Production of the Alzheimer amyloid beta protein by normal proteolytic processing.

The 4-kilodalton (39 to 43 amino acids) amyloid beta protein (beta AP), which is deposited as amyloid in the brains of patients with Alzheimer's diseases, is derived from a large protein, the amyloid beta protein precursor (beta APP). Human mononuclear leukemic (K562) cells expressing a beta AP-bearing, carboxyl-terminal beta APP derivative released significant amounts of a soluble 4-kilodalton beta APP derivative essentially identical to the beta AP deposited in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing full-length beta APP and M17 cells expressing only endogenous beta APP also released soluble 4-kilodalton beta AP, and a similar, if not identical, fragment was readily detected in cerebrospinal fluid from individuals with Alzheimer's disease and normal individuals. Thus cells normally produce and release soluble 4-kilodalton beta AP that is essentially identical to the 4-kilodalton beta AP deposited as insoluble amyloid fibrils in Alzheimer's disease.

Acetylcholine receptor antibodies in the Lambert-Eaton myasthenic syndrome.

Two patients were initially diagnosed with myasthenia gravis with elevated titers of acetylcholine receptor antibodies. Features including weakness that normalized with sustained contraction, areflexia, autonomic symptoms, and low-amplitude baseline compound muscle action potentials with abnormal increments following brief exercise and high-frequency repetitive stimulation, however, suggested that these patients had Lambert-Eaton myasthenic syndrome. One patient had antibodies directed against presynaptic calcium channels, confirming the diagnosis. The second patient was seronegative for these antibodies but had elevated titers of antistriated muscle antibodies. This shows that serologic studies can conflict with clinical and electrodiagnostic findings in patients with Lambert-Eaton syndrome. These cases also point out that acetylcholine receptor antibodies are not necessarily diagnostic of myasthenia gravis in patients with Lambert-Eaton syndrome. Instead, these antibodies could represent a nonpathogenic epiphenomenon.

Neuropathologic verification of Creutzfeldt-Jakob disease in the exhumed American recipient of human pituitary growth hormone: epidemiologic and pathogenetic implications.

Beginning at age 12, a boy with idiopathic hypopituitarism was treated with cadaver pituitary-derived human growth hormone during the period from 1963 to 1969. Fifteen years after the last treatment, the then 32-year-old man developed Creutzfeldt-Jakob disease (CJD). The illness was atypical in showing predominantly cerebellar signs, little mental deterioration, and no abnormal movements or periodic EEG activity. Examination of the embalmed brain, 7 months after interment, revealed the characteristic changes of CJD mainly in the cerebellum and basal ganglia. This case establishes the contamination of at least two American lots of human growth hormone and, together with other cases of iatrogenic disease, suggests that virus enters the brain from the blood, rather than along neural pathways.

Single photon tomography in Alzheimer's disease and the dementias.

Measurements of brain blood flow has evolved over the past 50 years, and during the latter half of that time radionuclide techniques have been used to study this important function. Using Xenon 133 and scintillation multiprobe systems, several teams of investigators measured regional cerebral blood flow (rCBF), and noted that under many circumstances it could be equated with local brain physiological activity. The dementias were investigated using the scintillation multiprobe method, and posterior flow deficits were described in patients who were thought to have Alzheimer's disease. The multiprobe technique gave way first to planar, and then tomographic imaging, with initial favorable results achieved by positron emission tomography (PET). Soon investigators learned to measure rCBF with single-photon emission computed tomography (SPECT) using high-sensitivity systems and 133Xe as a tracer, or high-resolution systems with 123I-iodoamphetamine (IMP), and later, 99mTc-HMPAO. Three-dimensional tomographic imaging shows to advantage the flow patterns that characterize Alzheimer's disease, with rCBF reductions in temporal, parietal, and sometimes frontal areas, as opposed to randomly distributed deficits in multiinfarct dementia, reduced frontal flow in entities such as Pick's disease, and others. Herein we will review our own experience with high-sensitivity rCBF SPECT in 119 patients with dementia, and with high-resolution SPECT, using a new, three-camera scanner and 99mTc-HMPAO in an additional 39 patients. SPECT rCBF study of patients with dementia and Alzheimer's disease, will aid in separating patients with untreatable Alzheimer's from those patients who may have treatable causes of dementia, and will be useful in evaluating experimental drugs for the treatment of Alzheimer's disease.

Experiences with depression in a dementia clinic.

