Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer's disease.

Previous studies examining the functional status of cortical muscarinic cholinergic M1 receptors have demonstrated an impairment in receptor-G protein coupling in Alzheimer's disease (AD) as measured by the inability of the receptor to form a high affinity agonist binding site. In order to investigate whether this alteration was a global phenomenon or a regional specific defect in signal transduction, we examined agonist binding at M1 receptors in three brain areas (superior frontal cortex, Brodmann areas 8 and 9; primary visual cortex, Brodmann area 17; and the dorsal striatum) within the same brain in controls and moderate to severe AD cases. Competition binding studies using the M1 antagonist 3H-pirenzepine (4 nM) in the presence of varying concentrations of the cholinergic agonist carbachol (50 nM to 1 mM) were performed in the presence and absence of GppNHp (100 microM), a non-hydrolyzable analog of GTP. In control membrane preparations, computer-assisted analysis of antagonist-agonist competition curves revealed that M1 receptor agonist binding fit a two site model with high and low affinity states in all three brain areas in the absence of GppNHp but only a single site in the presence of GppNHp. This is consistent with the ternary complex model of G protein-linked receptors. In contrast, curves obtained from both cortical regions from AD brains fit a single site model with low affinity in the presence or absence of GppNHp. On the other hand, agonist binding data obtained from the dorsal striatum of AD cases exhibited a two site fit, similar to that seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatosensory evoked potentials recorded directly from human thalamus and Sm I cortical area.

Somatosensory evoked potentials (SEPs) to median nerve stimulation were recorded from the nucleus ventralis caudalis. They consisted of monophasic or diphasic potentials with mean onset latency of 13.8 ms. More complex SEPs to median nerve stimulation were obtained from the cortex. The SEPs consisted of two major positive waves, P1 and P2, and were recorded over both the precentral and postcentral gyri, suggesting that somatosensory information converges to the motor cortex, probably to be used for the integration of critical motor activity. In two patients, it was noted that the motor representation of facial movements was larger than the correspondent sensory representation on the postcentral gyrus. This larger motor representation of the face and more specifically of the lips and tongue may be related to human acquisition of mimicry and articulation of language.

Clinical significance of periodic EEG patterns.

Generalized and focal periodic EEG patterns were studied in 62 patients. Generalized periodic suppression bursts and generalized periodic slow-wave complexes (GPSC) occurred in patients under anesthesia or drug intoxication, and with anoxic/metabolic encephalopathies. When these conditions were excluded, GPSC indicated the diagnosis of subacute sclerosing panencephalitis or other encephalitides. Suppression bursts in comatose patients after cardiorespiratory arrest indicate an unfavorable outcome. Generalized periodic triphasic waves occurred only in patients with metabolic-anoxic encephalopathies. Generalized repetitive sharp transients were observed in patients with anoxic encephalopathy. Periodic lateralized epileptiform discharges (26 cases) were associated with clinical seizures in 24 cases and were noted almost exclusively in destructive hemispherical lesions. Periodicity represents a profound disruption of normal electrophysiological rhythms and indicates either structural or functional involvement of cortical and subcortical structures.

Effects of aging on visual evoked responses.

The effects of aging of visual evoked responses (VER) and critical frequency of photic driving (CFPD) was studied in 74 volunteers aged 18 to 79. The amplitude of VER to pattern reversal stimulation did not vary with sex or age. The latencies of the first major negative and of the first major positive defection of the VER were significantly delayed (P less than .001) with advancing age. This increase of latency probably reflects a slowing of conduction velocity in the optic nerve or optic pathways or both. CFPD, defined as the highest frequency of photic driving response expressed in flashes per second, showed an inverse correlation, decreasing with age in older subjects. Critical frequency of photic driving is the electrophysiological counterpart of critical flicker fusion, which is known to decrease with advancing age. These data support the concept that aging influences the functions of specialized sensory systems.

The effects of epileptogenic activity on auditory evoked potentials in cats.

Epileptogenic foci were produced by application of penicillin to the auditory cortex of cats. A gradual modification of the evoked potentials to clicks and of the recovery cycle to paired clicks was noted following the application of penicillin. With the onset of interictal spikes, responses were initially depressed. The depression gradually changed till every click triggered a reflex epileptogenic spike. Areas surrounding the primary focus and areas at the mirror focus had depressed evoked potentials, while at the primary focus a click elicited reflex spikes. Progressive recruitment of cortical regions farther away from the primary focus was noted with increased epileptogenicity. The recovery cycle was also affected with prolongation of the absolute refractory period. These complex modifications of sensory input were closely related to the intensity of the epileptogenic disturbance, the distance of the area processing the information from the primary epileptogenic focus, and the time of arrival of the signal to be processed in relation to the interictal and ictal discharges.

