Selective decrease of large neurons in the neostriatum in progressive supranuclear palsy

In order to evaluate the quantitative changes in the neostriatum in progressive supranuclear palsy (PSP), sections of the caudate head (CN) and putamen (PT) from 4 PSP patients were stained with Klüver-Barrera, and the cell body and nuclear area of the neurons were measured by a digitizer. Obtained results were compared to those of 6 age-matched control and 4 Alzheimer's disease and senile dementia of Alzheimer type (AD/SDAT) subjects which were previously reported. The number of large neurons (nuclear area greater than 101 microns 2) in PSP was about 40% (P less than 0.01) and 30% (P less than 0.01) of that of the controls in CN and PT, respectively. In contrast, the number of small neurons in PSP (nuclear area less than 100 microns 2) was well preserved. The values were quite similar to those in AD/SDAT. The implications and possible significance are discussed.     

An autopsy case of neuronal intermediate filament inclusion disease with regard to immunophenotypic and topographical analysis of the neuronal inclusions

We report an autopsy case of neuronal intermediate filament inclusion disease (NIFID), in which pyramidal motor dysfunction preceded cognitive disturbance for 3 years from the onset. A 41‐year‐old Japanese man presented progressive spastic tetraparesis followed by cognitive impairment. His neurological symptoms gradually deteriorated and he died of pneumonia 16 years from the onset. His brain showed severe generalized atrophy with enlargement of ventricles. The microscopic examination revealed severe neuronal loss with gliosis and sponginess predominantly in the fronto‐temporal cortices, caudate and putamen. Many hyaline conglomerate inclusions (HC) without immunoreactivity for ‘fused in sarcoma’ protein (FUS) and some granular and small round FUS‐immunoreactive (FUS‐ir) neuronal cytoplasmic inclusions (NCI) were observed in the remaining neurons. Some neurons with HC had small basophilic inclusions which showed positive FUS‐ir, attached to HC in the cytoplasm. Otherwise, FUS‐ir large compact inclusions (so‐called Pick‐like) were also observed but were scarce. In the cerebral cortex and the neostriatum, frequency of the inclusions was well correlated with neuronal loss. In the brainstem, neuronal loss was mild and FUS‐ir inclusions dominated. In the subthalamic nucleus and red nucleus, there was no HC but there were many FUS‐ir inclusions without neuronal loss. The above findings suggest that cytoplasmic mislocalization and aggregation of FUS appear at the early stage of the disease, and the FUS aggregate process may not be a direct precedent structure of HC.     

The occurrence of large acetylcholinesterase-containing neurons in human neostriatum as disclosed in normal and Alzheimer-diseased brains

The human neostriatum was found to contain large neurons (maximum diameter: 30–40 μm) that stain intensely for acetylcholinesterase (AChE). These neurons are few in number, representing less than 5% of the total striatal neuronal population, and appear uniformly scattered throughout the caudate nucleus and putamen. They are morphologically similar to the AChE-containing neurons disclosed in the striatum of rat, cat and monkey after AChE inhibitor (DFP) pretreatment. In Alzheimer-diseased brains the number, morphological characteristics, and staining intensity of the striatal AChE neurons were found to be unaltered despite a marked loss of AChE cells in the adjoining nucleus basalis. These findings suggest that large intrinsic cholinergic neurons exist in human neostriatum and that these elements, in contrast to those of nucleus basalis, are not affected in Alzheimer's disease.     

An autopsy case of chorea-acanthocytosis. Special reference to the histopathological and biochemical findings of basal ganglia

