We review the evidence for altered gene expression in Alzheimer's disease brain and identify alternative molecular approaches for isolating additional novel markers. One marker, pADHC-9, was isolated from a human hippocampal cDNA library by differential screening with AD and control cDNA probes. This clone hybridizes to a 2 Kb RNA which is increased 2 fold in AD hippocampus. The deduced amino acid sequence of pADHC-9 codes for a 52 kDAL protein similar to a testicular sulfated glycoprotein secreted by rat Sertoli cells. The normal function of this protein in brain and whether that function is altered in Alzheimer's disease is unknown.

The effects of mechanically supporting a percentage of body weight on the gait pattern of spastic paretic subjects during treadmill locomotion was investigated. Electromyographic (EMG), joint angular displacement and temporal distance data were simultaneously recorded while 7 spastic paretic subjects walked at 0% and 40% body weight support (BWS) at their maximal comfortable treadmill speed. Forty percent BWS produced a general decrease in EMG mean burst amplitude for the lower limb muscles investigated with instances of more appropriate EMG timing in relation to the gait cycle. The joint angular displacement data at 40% BWS revealed straighter trunk and knee alignment during the weight bearing phase especially at initial foot-floor contact and midstance. An increase in single limb support time and a decrease in percentage total double support time were evident at 40% BWS. An increase in stride length and maximum comfortable walking speed was also seen with BWS. The use of BWS during treadmill locomotion as a therapeutic approach to retrain gait in neurologically impaired patients is discussed.

High iron concentrations have been reported in the brains of multiple sclerosis victims. To determine if there are abnormalities in general iron metabolism indicative of iron overload in MS, measurements of transferrin saturation, serum ferritin and red cell ferritin in 31 female and 18 male patients were compared to the results in 49 age- and sex-matched healthy controls. Compared to controls, mean serum ferritin in MS was high, whereas transferrin saturation and red cell ferritin were similar. High values in one or more individual test results were observed in eleven MS patients. They were prevalent in patients who required bilateral assistance to walk or were confined to a chair, and appeared to be related to the severity of the disease. An investigation was made into the relationship of the high serum ferritin values in MS to the HLA-A3 histocompatibility antigen, a marker of the hemochromatosis gene which is prevalent in MS. A statistically significant interaction was not found between serum ferritin and the presence of HLA-A3.

Study of dendritic morphology through Golgi impregnation techniques has significantly furthered our understanding of neuronal development, maturation, and senescence. It has also provided insight into the pathogenesis of a wide spectrum of disease processes ranging from brain malformations to degenerative disorders. Golgi impregnation remains virtually the only method for demonstrating dendritic morphology. It delineates the profile of the individual neuron and its dendritic ramifications with unsurpassed clarity. Although it has been widely applied to experimental neuroscience involving animal tissue, its application to human material has been limited. This review summarizes the information on dendritic development and pathology in the human brain revealed by the use of the Golgi method.

Temporal interictal rhythmic delta activity or TIRDA was found in 45 of the 127 recordings of patients with complex partial epilepsy (CPE) referred for both awake and sleep EEC TIRDA was more abundant during drowsiness and light sleep; it occurred more characteristically as trains of 50-100 µv sinusoidal or saw-toothed l-4Hz activity, recorded predominantly from anterior temporal regions. When occurring bilaterally and independently, TIRDA varied from side to side. TIRDA is often found in association with anterior temporal spikes or sharp waves (TS) particularly during sleep, as observed in 43 out of 45 EEGs. TIRDA can nevertheless occur as an isolated abnormality, as noted in two sleep and 12 awake study recordings. Because of its high specificity and positive predictive value over a large range of prevalence, TIRDA should be singled out as an accurate interictal indicator of CPE. In patients with isolated TIRDA, the cost of prolonged EEG recording during sleep for the purpose of activating TS has to be weighed against the yield of eventually confirming the obvious.

