PET study of cholinergic system in the brain]

Recently, we have developed a method to measure acetylcholinesterase (AChE) activity, a functional marker for cholinergic system, by positron emission tomography (PET) and carbon-11 labeled N-methyl-4-piperidyl acetate. Kinetic analysis of the radioactivity in the brain and the plasma yielded a rate constant "k 3" as an index of AChE activity. The ratios for the k 3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/3/8/10, respectively, corresponding well with AChE activity ratios in the brain at necropsy (1/3/8/38), except for the striatum. In 23 healthy volunteers (age range: 24-89 years), there was no age-related decline of k 3 values in the cerebral cortex, suggesting AChE activity is preserved in aged cerebral cortex. In 11 patients with Alzheimer's disease, there was a significant reduction (-24%) of k 3 values in the cerebral cortex and hippocampus, suggesting a loss of ascending cholinergic system from the basal forebrain to the cerebral cortex and hippocampus. In 16 patients with Parkinson's disease, there was a significant reduction (-18%) of k 3 values in the cerebral cortex. In 10 patients with progressive supranuclear palsy, there was a significant reduction (-38%) of k 3 values in the thalamus. This technique is useful for investigating central cholinergic system in neurodegenerative disorders with dementia.     

Preparation for reaching: a PET study of the participating structures in the human brain.

The regional cerebral blood flow (rCBF) was measured as an indicator of regional metabolic activity with positron emission tomography (PET) in eight subjects who, after seeing a screen with seven targets prepared themselves with their eyes closed to reach these targets. The preparation phase was associated with increases of rCBF in the prefrontal cortex, several remote visual association areas in the parietal lobe, the supramarginal gyrus, the ventrolateral thalamus and the cerebellar vermis. During the course of learning the activations in the parietal visual areas, the supramarginal gyrus and the prefrontal cortex prevailed as a sign of the visual spatial information; its transformation being kept in working memory. The other activations vanished. No activations were seen in the motor cortices, indicating that reaching is a task which does not require substantial preparatory activity of motor cortices prior to the go signal.     

Metabolic impairment in human amnesia: a PET study of memory networks.

Human amnesia is a clinical syndrome exhibiting the failure to recall past events and to learn new information. Its "pure" form, characterized by a selective impairment of long-term memory without any disorder of general intelligence or other cognitive functions, has been associated with lesions localized within Papez's circuit and some connected areas. Thus, amnesia could be due to a functional disconnection between components of this or other neural structures involved in long-term learning and retention. To test this hypothesis, we measured regional cerebral metabolism with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in 11 patients with "pure" amnesia. A significant bilateral reduction in metabolism in a number of interconnected cerebral regions (hippocampal formation, thalamus, cingulate gyrus, and frontal basal cortex) was found in the amnesic patients in comparison with normal controls. The metabolic impairment did not correspond to alterations in structural anatomy as assessed by magnetic resonance imaging (MRI). These results are the first in vivo evidence for the role of a functional network as a basis of human memory.     

Apoptosis during development of the human retina: relationship to foveal development and retinal synaptogenesis.

Apoptosis in the ganglion cell (GCL) and inner nuclear (INL) layers of human fetal retinae aged 14-35 weeks of gestation (WG) was investigated in relation to synaptogenesis and foveal depression formation. Terminal transferase dUTP-biotin nick end labeling (TUNEL) was used to identify apoptosis, and synapse development was demonstrated by synaptophysin immunoreactivity (-IR). The distribution of apoptotic cells and synaptophysin-IR was studied as a function of eccentricity. Between 14 and 23-24 WG in the GCL, rates of apoptosis were relatively low in central retina. A shallow fovea was detected at 23-24 WG. In the central GCL, the rate of apoptosis was 0.21% of viable cells compared with a higher incidence of 0.79-1.64% peripherally. Apoptosis in the INL was 2-8 times greater than that in the GCL. At 14-15 WG, peak death occurred at the incipient fovea; however, by 20 WG the distribution was bimodal, with peaks at more eccentric locations on either side of the incipient fovea with increasing age. Approximately 90% of INL apoptotic cells were in the middle and outer regions, suggesting that bipolar cells formed the majority of dying neurons. Synaptophysin-IR was present in cones, bipolar cells, and processes in the inner and outer plexiform layers at the incipient fovea at 14 WG and spread peripherally with increasing age. The peripheral margin of synaptophysin-IR coincided with areas of peak INL apoptosis. This pattern suggests that bipolar cell elimination is associated with the onset of synaptogenesis. Apoptosis in the GCL and INL is not a significant factor in foveal depression morphogenesis.     

Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18F-dopa PET study.

