Neuropathology For Medical Students > Chapter 11 Dementias
NEUROPATHOLOGY FOR MEDICAL STUDENTS
Presented by William I. Rosenblum, MD
PRETEST--the answers can be found in the chapter or click on link at end of chapter
 Name the 3 major causes of dementia and describe their histological hallmarks.
 What diseases are characterized by abnormal movements and dementia?
 What areas are affected in the diseases referred to in question 2?
 What is deposited in senile plaques and in the blood vessel walls of patients with Alzheimer's disease?
 There are 2 types of senile plaques--what are they and which type is better correlated with cognitive decline?
 Neurofibrillary tangles contain what material?
 What do tangles and the more important type of plaque have in common?
 Name a transmissible disease that is characterized by dementia.
 To what family of agents does the transmissible material belong?
Over the past 20 years there has been a explosion of knowledge concerning dementias. This explosion has been fueled almost solely by autopsy investigation of the brain. The background of this explosion is the realization that as people live longer the percentage of those who will become demented becomes a major health burden for society.
Originally, and still in the public mind, the dementia of concern was Alzheimer's disease. However, as explained below, autopsies reveal that there are an ever increasing number of diseases that are responsible for dementia. At present, with the possible exception of Alzheimer's disease, the underlying biochemical bases for the perturbed neuronal function has yet to be defined in these diseases.
Thus, they have been separated from each other solely on the basis of their histopathological hallmarks. This is a subject for specialists in neuropathology and perhaps for sub-specialists within neuropathology. This chapter will provide details only about the most common of the dementing disorders and will mention some of the others.
The prevalence of dementia is about 10% in Americans over the age of 65 and this prevalence rises exponentially with increasing age. Moreover, the term dementia implies severe cognitive decline, usually if not always accompanied by inability to adequately perform several functions of daily life. However, the same disease processes that produce dementia produce, in their earlier stages, lesser degrees of cognitive decline. Thus the disease processes producing dementias are responsible for a massive public health problem. As the plural word "dementias" implies, there are a number of underlying diseases responsible for cognitive decline.
This entity is a more common diagnosis in countries outside America. It is not, in fact, a single entity. The original concept was one of multi-infarct dementia. Here, the degree and location of lost brain tissue accounted for dementia. In fact, at least in my experience, we seldom see such cases. In saying this we must keep in mind that the diagnosis of dementia requires more than simply loss of memory. A loss in two or more dimensions of cognition is required.
In any case, the concept of vascular dementia has been expanded to include cases with marked loss of white matter whose pathogenesis is, in fact, uncertain, but which some workers ascribe to "vascular disease." A subset of this category may be Binswanger's disease. Dr Binswangers description of this condition focused upon the presence of atherosclerosis in the cerebral circulation. However, he also noted that the patients had hypertension.
Today we realize that the loss of white matter selectively involves the deeper portions of the white matter with relative sparing of the "U" fibers or arcuate zone. These are the fibers tangential to the base of the gyri; fibers that link one gyrus to another. We know of only one pathologic process that distributes itself in this manner. That process is cerebral edema. Consequently it is thought that Binswanger's disease may be cause by plasma leaks through small vessels damaged by high blood pressure, with the edema in turn causing damage to surrounding structures. Such degeneration is also found adjacent to contusions, tumors, abscesses and infarcts because of edema adjacent to these lesions.
There are those who think that so-called vascular dementia is very common. The debate about its frequency has not only been complicated by the problem of defining the entity but also, more recently, by the work of a few who insist that Alzheimer's disease may have a vascular trigger and/or a vascular component making the neuronal damage worse. This is discussed below.
This is generally considered to be the major dementia in America. It is characterized by atrophy and the microscopic presence of senile plaques and neurofibrillary tangles. This is shown below.
Atrophy--note wide sulci caused by narrowed [lost tissue] gyri
The oicture below shows a senile plaque, neuritic type, Bielschowsky stain--this stains normal axons black. The plaque contains dark black, swollen, distorted axons or dendrites. These distorted processes are called neurites. Electron microscopy shows them distended by a variety of debris.
Senile plaques of the neuritic type usually contain an amyloid. The brown clump in the center of the picture above is amyloid stained by the Bielschowsky stain. When the amyloid is present in a dense core, it may be seen as an eosinophilic mass on H&E or may be stained with any one of a variety of amyloid sensitive stains including PAS or Congo red. To assure specificity of the Congo red for amyloid it is essential to look at the slide under polarized light and demonstrate the "apple green" birefringence of the stained object. The figure below shows the Congophilia on the left and the green birefringence on the right.