Cerebral blood flow (CBF), cerebral blood volume (CBV), the CBF/CBV ratio – an index of the hemodynamic reserve capacity – the rate of oxygen metabolism (CMRO2), and the fractional extraction of oxygen by the brain (OEF) were studied by positron emission tomography (PET) in the cortical territory of both internal carotid arteries in 15 cases of transiently symptomatic or progressive extracranial atherosclerotic carotid disease. None of the patients had a major stroke or had a significant neurological deficit except 1 whose damaged hemisphere is excluded from study. All were asymptomatic at the time of PET scanning. Values were obtained in the middle cerebral artery (MCA) distribution, and in the anterior and posterior borderzone regions. Eight cases had unilateral carotid stenosis of 80% or greater and 7 had unilateral or bilateral occlusion of the origin of the internal carotid artery. Results obtained in patients were compared using Student's t-test, to those obtained in neurologically normal, elderly volunteers. Patients with carotid stenosis had a significantly decreased CBF (p<.025) and CBF/CBV ratio (p<.025) selectively in the anterior borderzone regions. This was accompanied by a trend toward elevated OEF and declining CMRO2 values. Patients with carotid occlusion had significantly decreased CBF (p<.005), decreased CBF/CBV ratio (p<.005) and decreased CMRO2 (p<.025) in the ipsilateral anterior borderzone and MCA territories. Similar changes were present in the opposite hemisphere of patients with bilateral carotid disease. These results indicate that carotid stenosis is associated with hypoperfusion and diminished hemodynamic reserve capacity in the anterior borderzone, and that carotid occlusion produces more widespread hypoperfusion and metabolic depression.

On three adjacent kibbutzim (collective rural communities) in the Negev (Southern Israel) 13 parkinsonian patients were found among a population of 592 persons 40 years or older. The clinical picture was not different from that of patients from other areas with idiopathic parkinsonism. Long term residence in the kibbutzim is characteristic of this population. In the past most of the drinking water has been supplied by wells from a common aquifer. From other patients with Parkinson's disease in the Negev, we estimated the age-specific incidence for the region. The incidence is about five times greater in each of these kibbutzim than in the remainder of the Negev. Although associations with rural residence and well water use have been reported elsewhere, clusters of this sort have not been reported. They strongly suggest that a common environmental factor exists.

Twenty-five patients with long-standing therapy resistant epilepsy were studied in an eight-month double- blind cross-over add-on trial with a daily dose of 15 mg flunarizine. In five patients the seizure frequency decreased 50% or more. The mean seizure frequency reduction in the patients on flunarizine was 35%. Particularly the control of secondary generalized seizures improved. Flunarizine did not significantly alter the plasma levels of the regular anticonvulsant drugs. Minimal adverse side effects were reported equally in the flunarizine and the placebo group. In three patients depressive symptoms improved and two patients became free of postictal headaches. Flunarizine appears to be a safe adjuvant anticonvulsant.

There is extensive evidence for decrements of gene expression in AD, at several levels in the process. There is also evidence for increments of expression of some genes. Message for the amyloid precursor protein (APP), for example, is elevated in surviving neurons of certain subcortical populations in AD. We evaluated expression of message for APP as well as for certain neuronal and glial cytoskeletal proteins in the cortex of six cases of AD. Neuronal mRNAs, including that for APP, were significantly decreased when compared with control cortex, whereas the glial mRNA was increased. We have projected studies to determine the evolution of these mRNA decrements in Alzheimer-type degeneration. The rationale for these studies and preliminary findings are discussed.

The contribution of various electroencephalographic electrodes in detecting spikes from patients with seizures of suspected anterior temporal origin was prospectively studied with a standard protocol. The following electrodes were studied: International Standard 10-20 positions F7-8 and A1-2, sphenoidal (SP), nasopharyngeal (NP), anterior temporal (Tl-2), mandibular notch surface (MNS), and mandibular notch subdermal (MNSD). Twenty patients were recorded of whom 16 demonstrated anterior temporal spikes. There was no difference in the number of spikes detected by SP, MNS, MNSD, or Tl-2 electrodes (p < 0.05); however these electrodes detected significantly more spikes than NP, F7-8, or A1-2. The SP electrode recorded spikes of highest amplitude (p < 0.05). We conclude that for patients suspected of having seizures of anterior temporal origin, (1) a substantial number of spikes will be missed if only the International Standard electrode system is employed; (2) in comparison to SP electrodes the noninvasive and easily applied MNS or Tl-2 electrodes will detect almost all spikes and should be used in outpatient EEG recordings; (3) NP electrodes provide no information that cannot be obtained by more reliable and better tolerated electrodes.