We measured striatal 18F-dopa influx constants (Ki) for 20 patients with isolated, predominantly postural, tremor (eight familial, 12 sporadic) and 11 with predominantly rest tremor. Results were compared with 30 controls and 16 Parkinson's disease (PD) patients. The eight familial essential tremor (ET) patients had normal striatal 18F-dopa uptake. Two of the 12 sporadic postural tremor patients had subnormal putamen 18F-dopa Ki, one (who later became akinetic) falling in the PD range. The mean putamen 18F-dopa uptake of the 11 rest tremor patients was reduced to PD levels (51% of normal). Our findings argue against an association between ET and PD, but support the existence of a "benign" tremulous variant of PD. The presence of low-amplitude rest tremor, cogwheel rigidity, reduced arm swing, and short tremor duration was not a useful predictor of nigral dysfunction in patients with postural tremor. In contrast, patients with predominantly rest tremor, particularly with onset in the leg, consistently showed reduced putamen 18F-dopa uptake.     

Cortical areas mediating stereopsis in the human brain: a PET study

Using PET, we investigated the neural substrates of stereodepth perception in humans. The presentation of Julesz-type random-dot stereograms (RDS) produced significant rCBF elevations in Brodmann areas (BA) 18, 19 and 7, all in the right hemisphere. Activation foci were also found in both middle temporal areas (MT). These results demonstrate that, as in primates, cortical area MT and extrastriate areas are central to stereovision and that a network of predominant right hemispheric regions is recruited to meet visuo-spatial processing demands associated with horizontal binocular disparity inputs.     

Biomechanical study of the lumbar spine using a unilateral pedicle screw fixation system

Lumbar fusion combined with unilateral pedicle screw fixation has received favourable clinical reports. However, there are very few reports about the biomechanical properties of this system. The purpose of this study was to compare the biomechanics of a unilateral pedicle screw system with a bilateral system. Two fresh lumbar vertebral columns from human cadavers were used. Seven models were prepared by the sequential damage and spinal instrumentation of each specimen. Bending and rotation tests were performed to clarify the range of motion for each model using a 6-axis material tester that we have developed. We showed that the unilateral pedicle screw system offers only uneven fixation. This results in dispersion of rigidity depending on the direction of bending and rotation. The bilateral pedicle screw system, however, allows excellent fixation in all directions.     

Monoamine neuron innervation of the normal human brain: an 18F-DOPA PET study

18F-DOPA positron emission tomography (PET) has been used for two decades to study the organization and pathology of the striatal dopamine system in the human brain, particularly in Parkinson's disease. High resolution 3D PET allows a more detailed analysis than previously available and was employed in this study to determine the regional uptake of 18F-DOPA in control brain. Eleven healthy volunteers underwent 18F-DOPA PET with a region of interest (ROI) study performed using individual volumetric MRI's coregistered to the PET ADD image. A Patlak linear graphical analysis was undertaken to obtain influx constant (Ki) values. The highest Ki values were from neostriatal areas, with a rostrocaudal gradient of increasing Ki values from head of caudate nucleus to rostral putamen to caudal putamen. However, Ki values for transaxial slices from dorsal to ventral through the caudate and putamen were uniform. Ventral striatum Ki was 81% with red nucleus and globus pallidus Ki values of approximately 40% of neostriatum. In limbic areas, highest values were obtained from amygdala (35% neostriatal Ki). Neocortical Ki values varied from 22% in temporal pole to 6% in occipital cortex of neostriatal values. Hypothalamic Ki was high (45%) in comparison to thalamus (17%) and retina (17%). 18F-DOPA is taken up by serotonin (raphe, 51%), and noradrenaline (locus coeruleus, 37%) as well as dopamine neurons. These data indicate that 18F-DOPA PET can be used with detailed, anatomically based ROIs as a tool for in vivo analysis of regional changes in monoamine neuron systems throughout the brain in Parkinson's disease and other disorders.     

Spasm of fixation: a quantitative study.

Spasm of fixation, consisting of impaired initiation of saccades in the presence of fixation target, but normal initiation in the absence of a fixation target, was measured in a patient with cerebral hemispheric damage. When a central target was constantly present, the patient made horizontal saccades to the sudden appearance of a second target at very prolonged latencies (mean 369 ms). In the absence of a central fixation target, saccadic latency decreased to normal (197 ms). Extinction of a target for a gap interval elicited very short latency movements (122 ms), termed express saccades. The intervals between self-paced horizontal refixation saccades with the head immobile were prolonged, whereas voluntary refixation saccades with the head free to move occurred at shorter intervals. We postulate that cerebral hemispheric damage may cause spasm of visual fixation by disinhibiting the substantia nigra pars reticulata, thereby inhibiting the superior colliculus.     

Involvement of the human cerebellum in short-term and long-term habituation of the acoustic startle response: a serial PET study.

