CNS Degenerative Diseases

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Alzheimer's Disease

Senile dementia of the Alzheimer's type (SDAT), or Alzheimer's disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. Familial cases with a defined inheritance pattern account for only 5 to 10% of Alzheimer's disease. Familial cases tend to have an earlier age at onset. Genetic defects in familial cases have been identified on chromosomes 21, 19, 14, 12 and 1.

The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis. Less than 1% of early onset AD cases are linked to a genetic defect on chromosome 21 (which may explain the appearance of Alzheimer's disease in persons with Down syndrome surviving to middle age) which affects amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that is toxic to neurons. About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14. A presenilin 2 gene has been discovered on chromosome 1, but this defect accounts for less than 1% of cases.

The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. A genetic locus on chromosome 12 that encodes for alpha-2-macroglobulin may be found in 30% of AD cases. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles.

Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. The definitive diagnosis is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation.

The confirmation of a diagnosis of AD is made at autopsy. The pathognomonic microscopic feature of AD is an increased number of neuritic plaques in the cerebral cortex. These neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques, which do not count toward the diagnosis of AD. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Other histologic features of AD include neurofibrillary tangles, amyloid angiopathy, and granolovacuolar degeneration.

Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer's disease. However, the significance of this finding is not clear. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer's disease is pneumonia, typically an aspiration pneumonia.

  1. Alzheimer's disease, gross.
  2. Alzheimer's disease, gross.
  3. Alzheimer's disease, gross.
  4. Alzheimer's disease, Bielschowsky silver stain, microscopic.
  5. Alzheimer's disease, thioflavin stain, microscopic.
  6. Alzheimer's disease, senile plaque, with Congo red stain, microscopic.
  7. Alzheimer's disease, neurofibrillary tangle, H and E stain, microscopic.
  8. Alzheimer's disease, neurofibrillary tangle, with Bielschowsky silver stain, microscopic.

Lewy Body Diseases

Dementia with Lewy bodies is a clinicopathological syndrome that may account for up to 20% of all cases of dementia in older patients, typically in their seventh and eighth decades. Diseases with Lewy bodies should also be considered in the differential diagnosis of a wide range of clinical presentations including episodic disturbances of consciousness, syncope, sleep disorders, and unexplained delirium.

There are three major syndromes associated with the appearance of Lewy bodies. These are: the movement disorder known as Parkinson disease, autonomic nervous system failure, and dementia. Parkinsonism, the most common syndrome with Lewy bodies, is a disease developing in middle age. In older persons, a mixture of cognitive, autonomic, and motor dysfunction is more common. Some older persons with dementia who are thought to have Alzheimer disease may actually have diffuse Lewy body disease, and some of those persons may have a movement disorder resembling Parkinson disease. Conversely, some patients initially presenting with Parkinson disease may develop manifestations of Lewy body dementia.

The clinical presentation of Lewy body disease varies according to the site of Lewy body formation and associated neuronal loss. In Parkinson disease, the Lewy bodies are found in the substantia nigra of the midbrain, coupled with the loss of pigmented neurons. In persons with the dementia of diffuse Lewy body disease, there are Lewy bodies in the neocortex. Some persons have the Lewy bodies in both locations. The basal ganglia and diencephalon may also be involved in some cases.

Lewy bodies are spherical, intraneuronal, cytoplasmic, eosinophilic inclusions comprising abnormally truncated and phosphorylated intermediate neurofilament proteins, alpha-synuclein, ubiquitin, and associated enzymes. Alpha-synuclein can also be found in another neurodegenerative disease known as multiple system atrophy.

  1. Diffuse Lewy body disease, microscopic.

Multi-infarct Dementia

Multi-infarct dementia (MID) can cause a dementia similar to Alzheimer's disease (AD). However, no pathologic findings are present characteristic of AD. Instead, there are multiple ischemic lesions in the cerebral cortex that cumulatively result in loss of enough neurons to produce dementia. Most patients with MID have an abrupt onset of cognitive symptoms along with an incremental loss of mental function. Focal neurologic deficits can be present, depending upon the size and location of the infarcts. In some cases, though, there is gradual loss of mental function. Pathologically, marked cerebral arterial atherosclerosis and/or thromboembolic disease can account for the appearance of many infarcts, typically small and scattered.