The pathological changes that occur in Alzheimer disease (AD) brain lead to a large loss of various classes of neurons and the production of novel proteinaceous elements such as neuritic plaques and neurofibrillary tangles. For the neuronal loss to occur and these elements to arise, there must be a disturbance in the expression or regulation of genes that code for proteins required for normal cell maintenance, or perhaps even for the expression of genes unique to AD. We describe the construction of a cDNA library from the human substantia innominata and strategies for isolating genes that are expressed differentially between brain regions and which may be affected by AD. Some of the results obtained using these strategies and a preliminary description of a novel brain specific mRNA of 15.5kb, whose expression is increased in AD affected temporal cortex, are presented.

We report a double blinded cross-over study involving Flunarizine versus placebo in the treatment of refractory childhood epilepsy. The patients studied were between the ages of 2 and 18; and were having more than 4 seizures per month not responsive to regular anticonvulsant medications. Of the 34 patients treated, 8 had a 50% decrease in their seizures during the placebo phase, 5 had a 50% decrease during the Flunarizine phase, and 1 patient had a 50% increase in seizures while taking Flunarizine. The remaining 25 patients showed no change in seizure activity in either phase. Patients having partial seizures with secondary generalization tended to do better on Flunarizine than those with other seizure types. Monitoring serum Flunarizine levels showed no significant difference between patients having improved seizure control and those who were unimproved. No significant side effects were noted with this medication, nor were any significant drug interactions noted.

Altered efficacy, from change in receptor discharge with different positions of the knee, was investigated in a heteronymous lb reflex of the human leg. The electrical stimulus was low threshold, to the common peroneal nerve. The divergence of the group I afferents was studied in the electromyograms (EMGs) of ipsilateral and contralateral thigh muscles. The stimulus evoked ipsilateral, short latency, excitation in the three quadriceps muscles studied and inhibition in the knee flexor semitendinosus (ST), with prior contraction of target muscles. This excitation and inhibition did not alter when studied over the range of the knee joint. The stimulus did not evoke responses in contralateral thigh muscles, contracted or relaxed. It is concluded that (1) any change in convergence from discharge of receptors, during extension of the limb, is small and sub-threshold, and (2) this spinal proprioceptive level of neural control appears to be directed primarily to the single limb.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities of lumbar cerebrospinal fluid (CSF) have been measured in seventeen patients with a clinical diagnosis of probable Alzheimer's disease (Prob AD), possible Alzheimer's disease (Poss AD), or dementia of non-Alzheimer aetiology (Non-AD). The three diagnostic groups did not differ with regard to the Km or saturation kinetic properties of AChE and BChE. The CSF AChE activity was significantly higher in Prob AD than in Non-AD patients. The groups did not differ significantly in BChE activity. The ratio of AChE to BChE activity was significantly higher in both the Prob AD and Poss AD groups than in the Non-AD group, and the ranges of values in the Prob AD and Non-AD groups did not overlap. Among patients in the Prob AD group, severity of dementia was correlated with both AChE activity and the AChE/BChE ratio, and progression of dementia over time was also correlated with AChE/BChE.

The AChE/BChE ratio correlated more strongly than AChE with severity and progression of dementia in Prob AD patients, and also better distinguished them from Non-AD patients, suggesting that AChE/BChE may be the more useful marker for diagnosis of AD. It is not clear from the results whether AChE/BChE is useful for diagnosis of the complex dementia cases in the Poss AD group.

We report the clinical and laboratory findings of six Canadian patients with progressive myelopathy associated with HTLV-1 infection. The diagnosis was suspected on clinical grounds and supported by serological studies and positive gene amplification. Only five had emigrated from an area endemic for HTLV-1 infection. Tropical spastic paraparesis should be considered in all patients with myelopathy, even those without standard serological markers of HTLV-1 infection. The pathogenesis of this condition and the serological and molecular biological means by which this diagnosis can be made are reviewed.