The figure below shows 6 or more diffuse plaques, adjacent to each other and stained with Bielschowsky stain. These plaques lack the well defined degenerate "neurites." They are more amorphous and are not stained by all stains. There frequency was not appreciated until Bielschowsky stain became a standard instead of other silver stains. Its use has confused the issue concerning the relationship of plaques distribution and plaque numbers to the degree of cognitive decline. Diffuse plaques are not statistically related to the degree of decline and in studies relating numbers of plaques to cognitive deficit, only neuritic plaques should be counted.
The figure below shows a dark black neurofibrillary tangle stained with Bielschowsky silver stain
In addition to these changes, Alzheimer patients have small vacuoles with central granules, in the cytoplasm of neurons especially in the temporal lobes [granulovacuolar change-not illustrated]. They also may have rod shaped eosinophilic Hirano bodies in the cytoplasm of neurons. Like neurofibrillary tangles, these Hirano bodies may be set free in the extracellular space if the neuron dies.
There are 2 Hirano bodies, one in each neuron, in the figure below
In the preceding paragraphs we have passed over two important issues. First, what is the relationship of plaques and tangles to cognitive decline? Second, what is the composition of the amyloid and of the tangles?
RELATION OF PLAQUES OR TANGLES TO THE DIAGNOSIS OF DEMENTIA: The number of tangles provides a better correlate of degree of cognitive decline than does the number of neuritic plaques.The number of tangles increases as cognitive decline increases. Moreover there is a "spread" of the disease process from hippocampus where it first appears to the adjacent, phylogenetically newer neocortex in temporal lobe and then to the neocortical areas in association with cortex, such as frontal lobe. When both neuritic plaques and tangles are present, the presence of even a few tangles in a single field in the neocortex suggests significant cognitive decline and is compatible with the diagnosis of Alzheimer's disease made on the basis of clinical findings. However some patients are "tangle rich but senile plaque poor". The dementia in these patients may represent a process other that true Alzheimers disease.
Some workers have shown that neither plaques nor tangles are as good a correlate of decline as is the number of synapses. The marker for synapses has been antibody to synaptophisin, a protein found in the presynaptic endings. This declines, supposedly with diminution of synapses.
The underlying disease process producing plaques and tangles is currently thought to be the same in cases involving only the temporal lobe or hippocampus and in cases with more extensive plaque and tangle distribution. These changes are generally age-related. Thus, in a sense, almost everyone living long enough will show evidence of Alzheimer's disease. For cases with minimal change one may use a term like "Alzheimer's type changes" when referring to the pathology. The same term might be used for cases with more than minimal [higher stage] of plaque and tangle formation, but with no clinical evidence of "dementia." However, we must remember that "dementia" is a term that has generally been applied to those with severe cognitive deficits; so severe that daily function is compromised and often laypersons can detect the diminished capacity of the affected person.
Where psychometric tests show less marked, but nevertheless definite malfunction, and where successive tests show progress of the process over time, Alzheimer's diseases is a probable cause. If death intervenes and autopsy reveals an intermediate stage of plaque and tangle formation it may be permissible to say that the patients decline was attributable to the Alzheimer's disease.
CHEMISTRY OF PLAQUES AND TANGLES: As mentioned earlier the neuritic plaques contain an amyloid. Amyloids are simply defined as fibrils of protein--really multimeric chains of peptides--that have a beta pleated sheet confirmation. This confirmation enables binding of the stains used to visualize amyloids and is responsible for the green birefringence of the Congo red stain.
Diffuse plaques contain the same peptides as those responsible for amyloid formation in the neuritic plaques. However, these peptides have not yet polymerized to form fibrils and lack sufficient beta sheet configuration to bind the dyes. However, for unknown reasons, the Bielschowsky silver stain stains these peptides and this accounts for the staining of diffuse plaques by that stain. The peptide involved is called beta A4 peptide. In Alzheimer's disease, this peptide is produced in abnormally large amounts form a normal amyloid precursor protein known as APP. The abnormal cleavage is dependent upon both a beta and a gamma secretase. The function of the APP is not known. The gamma secretase is closely associated with Notch protein synthesis and such proteins play an important role in embryologic development. For this reason some have suggested that Alzheimer's disease is an unfortunate consequence of living beyond the lifespan in which the secretase played a vital function, and develops as the secretase activity leads to toxic deposition of the beta A4.
This idea may be too fanciful, but in any case, the beta A4 itself has become the central figure in the pathogenesis of Alzheimer's disease. For many years attention was focused on the toxic properties of the extracellular amyloid in plaques. This, in turn, caused controversy with respect to whether such amyloid could be the initial causative factor. That amyloid is insoluble.
