and proximal upper limb. The weakness usually progresses slowly and life expectancy is normal. Mental retardation is common and there may be abnormalities of cardiac rhythm.
In this disease myotonia (delayed relaxation of muscles) is combined with dystrophy (muscle atrophy not secondary to peripheral nerve or anterior horn cell involvement). The disease, which is transmitted as an autosomal dominant condition, usually begins in childhood or young adult life (possibly infancy with maternal transmission). There are cases where it has been unrecognized until advanced ages, however. It is due to repeats in the sequence of the myotonic protein kinase gene. These repeats often get longer in sequential generations, with earlier onset of symptoms.
Myotonic dystrophy, as opposed to most forms of myopathy, is distal, affecting the muscles of the hands before more proximal musculature. In addition, facial and neck musculature are involved early. Evidence points to an abnormality of membranes that is not restricted to muscle. Numerous non-neurologic problems are found: frontal balding, testicular atrophy, diabetes, cardiac arrhythmias, and others. It progresses slowly. Many victims succumb to respiratory failure and superimposed infection by the fifth decade.
These conditions are discussed in Chapter 25 on infectious diseases. The group of diseases are caused by abnormal proteins (scrapie, kuru, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy) and the primary pathologic change is neuronal degeneration and reactive gliosis. These conditions are transmissible, but the "infectious agent" in these cases appears to be an abnormal protein rather than a virus, bacteria or parasite. It appears that some cases can be sporadic due to de-novo configurational changes in proteins.