Vascular headache of migraine-type may be a presenting symptom of multiple sclerosis (MS), a condition usually not considered in the differential diagnosis of a severe headache accompanied by neurological signs. We reviewed records of 1,113 patients with MS seen from 1967-1987 and found 44 cases whose initial attack or subsequent exacerbations were heralded by a migraine-type headache. Twenty-seven patients had no prior history of migraine, and of these, 12 presented simultaneously with their first headache and MS attack. Twenty-three patients had symptoms of a posterior fossa mass lesion. The significance of these results and possible pathogenesis is discussed.

Application of molecular biological techniques and sensitive elemental analysis have produced new evidence implicating aluminum as an important factor in down regulation of neuronal protein metabolism. Aluminum in Alzheimer's disease may act by electrostatically crosslinking proteins, particularly the methionine containing histone Hl°, and DNA. The consequence of such crosslinking is reduced transcription of at least one neuron specific gene, the low molecular weight component of neurofilaments. In the superior temporal gyrus in Alzheimer's disease, down regulation of this gene occurs in approximately 86% of surviving neurons and, therefore, aluminum must be considered as having an active role in the pathogenesis. Epidemiological studies are reviewed that independently support the hypothesis that environmental aluminum is a significant risk factor. Preliminary evidence also suggests that a disorder in phosphorylation may be an important initiating factor.

Fifty patients with ruptured intracranial aneurysms and 8 patients with elective clipping of unruptured aneurysms had daily transcranial Doppler (TCD) measurements performed. The highest mean middle cerebral artery velocity (MCA-Vel) was considered to be the best single parameter forjudging a patient's susceptibility to clinically significant vasospasm (VSP). Surgery for the clipping of unruptured aneurysms by itself does not lead to an increase in MCA-Vel. There is a progressive increase in MCA-Vel after subarachnoid hemorrhage (SAH) from aneurysms which peaks between 7 and 10 days. The MCA-Vel is higher on the side of the ruptured aneurysm and the degree of rise is greater if blood is seen on the initial CT scan. It is highly unlikely that a patient whose MCA-Vel remains under 100 cm/sec has a degree of angiographic VSP which causes clinical symptomatology. Patients whose MCA-Vel is > 200 cm/sec are at great risk of developing clinical symptomatology of VSP and are very likely to have significant angiographic VSP. There is a transitional zone in between these two levels.

Morbidity and mortality from pediatric head injuries associated with the use of off-road vehicles are increasing. We reviewed all such injuries admitted to acute care hospitals in the two largest urban centers in Manitoba between April 1979 and August 1986. Of 375 injured children, 83 suffered head injury, 70 boys and 13 girls. Ages ranged from 2 to 15 years, with a mean of 10.4 years. Head injury was defined as any injury involving face, scalp or nervous system. Dirtbikes were implicated in 34 accidents, snowmobiles in 28, 3-wheel ATV's in 19, and 4-wheel ATV's in 2. About 85% of accidents occurred in a rural setting. Loss of vehicle control was the most common cause of injury. Alcohol or drug abuse were not factors. Fifty (60.2%) patients suffered loss of consciousness, prolonged in 6 (7.2%). All head-injured children also suffered at least one associated injury, mainly involving the musculoskeletal system. Associated spinal injury occurred in 18%. The average hospital stay was 13 days. Three (3.6%) patients died as a result of head injury.

A thirty-eight-year-old man presented with a six year history of symptoms resembling an anterior horn cell disorder. There was progressive upper extremity wasting and weakness in the absence of sensory complaints. Electrophysiologic abnormalities were confined to motor nerve conduction and indicated a demyelinating process involving the brachial plexus and major proximal upper extremity nerve trucks bilaterally. Biopsy of the proximal right ulnar nerve revealed changes suggesting a chronic demyelinating process, and onion-bulb formations were present. Immunohistochemical staining for S-100 protein was positive in the cells comprising the onion-bulbs, indicating a Schwann cell, not a perineurial origin of these cells. After 8 years, symptoms have failed to appear in the lower limbs. Recent reports in the literature have begun to delineate the syndrome, which appears to represent an unusual, localized or multifocal, sometimes inflammatory, clinically benign neuropathy that can mimic motor neuron disease in its earlier stages. We report the first such case with underlying pathology.