Of 317 consecutive cases seen in a dementia clinic, 19 (6%) had little or no objective evidence of cognitive impairment on clinical examination and extensive neuropsychological testing. Of the remaining 298 cases, 192 (64%) were diagnosed as probable or possible Alzheimer's disease (AD). Of the 19 nondemented cases, 8 (42%) were thought to have cognitive difficulty due to depression. In the AD group, only 4 cases (2%) were thought to be depressed and only 2 of the 4 met DSM-III-R criteria for major depression. There was no relationship between Hamilton Rating Scale for Depression scores and either cognitive or behavioral measurements of dementia severity, suggesting that the difference between the two groups was not due to underreporting by AD patients. The authors concluded that a tertiary care setting, depression is a common cause of cognitive complaints in persons without organic disease and a rare cause of excess morbidity in AD.

The effect of acetazolamide on regional cerebral blood flow in patients with Alzheimer's disease or stroke as measured by single-photon emission computed tomography.

Regional cerebral blood flow (rCBF) was assessed in 35 patients with possible or probable Alzheimer's disease (AD) and in 16 patients known to have had at least one stroke. Patients were evaluated before and after the administration of 1 g acetazolamide (ACZ) by means of a rotating four-detector single-photon emission computed tomograph (SPECT) and inhaled Xe-133. RCBF values in mL/minute/100 g were derived from eight cortical regions of interest (ROI), and from the whole transverse section as a measure of whole brain flow (WBF). ROI/WBF ratios were calculated for each ROI in paired determinations done before and 15 minutes after the administration of ACZ. Results were compared with those previously obtained in a study of 15 normal, healthy volunteer subjects. ROI/WBF ratios greater than 2 standard deviations (SD) below the mean for a given ROI in the normal group were regarded as probably abnormal, whereas ratios greater than 4 SD below the mean were considered definitely abnormal. After ACZ administration, the number of ROI greater than 2 SD below the normal mean decreased significantly in the AD group and was unchanged in the stroke patients. However, the number of ROI/WBF ratios greater than 4 SD below the normal mean fell in the AD group and rose in the stroke group, with the difference in behavior highly statistically significant. Thus, the response of low-flow areas to ACZ differs in AD and in stroke, which could be of ultimate diagnostic significance.

Dystonia and parkinsonism.

Parkinsonism and dystonia may coexist in a number of neurodegenerative, genetic, toxic, and metabolic disorders and as a result of structural lesions in the basal ganglia. Parkinson's disease (PD) and the 'Parkinson-plus' syndromes (PPS) account for the majority of patients with the parkinsonism-dystonia combination. Dystonia, particularly when it involves the foot, may be the presenting sign of PD or PPS and these disorders should be suspected when adults present with isolated foot dystonia. Young age, female gender, and long disease duration are risk factors for PD-related dystonia, but dystonia in patients with PD is usually related to levodopa therapy. The mechanism of dystonia in PD is not well understood and the management is often challenging because levodopa and other dopaminergic agents may either improve or worsen dystonia. Other therapeutic strategies include oral medications (baclofen, anticholinergics and benzodiazepines), local injections of botulinum toxin, intrathecal baclofen, and surgical lesions or high frequency stimulation of the thalamus, globus pallidus, or subthalamus.

Botulinum toxin for the treatment of cervical dystonia.

Cervical dystonia (CD) manifests clinically through involuntary spasms of neck muscles, producing abnormal head and neck movements and postures, which is often associated with pain. CD is the most common form of focal dystonia presenting to movement disorders clinics. Chemodenervation with botulinum toxin (BTX) has become the first-line treatment for CD, producing satisfactory relief of symptoms in > 80% of cases. Unresolved issues that may impact on the overall results include the method of selection for injection sites (clinical vs. electromyography), dosing, dilution and the role and relative efficacy of the different BTX serotypes. A guiding therapeutic principle of BTX injections is to achieve optimal results with the lowest possible dosage and frequency of administration. This strategy is critical in order to keep the risk of immunoresistance at a minimum. Development of antibodies that block the effects of BTX, usually associated with frequent injections of high doses, is the main reason for secondary unresponsiveness to this treatment. Although the mechanism of denervation at the neuromuscular junction by BTX is relatively well understood, the role of changes in muscle spindles and myopathic pain mechanisms, as well as secondary changes at the level of the basal ganglia, thalamus and cortex and their role in response to BTX, all need further exploration.

Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial.