In more recent years, a possible more important aspect of the amyloid story has developed. It is now known that the initiating beta A4 peptide is soluble and first deposited in the neuronal cell body from where it travels down the axons. It is either "liberated" there to enter the extracellular space, perhaps first to form diffuse plaques, or it is directly liberated from the cell bodies of neurons that have died, presumably as a result of the presence of the peptide or as a result of other processes connected in some way with the abnormal cellular metabolism that produced the beta A4. A number of studies have shown good relationship between the total amount of soluble beta A4 in the brain and the degree of cognitive decline. It remains to be seen whether the beta A4 in the intracellular or the extracellular compartments play a more important role.
The central role of beta A4 has been apparently confirmed by the finding that all of the genetic variations leading to early onset and/or familial Alzheimer's disease involve genes that control beta A4 production. Moreover, the most important known factor predisposing to Alzheimer's disease is the presence of the E4 variant of the Apo E protein and Apo E4 binds to the beta A4 aiding in its precipitation within the extracellular space.
What about the tangles? Since their presence and distribution are related to cognitive decline, some workers focus on these rather than the beta A4 as the more important culprit. But it is known that decline begins long before tangle formation--at least in transgenic mice whose use has become central to experiments endeavoring to determine the causation of neuronal death and/or neurological malfunction. There may be a relationship between beta A4 and tangle production since the peptide interacts with cholinergic receptors and this interaction stimulates the abnormal phosphorylation of tau. The hyperphosphorylated tau is a major constituent of the tangle. It is also present in the degenerated neurites. Hence both tangles and neuritic plaques can be identified by staining with antibody to the abnormal tau. The electron microscopic picture of hyperphosphorylated tau shows it to be arranged in fibrillar form as paired helical filaments. In the picture below note how each elongate fibril is really composed of two distinct filaments. In favorable areas you can see indentations caused by one filament twisting across its mate.
Some workers believe that tangles are a nonspecific consequence of certain types of neuronal damage. Then their presence may simply mark the damage rather than be a cause of malfunction. But it is difficult to believe that the presence of tangles can be benign since the tangles are masses of abnormally phosphorylated tau protein--tau being required for microtubule assembly and microtubules being essential to transport of materials down axons.
Nevertheless, it is also true that human studies have shown the presence of large numbers of tangles in persons with little cognitive decline and little evidence of neuronal death. This has been seen for example in patients dying with Down's syndrome. Such patients with their aberrant 21 chromosome produce large amounts of beta A4 peptide at an early age because that chromosome is responsible for the APP [amyloid precursor protein]. The patients also develop tangles at an early age. Because large numbers of tangles have been seen throughout the adult life span of autopsied Down's victims, it is thought that the tangles may remain in neurons for many years without significant deleterious effects. It should be noted that it may be initially difficult to document cognitive decline in such people since their disease itself causes varying degrees of retardation.
New work shows that alterations in tau occur in stages with hyperphosphorylation occurring at the end. Enroute a variety of polymeric forms of tau are produced. Recent work suggests that these soluble forms of altered tau are toxic and that the final stage of tau transformation consists of hyperphosphorylation and binding to other cytoskeletal proteins. It is this binding that produces the tangle which we see with silver stains. Some workers suggest that it is the earlier , soluble forms of altered tau which are toxic and that the final tangle is actually helpful because it takes these toxic forms out of the picture. If true, this explains why tangles are a marker of disease but can exist by themselves without severe symptoms.Symptoms would only be present if the disease process which led to tangles has been acting unopposed throughout tangle formation--e.g. formation of toxic forms of A4Beta amyloid and of toxic soluble polymers of altered tau.
THE ACETYLCHOLINE STORY: There is degeneration of subcortical cholinergic nuclei in Alzheimer's disease with consequent loss of cholinergic markers in the cortical projections from these cell bodies. Not only may this be responsible for tangle production, but also for the driving of the abnormal cleavage of the APP. In any case, until recently, the only available drugs for slowing the progression of the disease have been inhibitors of acetylcholine esterase, the enzyme that breaks down acetylcholine. Presumably the modest but definite benefits of these drugs is based on preservation of remaining acetylcoline.
OTHER THERAPY: Because of the apparent central role of the amyloid recent attempts have been made to reduce the amyloid burden in the brain by immunizing against it. Transgenic mice, carrying genes that cause them to make human beta A4, form neuritic plaques and develop learning disorders. Immunization against the peptide reduces the amyloid burden and prevents or reverses the disease. When tried in humans there was clinical success and this was associated with development of antibodies against the peptide. Persons who failed to develop the latter were not helped clinically. In the one reported autopsy of a success there were far fewer plaques than would have been expected of someone with Alzheimer's disease. In spite of these exciting results the inoculation therapy has been abandoned [temporarily I hope] because approximately one in five patients developed an encephalitis which in almost all cases was transient. The basis for this encephalitis is currently under investigation.