Visual evoked potentials with hemifield pattern stimulation. Their use in the diagnosis of retrochiasmatic lesions.

We measured several parameters of cortical potentials evoked by visual stimulation to produce a profile suggestive of retrochiasmatic lesions. Characteristic abnormal responses included (1) very low amplitude or absent transient visual evoked potentials (T-VEPs) after stimulation of the affected hemifield, (2) reversal of normal pattern amplitude of the T-VEP distribution after stimulation of the affected hemifield, (3) abnormal lateral occipital ratio, (4) absent or very low amplitude steady-state VEPs after stimulation of affected hemifield, and (5) abnormal midoccipital ratio.

Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies.

Nineteen cases of generalized status myoclonicus (GSM) associated with acute anoxic and/or toxic-metabolic encephalopathy were studied. Generalized status myoclonicus was associated with coma in the overwhelming majority of patients (95%), although one patient had only clouding of consciousness. Generalized status myoclonicus occurred in 13 patients after cardiorespiratory arrest and in six patients after toxic-metabolic encephalopathy. Thirteen patients died, four survived in a chronic vegetative state, and two recovered without any permanent neurologic sequelae. Generalized status myoclonicus was preceded by generalized tonic-clonic seizures or generalized tonic-clonic status epilepticus in six patients (32%). The implications of these findings are discussed and a hypothesis that generalized status myoclonicus is a fragment of generalized tonic-clonic status epilepticus is proposed. Generalized status myoclonicus is a grave prognostic indicator that is often not compatible with useful recovery in spite of all therapeutic efforts. The final outcome is related to the underlying disease process. In our study, complete neurologic recovery was observed in two patients (11%).

Simultaneous recording of pattern electroretinography and visual evoked potentials in multiple sclerosis. A method to separate demyelination from axonal damage to the optic nerve.

Pattern electroretinograms (P-ERGs) and visual evoked potentials (VEPs) were recorded in 35 patients with multiple sclerosis and in 35 age-matched normal subjects. Four patterns of abnormalities were noted in the group with multiple sclerosis. The most frequent abnormality consisted of the following: normal P-ERG, delayed P100, and prolonged interpeak interval between the b-wave of the P-ERG and P100 (retinocortical time). This pattern indicates demyelination of the optic nerve. A second pattern consisted of absent P-ERG and absent VEP. This pattern was associated with optic atrophy and/or central scotoma, indicating severe optic nerve axonopathy with retrograde degeneration of ganglion cells. A third pattern consisted of normal P-ERG and absent VEP, suggesting a total block of transmission at the optic nerve. A fourth pattern consisted of present but low-amplitude P-ERG, delayed VEP, and prolonged retinocortical time, indicating a demyelinating process with partial axonal involvement. The concomitant use of P-ERG and VEP results in a better classification of the type and severity of dysfunction affecting the optic nerve. The prognostic value of the four patterns for recovery of visual function is discussed.

Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.

CONTEXT: Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. OBJECTIVE: To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. DESIGN: The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. PATIENTS: The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. MAIN OUTCOME MEASURES: Diagnosis of probable AD. RESULTS: We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. CONCLUSIONS: There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443

Visual function of the extrageniculo-calcarine system in man: relationship to cortical blindness.

A 72-year-old woman, blind for more than two years, had normal evoked potentials to visual stimulation. Destruction of both areas 17 and relative preservation of areas 18 and 19 was demonstrated. We concluded that in the presence of bilateral destruction of area 17, visual evoked potentials are mediated by extrageniculocalcarine pathways to secondary visual cortices, but this system is not capable of providing conscious visual perception in humans.

Visual evoked spectrum array and interhemispheric variations.

An EEG spectrum analysis during visual stimulation was computed in 19 normal subjects. Visual stimulation consisted of trains of flashes at frequencies ranging between 2.5 and 20 flashes per second. Recordings were carried out simultaneously from the right and left occipital regions with bipolar and referential montages. Compressed spectral arrays were computed for eight-second epochs at each recording site using a fast Fourier transform. The ratio of the spectral energy from homologus regions of right and left hemispheres at each stimulation frequency was determined. The ratios were graphically displayed in a visual evoked spectrum array (VESA) ratio plot (VESA-GRAM); the mean of the ratio plot was designated the VESA coefficient. The range of variation for these measurements was determined for normal subjects. An application of the technique to patients with hemianopia showed abnormal VESA (characterized by smaller spectral amplitudes over the appropriate hemisphere), abnormal VESA ratio plots, and high VESA coefficients. These preliminary findings suggest that VESA may be a promising method to detect retrochiasmatic visual defects.

Electroencephalographic activity after brain death.