Chorea-acanthocytosis has been separated as a clinical entity different from Huntington's chorea, mainly based on the clinical findings, but the histopathological and biochemical features of chorea-acanthocytosis, especially of basal ganglia, have not been well established, because only two such autopsy cases have been reported. The case presented here was a 39-year-old man at autopsy, with 10 years duration of typical symptoms and signs of chorea-acanthocytosis. At autopsy, the abnormal histopathological findings in the central nervous system were mainly confined to the striatum, where the caudate nucleus and putamen showed severe and moderate atrophy, respectively. Morphometric evaluation of the numbers of small and large neurons in the striatum with the adjustment for the shrinkage produced in the disease processes was performed. The numbers of small neurons in the caudate nucleus and putamen were 1% and 20% of each control, respectively. On the other hand, the large neurons in the caudate nucleus showed a reduction of diameters without a decrease in number and those in the putamen showed a mild decrease in number. In the biochemical studies, marked decrease of substance P (SP) level without definite decrease of choline acetyltransferase and glutamic acid decarboxylase (GAD) activities in both caudate nucleus and putamen was found. Substantia nigra, where no evident histopathological abnormalities were found, showed definite decrease of GAD activity and SP level. In the peripheral nervous system, the lateral branch of deep peroneal nerve showed mild degree of axonal degeneration. Neurogenic muscular atrophy with severe and mild degrees was found in extensor digitorum brevis and quadriceps femoris muscles, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Loss of neurons from the intracerebellar nuclei of the ageing mouse

The intracerebellar nuclei of the ASH/TO mouse brain were examined at 6, 22, 25, 28 and 31 months of age using quantitative histological techniques. Neuron number remained constant between 6 and 22 months of age but there was a statistically significant (P less than 0.01) decrease in neuronal number between 22 and 31 months of age with neuron number declining from 6970 +/- 690 at 22 months to 4140 +/- 246 at 31 months of age. Neuronal nuclear diameter remained constant between 6 and 25 months of age but increased from 10.6 +/- 0.6 microns at 25 months to 12.2 +/- 0.3 microns at 31 months of age. Whether this was due to an actual increase in nuclear diameter or to a proportionately greater loss of small neurons is not known.     

The frequency and distribution of medium-sized neurons with indented nuclei in the primate and rodent neostriatum

Nuclear morphology is known to distinguish two classes of medium-sized neurons in the neostriatum, spiny projection neurons which have an unindented nucleus and aspiny interneurons which exhibit enfoldings of their nuclear envelope. The frequency and distribution of medium-sized neostriatal neurons with indented nuclei were examined in the light microscope in semi-thick sections. Results showed that the proportion of neostriatal neurons with nuclear indentations was greater in the monkey (23%) than in the mouse and rat (4-5%). Also, nuclear enfoldings were found in more neurons of the monkey caudate than putamen, whereas in the rodent regional differences were not observed. Findings suggest that aspiny interneurons play a greater role in the integrative and functional organization of the neostriatum in the primate than in the rodent brain.     

Monkey globus pallidus external segment neurons projecting to the neostriatum.

Experiments were performed to assess the number and parvalbumin (PV) immunoreactivity of neurons participating in the pallidostriatal projection in macaque monkeys. Injection of WGA-HRP into the right caudate nucleus and the left putamen of a Macaca mulatta and a M. fuscata labeled a large number of the globus pallidus external segment (GPe) neurons. Counting neurons labeled with WGA-HRP and those stained with neuronal markers indicated that approximately 30% of GPe neurons project to neostriatum. Approximately 2/3 of the pallidostriatal neurons are PV-immunoreactive. This study revealed that a significant number of primate GPe PV immunoreactive neurons project to the neostriatum, and suggest that the pallidostriatal projection should be taken into account in the analysis of functional roles of the basal ganglia circuitry.     

Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements

We studied changes in basal ganglia neuronal activity associated with reaching movements of the arm in two monkeys. Data were obtained from 427 single neuronal units in putamen, 199 in caudate nucleus, and 216 in globus pallidus with multiwire electrodes allowing simultaneous recordings from multiple neurons. In all structures, changes in activity related to movement occurred most often after the onset of EMG: 43% of tested neurons in the putamen, 32% in the caudate nucleus, and 38% in the globus pallidus. Less frequently, changes began before EMG activation: 20% of neurons in the putamen, 19% in caudate nucleus, and 17% in globus pallidus. In general, these changes in neuronal activity lasted longer than EMG activity associated with reaching. The proportions of neurons activated were significantly larger in the putamen than the caudate nucleus. In the pallidum, the proportions were not statistically different from either the putamen or caudate nucleus, and no significant difference was found between the internal and external pallidal segments. Significant selectivity for movements to different targets was observed in 36% of neurons in the putamen, 28% in the caudate nucleus and 9% in the globus pallidus. The lower proportion in the globus pallidus compared to the striatum was significant (P < 0.002). Clusters of activated neurons were found in the striatum, however, the timing of changes was often different for individual neurons in these clusters. A cross-correlation analysis of the activity of neurons in the clusters revealed no evidence of common inputs, suggesting that striatal neurons in close proximity with neurons showing similar changes in activity are driven by different populations of neurons. In the putamen, the anatomical locations of neurons with changes in activity related to movement execution were on average significantly more posterior and lateral than neurons with changes related to the preparation of movement described earlier [31]. These findings support the view that the putamen and the caudate nucleus contain distinct functional areas. The present studies show that most anatomical regions in both the striatum and palladum participate in the control of executing reaching movements.     

Large neurons in the neostriatum in Alzheimer's disease and progressive supranuclear palsy: a topographic, histologic and ultrastructural investigation

Large neurons in the neostriatum of patients with Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) were investigated topographically, histologically and ultrastructurally. The number of large neurons whose nuclear area is greater than 101 microns2 was uniformly decreased in the neostriatum in PSP, but the decrease of these neurons in AD appeared to be more marked in the nucleus accumbens. Most of the remaining large neurons in both diseases contained neurofibrillary tangles (NFTs). In addition, some of the small neurons in PSP were positive for tau-immunostaining. Curly fibers were frequently observed in AD, but were absent in PSP. Ultrastructurally, NFTs in AD were composed mainly of paired helical filaments, whereas those in PSP contained straight tubules.     

Patterns of tachykinin expression and localization in developing feline neostriatum

The development of tachykinins in the neostriatum was determined qualitatively in order to characterize the ontogeny of an early-forming neostriatal peptidergic system. Tachykinins were detected by immunohistochemistry in fetal, postnatal, and adult cats. Neostriatal cells and neurites expressed tachykinins as early as fetal age 30 and increased in frequency progressively with age. Initial tachykinin expression occurred in neostriatal neurons during their postmitotic migration. In the head of the caudate nucleus, clusters of tachykinin-containing cells and fibers formed between fetal days 35 and 45, when the distribution of labeled neurons changed from a dispersed to an aggregated pattern. Between fetal days 45 and 50, tachykinin-rich neuronal clusters increased in frequency and were distributed throughout the rostral caudate nucleus. In contrast to neurons in clusters, neurons in the complementary neuropil expressed tachykinins largely postnatally. Postnatal morphological maturation of tachykinin-containing neurons paralleled the morphogenesis of medium spiny neostriatal cells. In addition, the caudate nucleus and putamen followed different spatiotemporal gradients of tachykinin expression. These results indicate that tachykinins are expressed in neostriatal neurons during the early ontogeny of the neostriatum and may function as trophic factors before synaptogenesis.     

An immunohistochemical investigation of the human neostriatum in huntington's disease

The neostriatum of 7 autopsied patients with Huntington's disease (HD) was examined immunohistochemically using purified antibody against calcineurin, which may be present only in the medium-size spinous neurons of the mammalian striatum. This study revealed a marked loss of calcineurin-positive cells in the caudate nucleus and the putamen in all HD patients, compared with control subjects, and there was some variation among the HD patients. Four HD patients showed significantly lower density of calcineurin-positive cells in the caudate nucleus than in the putamen. The remaining calcineurin-positive cells in the caudate nucleus and the putamen had a mosaic-like pattern, demonstrating a subregional difference in distribution. This finding suggests that there are subregional as well as compartmental differences in the vulnerability of the calcineurin-positive cells in the striatum of patients with HD.     