  1. Multi-infarct dementia, gross.

Pick's Disease

This is an uncommon cause for dementia, but it appear similar to Alzheimer's disease. The cerebral atrophy with Pick's disease is lobar and typically involves the frontal and temporal lobes. This atrophy is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Pick bodies, cytoplasmic inclusions that are highlighted by silver stain, are seen in the cortex.

Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in Pick's disease. The abnormal tau may be present in the microscopically apparent Pick bodies, which have partially degraded (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin) tau fibrils.

  1. Pick's disease, gross.
  2. Pick's disease, gross.

Huntington's Disease

This is autosomal dominant in inheritance and the patient's usually present between the ages of 20 and 50 years, with a course that averages 15 years to death. Patients may either present with choreiform movements, character change, or psychotic behavior. The genetic defect is localized to chromosome 4. The abnormal gene, called HD, on chromosome 4 encodes for a protein, called huntingtin, that contains increased trinucleotide CAG repeat sequences. The greater the number of repeats, the earlier the onset of the disease. Spontanenous new mutations are uncommon.

Pathologically there is severe loss of small neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. There is a loss of gamma aminobutyric acid (GABA), acetylcholine and substance P.

  1. Huntington's disease, gross.
  2. Huntington's disease, microscopic.

Parkinson's Disease

Most cases are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata. Patients usually present with movement problems such as a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the patient's facies will become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. Idiopathic Parkinson's disease commonly begins in late middle age and the course is slowly progressive. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss.

Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed diffuse Lewy body disease (DLBD), or Lewy body dementia, and it is in the differential diagnosis for Alzheimer's disease. Pathologically, Lewy bodies in association with Parkinson's disease are found within the cytoplasm of pigmented neurons. For a diagnosis of DLBD, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo. Immunohistochemical staining with antibody to alpha-synuclein is positive in these Lewy bodies.

The rare familial forms of Parkinson's disease include an autosomal dominant form with mutations in the alpha-synuclein gene and an autosomal recessive form with mutations in the ubiquitin-protein ligase (parkin) gene.

  1. Parkinson's disease, gross.
  2. Parkinson's disease, microscopic.
  3. Lewy bodies, H and E stain at the left, immunoperoxidase staining with antibody to ubiquitin at the right, microscopic.

Amyotrophic Lateral Sclerosis

ALS (also known as Lou Gehrig's disease after the famous Yankee first baseman who had this disease) results from loss of motor neurons which is most striking in the anterior horn cells of spinal cord but may involve cranial motor nuclei and Betz cells. The loss of anterior horn cells leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. Because of the loss of upper motor neurons, there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown. Most cases occur sporadically, but 1 to 10% of cases may have an autosomal dominant inheritance pattern.

  1. Amyotrophic lateral sclerosis, gross.
  2. Amyotrophic lateral sclerosis. microscopic.
  3. Amyotrophic lateral sclerosis, microscopic, Luxol fast blue stain.
  4. Amyotrophic lateral sclerosis, muscle biopsy, microscopic, trichrome stain.

Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, with 80% of cases occurring between the ages of 50 and 70, but cases can occur in young adults. The course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is six months. CJD is a uniformly fatal rapidly progressive dementia.

The clinical features of CJD include dementia, often with psychiatric or behavioral disturbances, in 100% of cases. About 80% of cases are marked by the appearance of myoclonus. By electroencephalography (EEG), there are periodic biphasic or triphasic synchronous sharp-wave complexes that are superimposed upon a slow background rhythm. Both myoclonus and characteristic EEG changes may subside late in the course of disease. Other neurologic findings may include cerebellar signs, pyramidal tract signs, extrapyramidal signs, corticla visual defects, abnormal extraocular movements, lower motor neuron signs, vestibular dysfunction, seizures, sensory deficits, and autonomic abnormalities.