Fifty-six consecutive patients clinically diagnosed as brain dead were seen at Loyola University Medical Center, Maywood, Ill, from January 1984 through May 1986. Eleven (19.6%) of the 56 patients had electroencephalographic (EEG) activity following the diagnosis of brain death. The mean duration of the observed EEG activity was 36.6 hours (range, two to 168 hours). Three patterns of EEG activity were observed: (1) low-voltage (4 to 20 microV) theta or beta activity was recorded in nine (16.1%) patients as long as 72 hours following brain death. Neuropathologic studies in one patient showed hypoxic-ischemic neuronal changes involving all cell layers of the cerebral cortex, basal ganglia, brain stem, and cerebellum; (2) sleep-like activity (a mixture of synchronous 30 to 40 microV theta and delta activity and 60 to 80 microV, 10 to 12 Hz spindle-like potentials) was noted in two (3.6%) patients for as long as 168 hours following brain death. Pathologic studies in both cases demonstrated ischemic necrosis of the brain stem with relative preservation of the cerebral cortex; and (3) alpha-like activity (monotonous, unreactive, anteriorly predominant, 25 to 40 microV, 9 to 12 Hz activity) was observed in one (1.8%) patient three hours following brain death. Regardless of activity on the EEG, none of the patients recovered. The occurrence of EEG activity following brain death would suggest reliance on the EEG to confirm brain death may be unwarranted. The use of the EEG as a confirmatory test of brain death may be of questionable value.

Digital subtraction arteriography. A new method for evaluation of extracranial occlusive disease.

Digital subtraction arteriography (DSA) allows visualization of both the intracranial and extracranial vasculature following an intravenous injection of contrast medium. One hundred consecutive patients were evaluated using this modality. In 32, DSA was compared with conventional arteriography. The degree of internal carotid artery stenosis and/or occlusion shown by DSA was confirmed by conventional arteriography in 27 cases (84%). Abnormalities of the extracranial vasculature was demonstrated by DSA in 60% of patients with suspected cerebrovascular disease. Digital subtraction arteriography demonstrated significant stenosis or occlusion of the carotid arteries in 30% of patients in whom Doppler and radionuclide studies were normal. Digital subtraction arteriography is useful in evaluation of the extracranial vasculature in a variety of clinical conditions. In some instances it serves as a substitute for conventional arteriography. However, its exact place in evaluation of extracranial vasculature disease remains to be defined.

Determination of regional cerebral blood flow in patients with cerebral infarction. Use of fluoromethane labeled with fluorine 18 and positron emission tomography.

Regional cerebral blood flow (rCBF) was determined using the tissue kinetic of fluoromethane labeled with fluorine 18 and positron emission tomography (PET) in 13 normal subjects and 21 patients with cerebrovascular diseases. The mean brain rCBF was 42.9 +/- 4.3 mL/100 g/min during the resting state. The highest rCBF (60 +/- 8 mL/100 g/min) was noted in the mesial occipital region corresponding to cortical area 17. All 17 cases of cerebral ischemic infarcts had depressed rCBF in the hemisphere ipsilateral to the infarct. Every area of decreased density shown in the conventional computed tomograms (CT) was detected on the PET as an area of decreased rCBF (mean rCBF of infarcted area, 14.3 +/- 6 mL/100 g/min). The PET images showed a wider area of depressed rCBF than the region of the anatomic infarct. Five types of remote effects were noted in areas without structural damage: (1) decreased flow in the thalamus and caudate ipsilateral to the infarct; (2) decreased flow in the hemisphere contralateral to the cerebral infarct; (3) decreased flow in the cerebellar hemisphere contralateral to the cerebral infarct; (4) decreased flow in the visual cortex distal to the optic radiation lesion; and (5) decreased flow in the frontal cortex ipsilateral to the infarct. The effects in the contralateral hemisphere and the cerebellum were present only in the acute postictal phase. In four cases of transient ischemic attacks, rCBF was normal. It is concluded that this technique of measuring rCBF is a reliable method of identifying cerebral ischemia and that the determination of the extent of impaired rCBF provides a more accurate assessment of the region of brain dysfunction than CTs.

Simultaneous recording of pattern electroretinogram and visual evoked responses in neuro-ophthalmologic disorders.

Simultaneous pattern electroretinograms (P-ERG) and pattern visual evoked potentials (P-VEP) to transient and steady-state checkerboard pattern reversal were recorded in 52 normal volunteers. Twenty-seven patients were also studied. Three patterns of abnormalities emerged. Pattern 1 with prolonged P-ERG, prolonged P-VEP, and normal retino-cortical time (RCT) was found exclusively in early maculopathies. Pattern 2 with normal P-ERG, prolonged P-VEP, and prolonged RCT was found in optic nerve lesions without optic atrophy, probably indicating the presence of a demyelinating lesion of the optic nerve. Pattern 3, with very small or absent P-ERG and P-VEP, was observed in both maculopathies and optic atrophies.