The neostriatum and nucleus accumbens in parkinsonism-dementia complex of Guam: a pathological comparison with Alzheimer's disease and progressive supranuclear palsy

The neostriatum, nucleus accumbens and basal nucleus of Meynert (bnM) in the parkinsonismdementia complex of Guam (Guam PDC) were examined immunohistologically, ultrastructurally, quantitatively and topographically, and the results were compared with those in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Compared to neurologically normal controls, the number of large neurons in Guam PDC was reduced by approximately 70% in the caudate nucleus and putamen and by more than 90% in the nucleus accumbens. The decreased number of large neurons in the neostriatum was significantly correlated to that in the bnM. The remaining large neurons and many of the medium-sized neurons in the neostriatum and nucleus accumbens were immunopositive for tau protein and contained varying amounts of 21- to 25-nm-wide paired helical filaments (PHFs) admixed with straight tubules. Curly fibers and circularly arranged reactive astrocytes were seen in the nucleus accumbens of many PDC patients. Collectively, these findings, which are similar in part to those of AD and differ from those of PSP, suggest that the large neurons in the neostriatum and nucleus accumbens in Guam PDC degenerate through PHF formation, and that extremely severe loss of large neurons in the nucleus accumbens may be linked to marked degeneration of the limbic and ventral tegmental areas and nucleus dorsal raphe.Supported in part by the Grant-in-Aid for Scientific Research on Priority Areas No. 02240104 from the Ministry of Education, Science and Culture, Japan     

Loss of DARPP-32 and calbindin in multiple system atrophy

We evaluated the immunohistochemical intensities of α-synuclein, phosphorylated α-synuclein (p-syn), dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), calbindin-D 28k, calpain-cleaved carboxy-terminal 150-kDa spectrin fragment, and tyrosine hydroxylase in multiple system atrophy (MSA). The caudate head, anterior putamen, posterior putamen, substantia nigra, pontine nucleus, and cerebellar cortex from six MSA brains, six age-matched disease control brains (amyotrophic lateral sclerosis), and five control brains were processed for immunostaining by standard methods. Immunostaining for α-synuclein, p-syn, or both was increased in all areas examined in oligodendrocytes in MSA. Immunostaining for DARPP-32 and calbindin-D 28k was most prominently decreased in the posterior putamen, where neuronal loss was most prominent. Immunostaining for DARPP-32 and calbindin-D 28k was also diminished in the anterior putamen and caudate head, where neuronal loss was less prominent or absent. Calbindin immunostaining was also decreased in the dorsal tier of the substantia nigra and cerebellar cortex. Loss of immunostaining for DARPP-32 and calbindin-D 28k compared with that of neurons indicates calcium toxicity and disturbance of the phosphorylated state of proteins as relatively early events in the pathogenesis of MSA.     

Damage to dopamine systems differs between parkinson's disease and alzheimer's disease with parkinsonism

Parkinsonism occurs in approximately 35 to 40% of patients with Alzheimer's disease (AD) even with little or no neuronal degeneration in the substantia nigra, which in idiopathic Parkinson's disease (PD) results in the severe loss of striatal dopamine transporter sites. It is not known if there is a loss of striatal dopamine transporter sites in AD with coexistent parkinsonism (AD/parkinsonism). We quantified the pattern of these sites in the striatum and midbrain of patients with the clinical diagnosis of PD, AD, and AD/parkinsonism in comparison with a group of age-matched control subjects. We also quantified the number of D2 receptors and the levels of tyrosine hydroxylase in the substantia nigra and ventral tegmental area of same groups. The results showed that in AD the loss of dopamine transporter sites was restricted to the nucleus accumbens. The loss of these sites in the AD/parkinsonism group was more extensive than in the AD group, with the most severe losses in the rostral caudate and putamen and least in the caudal caudate and putamen. While the PD group showed an equally severe reduction in numbers of sites, the caudal to rostral gradient of loss differed from that in the AD/parkinsonism group. The PD group also showed a marked loss of dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors (located on dopamine neurons) in the substantia nigra and ventral tegmental area. In contrast, no reductions in dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors were observed in the substantia nigra and ventral tegmental area of the AD or AD/parkinsonism groups. Thus, the loss of striatal dopamine transporter sites in AD/parkinsonism may be related to the clinical parkinsonian symptoms. However, the loss is not simply the result of neuronal degeneration in the substantia nigra, but must derive from other processes.     