Routine laboratory findings are not helpful. There is no dysfunction of major organ systems besides the central nervous system. Cerebrospinal fluid (CSF) will not show an increase in cells or immunoglobulins, and occasionally a mildly elevated protein. An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein may be found in association with viral encephalitis and stroke. A Western blot assay or immunoperoxidase staining of cells can be performed to try and identify PrPres in biopsied lymphoid tissue (tonsil), but this may not always be helpful.

There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy.

The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be. The PrPres can be identified in tissues with immunoperoxidase staining.

The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by a gene on chromosome 20. It is thought that the normal cellular prion protein, designated PrPc, is converted via a conformational change to an abnormal form of PrP, designated PrPSc, that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein, thus designated PrPres accounts for the degenerative changes in the cerebral cortex by inducing conformational change in the normal PrP, designated PrPC. The accumulation of PrPres leads to loss of neuronal cell function, vacuolization, and death.

These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact, in the workplace, or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP.

Further evidence for genetic mutation comes from the appearance of familial cases of CJD. About 15% of CJD cases are familial, with clusters reported in Chile, Slovakia, and Italy. Transmission in familial cases appears to be autosomal dominant, and the onset is earlier in life and the course more prolonged than for sporadic cases. In familial cases of CJD, the typical EEG changes are often lacking, and the 14-3-3 protein is absent from CSF half the time.

The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present. In 37% of healthy persons, both inherited PrP genes code for methionine, and half have M/V. 73% of persons with sporadic CJD have the M/M phenotype, and 100% of persons with variant CJD have this phenotype. However, subgroups of sporadic CJD can be found with all polymorphisms, but differing characteristics, as shown the the table below:

GroupCodon 129Major Clinical Findings
1M/MDementia with occasional visual disturbances and ataxia
2M/MDementia
3M/VAtaxia with dementia; Kuru-type plaques histologically
4V/VAtaxia

CJD is one form of spongiform encephalopathy, other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness in the 1990's that were characterized by younger age of onset, lack of characteristic EEG findings, longer course of disease, and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent.

  1. Creutzfeldt-Jakob disease, high power microscopic.
  2. Creutzfeldt-Jakob disease, high power microscopic.
  3. Creutzfeldt-Jakob disease, medium power microscopic.
  4. Creutzfeldt-Jakob disease, high power microscopic.
  5. Variant Creutzfeldt-Jakob disease (vCJD), high power microscopic.
  6. Creutzfeldt-Jakob disease, MRI scan.

Other Degenerative Diseases

Frontal lobe degeneration (FLD), also called frontotemporal dementia or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech, disinhibition, apathy, personal neglect, and finally mutism. The mean age of onset is in the 6th decade. About 90% of cases are sporadic and the rest familial. The gross pathologic findings are similar to Pick's disease, with marked atrophy in a frontal lobe and sometimes temporal lobe distribution. Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, and no increase in neuritic plaques. Pick bodies may appear in 15% of cases. Aggregates of tau protein are not common in sporadic cases. Both straight filaments and neurofibrillary tangles with paired helical filaments of mutant tau protein have been found in familial cases.

Corticobasal degeneration (CBD) is classified as an akinetic rigid movement disorder classically consisting of progessive asymmetric rigidity and apraxia with late development of cognitive decline. However, a wider clinical spectrum, including dementia as an early finding, is possible. Postmortem gross features include asymmetrical cortical atrophy of the posterior frontal, parietal, and the peri-Rolandic cortex contralateral to the limbs most severly affected in life. Histologic findings include focal/asymmetric neocortical atrophy, which predominantly involves the frontoparietal region in most cases, and ballooned achromatic neurons. Basal ganglia and nigral degeneration are often but not always present. The etiology is unknown but molecular studies indicate glial and neuronal accumulation of the tau protein in affected areas. There is substantial pathological and clinical overlap with other neurodegenerative disorders such as Creutzfeld-Jakob disease, progessive supranuclear palsy, Alzheimer's disease, and Pick's disease. This can make unequivocal diagnosis difficult.

Multiple system atrophy (MSA) has features that overlap striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson's disease. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions.

Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer's disease. The diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter, and substantia nigra. Mutant tau protein has been found in association with PSP.

  1. Progressive supranuclear palsy, globose tangle, Bielschowsky stain, microscopic.

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