Images in Pathology: Alzheimer's Disease

JOURNAL OF INSURANCE MEDICINE Copyright Q 2002 Journal of Insurance Medicine J Insur Med 2002;34:127±130 GRAPHICS SECTION Images in Pathology: Alzheimer's Disease Venita Jay, MD, FRCPC The review describes the histopathology and pathophysiology of Al- Address: Manulife Reinsurance, 200 zheimer's disease. Bloor Street East, Toronto, Ontario M4W1E5, Canada. Key words: Alzheimer's disease, dementia, histopathology. early a century ago, Alois Alzheimer de- occupational status and fewer years of edu- Nscribed the ®rst case of the disease that cation.3 now bears his name.1 Alzheimer's ®rst en- A clinical diagnosis of AD can be quite ac- counter with this fateful case was in 1901, curate in the hands of an experienced physi- when a 51-year-old woman was admitted cian. Clinical workup includes screening for with aphasia, poor memory, lack of orienta- other causes of dementia in the elderly and tion, paranoid ideation, unpredictable behav- exclusion of other etiologies (eg, hypothy- ior, hallucinations and severe cognitive de®- roidism, drug-induced encephalopathy, cits. After her death in 1906, Alzheimer re- chronic subdural hematoma, brain tumor). ported the autopsy ®ndings in a landmark While neuropsychological testing, metabolic presentation entitled, ``On a Peculiar Disease neuroimaging, and cerebrospinal ¯uid tau Process of the Cerebral Cortex.'' Alzheimer's levels have been used to increase con®dence original pathological description of cerebral in the probability that the dementia is due to atrophy, neuro®brillary change and loss of AD, an unequivocal diagnosis of AD can be neurons, remains remarkably accurate to this rendered only on neuropatholgical examina- day.1 tion of brain tissue.5,6 By CT or MR imaging, Today, Alzheimer's disease (AD) is recog- there is evidence of cortical atrophy (notably nized as the most common cause of dementia the medial temporal lobe), with parietotem- in the elderly, accounting for over 50% of cas- poral hypoperfusion on positron emission to- es.2,3 The most potent risk factor for AD is mography (PET) and single photon emission increasing age and the presence of the apo- computed tomography (SPECT).2 This selec- lipoprotein e4 allele. The lifetime risk of AD tive early involvement of the medial temporal for an individual without the e4 allele is 9%, lobe is utilized in the diagnosis of AD by neu- while the lifetime risk of an individual car- roimaging.5 rying at least one e4 allele is 29%.4 AD is From a pathological perspective, the brain more common among women than men with in AD is reduced in weight, with especially a ratio of 1.2 to 1.5.3 Other risk factors impli- pronounced atrophy of the medial temporal cated in some studies include head injury, lobe, and atrophy of the temporal, parietal family history of dementia, lower income and and frontal association cortices.5,6 Primary 127 JOURNAL OF INSURANCE MEDICINE cortical areas (primary motor, sensory and vi- phorylated as well as abnormally phosphor- sual cortex) and most subcortical structures ylated tau protein.7 Normal adult tau is a sol- are relatively preserved. The lateral ventricles uble microtubule binding protein that is pri- are dilated secondary to cerebral atrophy. The marily localized in axons and plays an im- hippocampus and amygdala are atrophic. portant role in the polymerization and The locus ceruleus often shows loss of pig- stabilization of microtubules.5 The abnormal- ment. ly phosphorylated tau of AD is less able to At a microscopic level, there is diffuse loss bind microtubules, presumably leading to of large pyramidal neurons in the cerebral microtubule depolymerization, disrupted ax- cortex in AD, especially involving the multi- onal transport, compromised synaptic trans- modal association cortices.6 There is also neu- mission, and ultimately neuronal death.5 ronal loss in the hippocampus, amygdala, As shown in Figure 1B, another patholog- basal forebrain, and locus ceruleus. There is ical hallmark of AD is the neuritic plaque. a substantial loss of synapses, which corre- Neuritic plaques have a dense core of extra- lates with the degree of cognitive impair- cellular amyloid surrounded by an amyloid ment. Concomitant with the cerebral atrophy, corona, in which dystrophic neurites (con- there is astrocytic gliosis. taining abnormal tau/paired helical ®la- Alois Alzheimer used the newly developed ments) and processes of reactive microglia Bielschowsky's silver staining method to are incorporated. Large numbers of neuritic demonstrate the neuro®brillary tangles in plaques accumulate in the cerebral cortex in neurons of the cerebral cortex of his famous AD. Senile plaques of aging (nonneuritic se- patient.1 The Bielschowsky stain continues to nile plaques or diffuse plaques) are seen in be widely used to demonstrate AD patholo- elderly people without dementiaÐthey lack gy. Figures 1A and 1B illustrate the classical the amyloid core, dystrophic neurites, and pathological ®ndings in ADÐneuro®brillary the in¯ammatory microglial response. On tis- tangles and neuritic plaques in a section of