OTHER ISSUES: Alzheimer brains have significant evidence of inflammation and excessive free radical production.. Many workers have focused upon the inflammation --cause undetermined--as the originating factor in Alzheimer's disease. Whether initiating or not, it may be that inflammation contributes to neurologic decline. This remains to be proven.
Also remaining to be proven is the assertion that there is an important causative vascular factor in Alzheimer's disease. The beta A4 peptide deposits itself in blood vessel walls. In transgenic mice this deposition has been shown to be related to diverse malfunctions of mechanisms producing altered microvascular tone in response to stimuli calling for increased blood flow. Hence the amyloid may be responsible for causing oxygen lack to neurons under certain circumstances. Addition of insoluble or of soluble beta A4 to the vessels also produces these derangements. The deposition may also cause abnormal increases in vascular permeability leading to local edema. Humans with Alzheimer's disease also show abnormal cerebrovascular response or declines in cerebral blood flow. However there is no prospective, age-matched study comparing those who later develop Alzheimer's disease with those who do not, and showing abnormal cerebrovascular responses or decline in cerebral blood flow prior to the development of the disease and unrelated to age.
However there is evidence relating the presence of major vascular pathology--recognizable infarcts--to development of Alzheimer's diseases [i.e. dementia attributable to the plaques and tangles or to the process producing them]. The numbers of plaques and tangles associated with the presence of Alzheimer's disease at autopsy is reduced in persons with infarcts. In other words the threshold which the pathologist should require before supporting a diagnosis of Alzheimer's disease is shifted to the left in the presence of plaques and tangles. This may reflect the reduction of neuronal "reserve" caused by the infarcts. The concept of "reserve" may also explain why a given level of plaque and tangle burden does not produce the same amount of cognitive decline in every person so burdened. Those with a bigger "reserve" of neurons or with a greater expansion of neuronal dendritic branches may be more able to tolerate the process that produced the cognitive decline.
SUMMARY CONCERNING ALZHEIMER'S DISEASE--At present it appears that either beta A4 amyloid is a major toxic factor for neurons and their processes. It is possible that there are other "toxic pathways" triggered by the metabolic pathway that produces too much beta A4. There may be other pathogenetic factors that are also at work, such as a decline in cholinergic pathways. There may even be a link between acetylcholine and its receptors, such that the synthesis of beta A4 and the abnormal phosphorylation of tau [tangle production] are affected by degeneration of cholinergic nerves. Inflammation and microvascular malfunction may be additional factors, and these in turn may depend upon deposition of beta A4.
As noted in the preceding section, Alzheimer's disease is characterized by abnormal phosphorylation of tau. There are other dementias in which tau is abnormally phosphorylated. These are not characterized by plaque and tangle formation, though, with increasing age, the latter may also be found in such cases. Detailed discussion of the non-Alzheimer tauopathies is beyond the scope of this chapter. Each is quite rare. Some are characterized by abnormalities in oligodendroglia [tau inclusions] or by "tufted" astrocytes. One of them-Pick's disease, is characterized by neuronal inclusions known as Pick bodies. When dementia was present and an alternate cause is not demonstrable , these tauopathies should be considered. This is especially true if the clinical picture includes evidence of extrapyramidal tract dysfunction, which is characteristic of some tauopathies.
DIFFUSE LEWY BODY DISEASE
After Alzheimer's disease and perhaps vascular dementia, the most common dementing illness is diffuse Lewy body disease. Two Lewy bodies are illustrated below. They are the eosinophilic [pink] intracytoplasmic inclusions in the neurons that contain brown neuromelanin.
The Lewy bodies in the figure are in the substantia nigra. They will be found in this location in both Parkinson's disease and in diffuse Lewy body disease. However, in the latter they are also present in many areas of the cerebrum including the temporal lobe, the cingulate gyrus and the frontal lobes. Antibody against alpha synuclein stains both the Lewy bodies and abnormal axons or dendrites in diffuse Lewy body disease. The latter have been called Lewy neurites.
The number of Lewy bodies cannot explain dementia in these cases. The underlying process producing the dementia is not known but may have to do with the number of Lewy neurites, especially since many of these are found in association with synapses..
Diffuse Lewy body disease should be distinguished from the dementia that can accompany Parkinson's disease. In the latter, the distribution of the Lewy bodies is more circumscribed.
This disease produces dementia as well as chorea. It is discussed in the chapter concerning basal ganglia diseases.
These diseases [e.g. Jakob Creuzfeldt disease] produce dementia. They are discussed in the chapter on viral diseases. This arrangement of text was chosen because prion diseases, though not caused by an infectious agent, are transmissible, albeit by direct implantation of prion into eye or brain, or by ingestion of contaminated meat.