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Diagnostic Criteria for Neuropathologic Assessment of Alzheimer’s Disease

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Abstract

Prior to any evaluation of morphologic brain changes, a decision must be made whether a given alteration is associated with aging or with disease. Patients with disease-related lesions may be in a clinically silent phase of a disease or show overt symptoms. Neurofibrillary tangles and neuropil threads are the hallmarks of Alzheimer’s disease. They should not be considered to be age-related changes, even when they are present only in small numbers. In general, the initial changes consist of neurofibrillary tangles and neuropil threads. Plaques (amyloid deposits and/or neuritic plaques) are consistently present in the end stage of the disease. Initial neurofibrillary tangles and neuropil threads develop at specific cortical predilection sites. The changes then spread in a predictable, nonrandom manner across other portions of the telencephalic cortex. The sequential changes in the distribution pattern of the lesions provide the basis for a staging procedure that takes the slow and gradual progression of the destructive process into consideration. The staging procedure provides accurate diagnoses in the initial stages and even reveals brain changes developing prior to the appearance of clinical symptoms. It is thus advantageous in characterizing nondemented controls. The staging procedure can be carried out easily and does not require knowledge of clinical data, quantitative assessments, or adjustments for the age of the patients. Application of advanced silver techniques (Gallyas, Campbell-Switzer) to demonstrate Alzheimer’s disease-related lesions also allows recognition of the hallmarks of other disorders, such as Lewy body disease (Parkinson’s disease) and dementia with argyrophilic grains, which frequently co-occur with Alzheimer’s disease.

Section snippets

Age-related vs. disease-related changes

IN recent decades the populations of developed industrial countries have experienced a marked increase in life expectancy. The distressing aspect of this change is the growing number of elderly people in clinically recognizable stages of slowly progressing illnesses 3, 22, 29, 30. Hence, it is important to distinguish disease-related lesions from morphologic changes inevitably developing with advancing age [16]. Regarding the brain, some age-related changes specifically develop only in humans.

Neuropathologic diagnosis of Alzheimer’s disease

A definite clinical diagnosis of Alzheimer’s disease (AD) cannot presently be made. Both false-positive and false-negative diagnoses occur in a significant proportion of cases, underscoring the necessity for neuropathologic confirmation of clinical assumptions [6]. Postmortem diagnosis of AD, by definition, requires proof of the presence of neurofibrillary tangles in the brain (cases of dementia without these changes must be classified as non-Alzheimer dementias). Brain changes found in cases

Brain-amyloid deposits

Amyloid protein deposits are abnormal structures that frequently, though not inevitably, occur in the brains of aged individuals. Simple amyloid deposits appear as patches and/or cored structures. Upon superficial examination, such cored structures can easily be mistaken for neuritic plaques. The term “senile plaque” is used variously for simple amyloid deposits, as well as for ill-defined amalgamations of simple amyloid deposits and neuritic plaques with dystrophic neurites containing

Neurofibrillary changes

Neurofibrillary changes of the Alzheimer type do not inevitably occur in the brain of aged individuals and thus must be considered abnormal. The distribution pattern and density of neurofibrillary tangles and neuropil threads roughly correspond to the clinical expression of AD 2, 3, 4, 5, 13, 17, 28.

The neurofibrillary changes developing in Down’s syndrome are virtually identical to those seen in AD. Elderly individuals suffering from Down’s syndrome are particularly prone to development of AD.

Evolution of the neurofibrillary changes

An early indicator of the brain destruction in AD is the subtle decline of memory functions. The clinical symptoms gradually worsen, eventually including impairment of somatomotor function. The progression of symptoms reflects the gradual development of AD-related brain changes. A particular weakness of the criteria presently in use in the neuropathological confirmation of AD is the allowance of only the distinction of fully developed cases of AD on the one hand and a broad spectrum of

Co-occurrence of other diseases

Very frequently, the brains of elderly demented patients are affected by more than one disease. A large proportion of mentally impaired Parkinson patients have concomitant AD-related pathology [15]. In addition, changes in brain vessels and specific lesions of non-Alzheimer dementias [8]often co-occur with Alzheimer-related pathology and complicate the pathological picture.

By applying the recommended advanced silver methods (the Gallyas technique for neurofibrillary changes and the

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