Distribution of GABA-immunoreactive neurons in the basal ganglia of the squirrel monkey (Saimiri sciureus)

The distribution of GABA-immunoreactive neurons was visualized in the basal ganglia of the squirrel monkey (Saimiri sciureus), by using a highly specific antiserum raised against GABA-glutaraldehyde-lysyl-protein conjugate and revealed by the indirect peroxidase-antiperoxidase immunohistochemical method. In the dorsal striatum, GABA-immunoreactive nerve cell bodies were small to medium in size (sectional area ranging from 90 to 125 microns2), but some larger ones (500-600 microns2) were also found. These cells displayed no obvious clustering but were significantly more numerous in the caudate nucleus than in the putamen; their number was also markedly greater at caudal than at rostral striatal levels. A moderate number of evenly distributed positive axon terminals were visible in both the caudate nucleus and the putamen. In the ventral striatum, GABA-immunoreactive nerve cell bodies and axon terminals were seen in fair number within the nucleus accumbens and in the deep layers of the olfactory tubercle. Many positive terminals but no somata were found in the islands of Calleja. In the globus pallidus, virtually all nerve cell bodies were GABA-immunoreactive and the neuropil exhibited a multitude of positive terminals. In the substantia innominata, clusters of small, globular GABA-immunoreactive somata were scattered among aggregates of larger, nonimmunoreactive neurons belonging to the nucleus basalis, and the whole region showed a low to moderate number of evenly spread GABA-positive terminals. In the subthalamic nucleus, nerve cell bodies were generally surrounded by several GABA-positive terminals but were not themselves immunoreactive. The substantia nigra showed many GABA-immunoreactive somata, which predominated in the pars lateralis and diminished progressively in number along the lateromedial axis of the pars reticulata. These cells formed a rather pleomorphic group comprising round, fusiform, or polygonal elements of relatively large size (sectional area ranging from 200 to 800 microns2). In the pars compacta and ventral tegmental area, a few GABA-immunoreactive neurons of small size were dispersed among larger, unreactive neurons. In both pars lateralis and pars reticulata of the substantia nigra, the number of GABA-positive terminals was high and their distribution was rather uniform; a smaller number were visible in the pars compacta of the substantia nigra and in the ventral tegmental area. The present results demonstrate that GABA-containing neurons are widely and heterogeneously distributed in the various components of the squirrel monkey's basal ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Short- and long-term survival of large neurons in the excitotoxic lesioned rat caudate nucleus: a light and electron microscopic study

Large striatal neurons are spared in caudate tissue from postmortem brain of patients with Huntington's disease (HD) and in the rat caudate lesioned with excitotoxins at short postlesion intervals. In order to determine the survival of large neurons and other effects of excitotoxicity at longer postlesion intervals the rat caudate nucleus was examined 2, 7, and 30 weeks after intrastriatal injections of the excitotoxin, quinolinic acid. The caudate nucleus diminished in size progressively up to 30 weeks postlesion due to 1) shrinkage and compacting of the lesion zone and 2) reduction in area of intact caudate, apparently due to gradual loss of the remaining caudate neurons. In Nissl-stained sections of the lesion zone where total neuronal density was less than 5% of contralateral control, large neurons were present at all postlesion intervals, forming 38-58% of the remaining neurons. Unexpectedly, a fivefold reduction in the number of large neurons was observed between 2 and 30 weeks postlesion. Also, at 7 and 30 weeks postlesion most of the large neurons were confined to the peripheral region of the lesion. At all postlesion intervals, large neurons retained ultrastructural integrity and some synaptic inputs despite the severe disruption of the surrounding neuropil. Surrounding the lesion zone was a transition zone which exhibited a decrease in total neuronal density to 53-74% of control. In this region the density of large neurons was not diminished, and the proportion of large neurons was elevated in comparison to that of controls at all postlesion intervals. Findings suggest that following excitotoxic lesion of the caudate nucleus there are marked differences between short- and long-term postlesion intervals in the survival and distribution of large neurons. We speculate that an imbalance in the synaptic connections with other caudate neurons leads to the persistent loss of large neurons in the lesion zone at long postlesion intervals. A transition zone surrounding the lesion, where cell loss is less severe than in the lesion zone, exhibits features more characteristic of the neuropathology of HD.     