OBJECTIVE: Numerous studies have shown an involvement of the human cerebellum in motor learning, but little is known about the role of the cerebellum in learning of unspecific aversive reactions. The present study sought to distinguish which areas of the human cerebellum and brain-stem are involved in short-term habituation (STH) and long-term habituation (LTH) of the acoustic startle response. METHODS: On 5 consecutive days 42 acoustic startle stimuli were applied each day in 8 male healthy subjects. On the first and on the fifth day of the experiment [15O]H2O PET scans were performed. RESULTS: Electromyographic recordings revealed a significant decrease of the startle response within each day (STH) and across the 5 days of the experiment (LTH). On both days a decrease of regional cerebral blood flow (rCBF) across PET scans was found in the medial cerebellum most probably reflecting reduced sensory feedback during STH. Between days an increase of rCBF in the dorsomedial pons, in the mesencephalon and in an area of the medial cerebellum was observed. These activations may reflect increased inhibition of the startle response during LTH and correspond to previous animal lesion studies. Furthermore, during LTH an increase of rCBF within the lateral cerebellum in lobule HVI/Crus I was detected. CONCLUSIONS: These results suggest that distinct parts of the medial and lateral cerebellum are involved in habituation of the acoustic startle response. Lobule HVI/Crus I most likely plays a more general role in implicit learning processes considering its involvement in several conditioning paradigms. SIGNIFICANCE: The results of the present study contribute to the understanding of cerebellar involvement in learning of unspecific aversive reactions.     

Hemi-parkinsonism in multiple system atrophy: a PET and MRI study

We selected 6 patients presenting with hemi-parkinsonism from a total of 20 patients with probable multiple system atrophy (MSA) and studied their nigrostriatal lesions using magnetic resonance (MR) imaging and positron emission tomography (PET) with ¹⁸F-labeled 2-deoxy-2-fluoro- -glucose (FDG). T₂ weighted MR images demonstrated a decreased signal intensity in the putamen of all patients. This decreased signal was more intense in the nucleus contralateral to the affected body side in 5 patients. A decreased signal in the substantia nigra was found, expanding more on the contralateral side in 3 patients. T₁-weighted images showed that the contralateral putamen was smaller in size than the ipsilateral. These findings indicated that the iron deposit and the neuronal cell loss in the degenerative process were more remarkable in the contralateral nuclei. FDG uptake in 5 patients had likewise declined more in the contralateral than in the ipsilateral putamen. The study shows that these patients have the nigrostriatal lesions as described in previous reports on MSA and that an asymmetric lesion relating to clinical signs is present in the nigrostriatal system. When a patient presents with hemi-parkinsonism alone, MR imaging and PET/FDG are useful for the clinical diagnosis of MSA.     

Involvement of the human cerebellum during habituation of the acoustic startle response: A PET study

The present study investigated the involvement of the humancerebellum in the habituation of the acoustic startle response usingPET. The startle response was elicited in seven young, healthy subjectsby a tone presented via headphones. Startle responses were recordedfrom the right sternocleidomastoid muscle. Regional cerebral blood flow(rCBF) was assessed in nine scans and one startle stimulus was appliedduring each scan. The reduction of size of the sternocleidomastoidmuscle response was correlated with changes in rCBF during the ongoingprocess of startle response habituation. A significant decrease of rCBFwas found in the medial cerebellum. These data are consistent with aninvolvement of the medial parts of the human cerebellum innon-associative learning as proposed by previous animal studies.

     

PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette''s syndrome.

Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourette's syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourette's syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourette's syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourette's syndrome and that Tourette's syndrome does not arise from a primary dysfunction of dopaminergic terminals.     

Cerebral metabolic changes in early multiple system atrophy: a PET study

Previous positron emission tomography (PET) studies have shown widespread hypometabolism in the brain of advanced MSA but the time course of these metabolic abnormalities is largely unknown. In order to clarify the principal disease processes in multiple system atrophy (MSA) in the early stage, we investigated regional cerebral glucose metabolism (rCMGglc) and nigral dopaminergic function in nine patients with early stage of MSA using [(18)F]fluorodeoxyglucose (FDG) and 6-L-[(18)F]fluorodopa ((18)F-Dopa) positron emission tomography (PET) (two men and seven women; age, 59.3+/-5.4 years; disease duration, 29.7+/-14.6 months). The rCMRglc in the early MSA patients significantly decreased in the cerebellum, brainstem, and striatum compared with that in nine normal subjects. A significant correlation was found between the severity of autonomic dysfunction and rCMRglc within the brainstem. The severity of extrapyramidal signs also correlated with the decline of F-Dopa uptake but not that of rCMRglc within the striatum. The degree of atrophy on MRI has correlated with neither the clinical symptoms nor rCMRglc at the cerebellum and the brainstem. Our PET studies demonstrated widespread metabolic abnormalities except for the cerebral cortex in the brain of MSA even in the early stage. The hypometabolism in the brainstem was tightly linked to the autonomic dysfunction. Not the striatal dysfunction but the nigral damage may be responsible for the extrapyramidal symptoms in early MSA.     