sue sections, amyloid is demonstrated by the cortex stained by the Bielschowsky stain. congo red stain or by ¯uorescence after thio- The neuro®brillary lesions of AD present ¯avin staining. in the form of neuro®brillary tangles, neuro- Other pathological ®ndings on microscopy pil threads, and neuritic plaques.2,5,6 Neuro- include Hirano bodies and granulovacuolar ®brillary tangles are ®lamentous inclusions degeneration (GVD) in the neurons of the within the neuron body and proximal den- hippocampus (clear vacuoles pushing the cy- drites (Figure 1A). Whereas, neuropil threads toplasm and containing a basophilic granule). (which have a thread-like appearance) are In some studies, the number of neurons af- found in distal dendrites and axons.5 fected by GVD correlated with the duration At an ultrastructural level, neuro®brillary of dementia.2 In AD patients, there is also ce- tangles are composed principally of paired rebrovascular pathology with deposition of helical ®laments, which are intraneuronal amyloid in blood vessels (cerebral amyloid proteinaceous structures composed of an ab- angiopathy). normal form of the tau protein.2,5,6 Paired he- In AD, there is a highly selective distribu- lical ®laments accumulate in neuronal cell tion of neuro®brillary lesions and to a lesser bodies (neuro®brillary tangles), in neuronal extent of neuritic plaques. Regions most af- processes throughout the cortex (neuropil fected with neuro®brillary tangles are the me- threads), and in distended neuronal process- dial temporal lobe, amygdala, the association es (dystrophic neurites) around the extracel- cortices, and the nucleus basalis of Meynert. lular amyloid deposits in the neuritic plaque Within the entorhinal cortex, there is also a of AD. selective involvement of certain neuronal lay- Biochemically, neuro®brillary tangles are ers (layers II and IV) with relative sparing of composed of a poorly soluble hyperphos- layers III, V, and VI. It is noteworthy that the 128 JAYÐPATHOLOGY OF ALZHEIMER'S DISEASE Figures 1A and 1B. Section of cerebral cortex stained by the Bielschowsky stain demonstrating neuro®brillary tangles (arrowheads) (A, high power view) and several neuritic plaques (arrowheads) (B, medium power view). large projection neurons in layers II and IV In terms of correlating pathology with clin- link the hippocampus with the association ical severity, there is a strong correlation be- cortices.5 This disruption of the neural link between the density of neuro®brillary tangles tween the hippocampus and the rest of the and the severity of dementia (speci®cally brain contributes to the amnesia in AD.5 neuro®brillary tangles in the neocortical as- 129 JOURNAL OF INSURANCE MEDICINE sociation areas).5 Correlations between senile 21) have been found.3 Other mutations have plaques and dementia have been more con- been found to involve genes on chromosome troversial, but mature neuritic plaques with 14 (presenilin-1 gene) and chromosome 1 an amyloid core do correlate with dementia, (presenilin-2 gene).3 albeit not as strongly as neuro®brillary tan- A problem in terms of a diagnosis based gles.5 on tissue pathology alone is the fact that the The neuro®brillary tangles and neuritic microscopic lesions of AD may occur to a plaque lesions of AD are accompanied by an minimal or modest degree in nondemented in¯ammatory reaction including proliferation elderly people. As a practical guide, the ®nd- of microglia and astrocytes, prompting re- ing of neuro®brillary tangles in a neocortical search into the role of anti-in¯ammatory brain biopsy allows for a relatively certain di- medication in AD.2 agnosis of AD.2 If neuro®brillary tangles and Several neurotransmitter systems are af- neuritic plaques are abundant throughout the fected in AD. There is a severe loss of cholin- neocortex and the hippocampus at autopsy, ergic neurons in the nucleus basalis of Mey- then a neuropathologic diagnosis of AD is nert of the forebrain.5 Abnormalities of the relatively straightforward.2 Neuro®brillary cholinergic systems form the basis of phar- tangles without neuritic plaques are also en- macotherapeutic interventions aimed at en- countered in a number of other ``tauopathies'' hancing cholinergic activity. Cholinesterase such as supranuclear palsy and dementia inhibitors are the only medications approved pugilistica,2,7 but a combination of tangles, by the U.S. Food and Drug Administration as neuritic plaques, vascular amyloid, and gran- treatment for AD.3 In addition to cholinergic ulovacuolar degeneration is diagnostic of AD. neurons, other neurotransmitter systems are This article is intended only as a brief overview also affected including the locus ceruleus of the pathology and does not represent an ex- (norepinephrine) and the raphe nuclei (sero- haustive review of the pathological or clinical lit- tonin).5 erature on the subject. The amyloid protein in the neuritic plaques and vessels in AD is beta-amyloid (beta/A4 REFERENCES protein, amyloid b-peptide). It is derived from a larger protein, the A4 (amyloid pre- 1.

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