Visual electroencephalographic computer analysis (VECA). A new electrophysiologic test for the diagnosis of optic nerve lesions.

The function of optic pathways was studied by visual electroencephalographic computer analysis (VECA). Pattern and flash stimuli were used. The VECA profile was abnormal in two types of lesions: pathology involving the eye, and pathology involving the optic nerve. When ocular pathology is excluded, an abnormal profile indicates optic nerve dysfunction. Of the multiple sclerosis patients tested, 77 percent had an abnormal VECA profile. The test was always abnormal in patients with optic neuritis. Delayed visual evoked responses occurred in 18 of 29 multiple sclerosis patients judged to be clinically without visual deficits. VECA is reliable and sensitive for detecting clinical and subclinical optic nerve pathology.

Amplitude difference between pattern-evoked potentials after left and right hemifield stimulation in normal subjects.

The amplitude of visual evoked potentials (VEPs) to pattern hemifield stimulation was measured in 14 normal right-handed subjects. The paired t test was used to determine if the values differed between right and left hemifield stimulation. The amplitude of transient VEPs from a midoccipital electrode and a lateral occipital electrode ipsilateral to the hemifield stimulated was significantly greater with right hemifield stimulation. This result is compatible with neuroanatomic asymmetries of human striate cortex. Amplitude distribution over the scalp was markedly different between transient and steady-state VEPs that probably reflect activities of different populations of cortical neurons.

Topographic mapping of electrophysiologic measures in patients with homonymous hemianopia.

We analyzed electroencephalographic (EEG) activity and spatial distribution of the pattern-reversal visual evoked potential (PVEP) in 20 patients with unilateral lesions in the retrochiasmal visual pathways. Focal abnormalities that were consistent with lesion location were present in the topographically analyzed EEG or VEP of 85% of the patients, compared with a 70% detection rate for conventional analysis techniques. Quantitative analysis of spectrally analyzed EEG revealed focal abnormality in 7 patients whose conventional EEG was interpreted as either normal or diffusely slow. However, focal paroxysmal spikes present in the EEG of 1 patient were missed by EEG mapping, and a false localization of quantitative EEG abnormality contralateral to the lesion occurred in 1 patient. Topographic analysis of the PVEP was no more sensitive to retrochiasmatic lesions than conventional analysis of 2 lateral occipital electrodes. We conclude that topographic mapping is a valid technique in the detection of localized cerebral lesions.

Cortical blindness and residual vision: is the "second" visual system in humans capable of more than rudimentary visual perception?

We studied 12 patients with static cortical blindness to evaluate residual vision after destruction of area 17 and to assess the visual capacity of the subcortical "second" visual system in humans. In each case, the cause was bilateral infarction of the occipital lobes. Five patients had total blindness, and four had residual rudimentary vision (RRV), characterized by homonymous areas of light perception in the peripheral field and ability to detect moving objects. Only three patients had the ability to read; two of these had spared macular vision, and the other had spared left homonymous hemimaculae and spared temporal crescent. Neuroimaging and visual evoked potentials (VEPs) correlated with the extent of the visual dysfunction. Total destruction of area 17 bilaterally was associated with total permanent visual loss. The larger the amount of spared visual cortex, the better the vision. Positron emission tomography (PET) or single photon emission computed tomography (SPECT) demonstrated retained metabolic activity in islands of preserved area 17 in patients with some residual vision. VEPs were present in totally blind individuals. We conclude that, in humans, useful visual function is preserved only when a critical amount of area 17 is spared. The subcortical second system may participate in the generation of VEPs, but is incapable of conscious visual perception.

Spatial frequency evoked visuograms in multiple sclerosis.

We obtained steady-state visual evoked potentials (VEPs) to sinusoidal gratings alternating at 4 Hz with spatial frequencies varying from 0.5 to 8 cpd in 21 normal controls and 21 patients with multiple sclerosis (MS), and analyzed responses by fast Fourier transform. Amplitude- and phase-spatial frequency functions were obtained and referred to as amplitude and phase "visuograms." We observed two types of abnormalities in the phase visuograms of MS patients: (1) abnormal responses at all spatial frequencies tested (37%), and (2) abnormal responses only at selective spatial frequencies (52%). Some patients had phase lag limited to low, middle, or high spatial frequencies. Steady-state and transient VEPs to 2 and 4 cpd showed a similar percent of abnormalities. The use of more than one spatial frequency stimulus increased the diagnostic yield by 17%. Our data confirm that MS may selectively affect specific neuronal channels within the visual pathways.