Direction of cross-modal information transfer affects human brain activation: a PET study

The purpose of this study was to determine the functional organization of the human brain involved in cross-modal discrimination between tactile and visual information. Regional cerebral blood flow was measured by positron emission tomography in nine right-handed volunteers during four discrimination tasks; tactile-tactile (TT), tactile-visual (TV), visual-tactile (VT), and visual-visual (VV). The subjects were asked either to look at digital cylinders of different diameters or to grasp the digital cylinders with the thumb and index finger of the right hand using haptic interfaces. Compared with the motor control task in which the subjects looked at and grasped cylinders of the same diameter, the right lateral prefrontal cortex and the right inferior parietal lobule were activated in all the four discrimination tasks. In addition, the dorsal premotor cortex, the ventral premotor cortex, and the inferior temporal cortex of the right hemisphere were activated during VT but not during TV. Our results suggest that the human brain mechanisms underlying cross-modal discrimination have two different pathways depending on the temporal order in which stimuli are presented.     

Aging of the human neuromuscular system.

Loss of cells from the motor system occurs during the normal aging process, leading to reduction in the complement of motor neurons and muscle fibers. The latter age-related decrease in muscle mass has been termed "sarcopenia" and is often combined with the detrimental effects of a sedentary lifestyle in older adults, leading to a significant reduction in reserve capacity of the neuromuscular system, which is the primary subject of this review. Clear evidence of this aging effect is seen when voluntary or stimulated muscle strength is compared across the adult lifespan, with a steady decline of approximately 1-2% per year occurring after the sixth decade. Interestingly, when compared with isometric contractions, the effect of aging is more pronounced for concentric movements and less for eccentric movements (i.e., muscle shortening versus lengthening). This phenomenon appears to be linked to the stiffer muscle structures and prolonged myosin crossbridge cycles of aged muscles. It is encouraging that the capability of physiological adaptations in the motor pathways remains into very old age--when an appropriate exercise stimulus is given--and long-term prevention strategies are advocated to avoid excessive physical impairments and activity restrictions in this age group.     

Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study.

BACKGROUND: Preclinical studies demonstrate that 17beta-estradiol (E(2)) increases serotonin-2A receptor (5-HT(2A)R) density in rat frontal cortex. METHODS: We investigated the impact of hormone replacement therapy on 5-HT(2A)R binding potential (BP) using positron emission tomography and [(18)F]altanserin in five postmenopausal women. Subjects were imaged at baseline, following 8 to 14 weeks of transdermal E(2), 0.1 mg/d, and following 2 to 6 weeks of E(2) plus micronized progesterone (P) 100 mg per os twice daily. Regional BPs in the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex were calculated by Logan analysis. RESULTS: There was a main effect of time (p = .017) for 5-HT(2A)R BP, which increased 21.2%+/-2.6% following combined E(2) and P administration relative to baseline. This effect was evident in all cerebral cortex regions examined. CONCLUSIONS: 5-HT(2A)R BP increased in widespread areas of the cerebral cortex following combined E(2) + P administration.     

Involvement of the human cerebellum in fear-conditioned potentiation of the acoustic startle response: a PET study

Fear-conditioned potentiation of the startle response was used to study the role of the cerebellum in associative learning of non-specific aversive reactions in healthy human subjects using PET. Prior PET scanning initially neutral light stimuli were paired with painful electric shocks (fear-conditioning phase). Four PET-scans each were performed with presentation of acoustic startle stimuli (T), fear-conditioned light stimuli (L) or acoustic stimuli paired with light (LT, potentation phase). As a measure of fear-conditioning subtraction of condition T from LT revealed an increase of regional cerebellar blood flow (rCBF) in the left cerebellar hemisphere. Subtraction of condition L from LT, as a measure of fear-conditioned potentiation, revealed an increase of rCBF in the medial cerebellum. Different parts of the cerebellum appear to be involved in this form of motor associative learning.     

Studies to improve fixation of human nerves. 1. Effect of duration of glutaraldehyde fixation on peripheral nerve morphometry

No change in the transverse fascicular area of rat peroneal nerve occurred when the duration of fixation in 2% glutaraldehyde was increased from 1 to 12 hr. Shrinkage in endoneurial area was inferred from the development of clefts. The number of myelin lamellae remained constant when the nerve was fixed in glutaraldehyde for 1 or for 12 hr. Unequivocal shrinkage of axis cylinders occurred with prolongation of glutaraldehyde fixation beyond 1 hr. In nerves fixed for 12 hr, this shrinkage was approximately 20%, compared to the area at 1 hr.