To compare autonomic effects of botulinum toxin (BTX), we randomized patients with cervical dystonia to receive either BTX-A or BTX-B in a double-blind manner. Efficacy and physiologic questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with BTX-B had less saliva production (p < 0.01) and greater severity of constipation (p = 0.037) than those treated with BTX-A, but did not differ in other tests of autonomic functions.

Focal dystonia: the role of botulinum toxin.

Botulinum toxin (BTX) has been found to be effective in a wide range of focal dystonias. Debate surrounds the selection of injection sites. In general, localization is satisfactory by clinical examination, but poor response, requiring localization of deep muscles, may necessitate use of electromyography for localization. Delineation of optimal doses of BTX is a work in progress; as studies have tended to show efficacy at lower doses than used in the past, the trend is to use lower doses. This is important, because development of antibodies to BTX, the main reason for secondary resistance to this treatment, is more frequent with larger doses and shorter inter-injection intervals. Although the mechanism of denervation of the neuromuscular injunction by BTX is relatively well understood, secondary changes at the level of the basal ganglia, thalamus, and cortex, and their role in response to BTX, need further exploration.

Evaluation of quantitative measures of upper extremity speed and coordination in healthy persons and in three patient populations.

Upper extremity tracking tests have been used extensively in clinical studies in patients with neurologic disorders. We evaluated several new measures of upper extremity performance derived from step-response and phase-plane analysis techniques; both techniques are founded in automatic control theory. Using a computer-based tracking test, a visual step function stimulus was applied in 15 healthy subjects and 45 patients from multiple sclerosis, myasthenia gravis, and Parkinson disease populations. The upper extremity response of the subject was analyzed to find the reliability and discriminating power measures that quantify speed, coordination, and steadiness of the upper extremity response during the tracking task. Results show that reliability of the measures, although variable across the populations tested, is generally high (greater than 0.7). The speed and coordination measures derived from phase-plane analysis are more discriminating than the measures of step-response analysis for the populations tested. Some of the measures may be useful for monitoring patient performance, the other measures can be potentially helpful in diagnosis of the disorders.

Cognitive deficits in asymptomatic first-degree relatives of Alzheimer's disease patients.

The present study was designed to determine whether neuropsychological deficits exist in asymptomatic first-degree relatives of Alzheimer's disease (AD) patients. The neuropsychological performances of 20 first-degree asymptomatic relatives of NINCDS-ADRDA diagnosed AD patients were compared to 20 normal controls without family history of AD. Cognitive functions assessed included intelligence, memory, overall brain function, verbal learning, and language and constructional abilities. Significant statistical differences were found between the groups across several cognitive areas indicating lower functioning in the first-degree relatives of AD patients. Fifty percent of the first-degree subjects but only 20% of controls showed a pattern of significant neuropsychological deficit. The results demonstrate neuropsychological deficits in asymptomatic first-degree relatives of AD patients, suggesting that preclinical markers for AD may be present long before the clinical manifestation of the disease.

Brain blood flow in the dementias: SPECT with histopathologic correlation.

Single photon emission computed tomography (SPECT) of regional cerebral blood flow (RCBF) has been employed experimentally in the assessment of patients with dementia. The standard with which the SPECT diagnosis has been compared previously has been the initial clinical diagnosis. Recognizing that histopathologic diagnosis would be a more reliable standard, the authors compared SPECT diagnoses and clinical diagnoses with histopathologic diagnoses in a series of 18 patients who had been referred by the Alzheimer Disease Research Center. SPECT RCBF studies were carried out prospectively in 15 patients with an inhaled xenon-133 SPECT technique and in three patients with technetium-99m hexamethyl-propylene-amine oxime and triple-camera-scanner SPECT. When compared with histopathologic diagnosis, clinical diagnosis was correct in 15 of 18 patients; visual scanning diagnosis, in 13 of 18; and Xe-133-SPECT diagnosis based on quantitative ratios in regions of interest, in 14 of 15 (13 of 13 with Alzheimer disease).

Xenon-133 SPECT-determined regional cerebral blood flow in Alzheimer's disease: what is typical?

A study of 76 consecutive xenon-133 SPECT studies of regional cerebral blood flow was undertaken to determine the frequency of various patterns of blood flow in cases of clinically diagnosed probable and possible Alzheimer's disease. The reference tomographic section was a slice 6 cm above and parallel to the canthomeatal line. With the use of this technique, the "classic" finding of bilateral temporoparietal (TP) flow reductions as the sole abnormality occurred in only 28% of cases. Bilateral TP reductions accompanied by bilateral or unilateral frontal flow reductions were nearly as common (24%), and other patterns accounted for the other 48% of cases.