The nigrostriatal projection in the cat: Part 1. Silver impregnation study

The course and destination of the degenerating nigrostriatal fibers were studied by selective silver impregnation methods in 37 cats with unilateral lesions in the substantia nigra.The nigrostriatal fibers ascend along the dorsomedial border of the substantia nigra to the prerubral area; they proceed for a short distance through the lateral hypothalamus, enter the medial part of the internal capsule and run in a dorsorostral direction to reach the head of the caudate nucleus and the rostral portion of the putamen. A smaller number of degenerating fibers obliquely cross the peduncular part of the internal capsule and traverse the entopeduncular nucleus and the pallidum to terminate in the central and caudal portions of the putamen.Some features of the topical distribution of the nigrostriatal tract are described. Apparently, the more anterior part of the pars compacta sends axons primarily to the head of the caudate nucleus and to the most rostral putamen. The most medially situated nigral neurons project to the fundus striati. The posteromedial cell groups of the pars compacta innervate primarily the central putamen and the caudal part of the caudate nucleus. The projection of the lateral cell group of the posterior zona compacta to the caudal putamen is sparser than from the other nigral groups, suggesting that a part of them has another destination, possibly lower in the neuraxis. The contribution of the pars reticulata to the nigrostriatal connections seems to be modest, according to the small number of neurons; they project to the lateral caudate and putamen. Thus, the ascending nigrostriatal fibers mirror the distribution of the descending striatonigral fibers.No convincing evidence for the existence of a nigroentopeduncular and nigropallidal projection was found.     

Topographic intermingling of striatonigral and striatopallidal neurons in the rhesus monkey.

The topography and interrelationship of striatofugal neurons have been examined using a double retrograde tracing paradigm to label striatopallidal and striatonigral neurons in the same neostriatum. The rostral globus pallidus and the rostral substantia nigra in the same hemisphere were injected simultaneously with fluorescent tracers in three monkeys. In addition, the caudal globus pallidus and the caudal substantia nigra were injected separately in a fourth and fifth monkey with a fluorescent dye and wheat germ agglutinin-horseradish peroxidase (WGA-HRP), respectively. Digitized plots of fluorescent dye-labeled neurons revealed that large numbers of striatonigral projection neurons lie within both neostriatal nuclei, i.e., the caudate and putamen. Similarly, neurons innervating the globus pallidus were found in both caudate and putamen. The distribution of retrogradely labeled neurons observed was consistent with the topography of striatofugal projections that has been described previously, i.e., the rostrocaudal and mediolateral axes of the neostriatum are preserved in the striatopallidal and striatonigral projections (e.g., Szabo, '62, '67, '70, '72) and the dorsoventral axis is inverted in the projection of the neostriatum onto the nigra but not in the striatopallidal projection (Nauta and Domesick, '79; Gerfen, '85). Analysis of cases in which striatonigral and striatopallidal neurons were present in large numbers within the same region of the neostriatum disclosed that the two populations are intermingled such that small clusters of striatopallidal neurons are surrounded by striatonigral neurons and vice versa. The clustered arrangement of striatofugal neurons observed in the fluorescent cases was unambiguous in a case in which HRP was injected into the caudal substantia nigra. In this case, both anterogradely labeled terminals and retrogradely labeled neurons exhibited a striking, compartmental-like distribution in the posterior putamen. Our observations indicate that the matrix compartment of the neostriatum is comprised of a patchwork of interposed clusters of nigral and pallidal efferent neurons. We hypothesize that these clusters of efferent neurons may direct interdigitated cortical inputs into distinct nigro- and pallido-thalamic pathways. In view of the parallel nature of processing throughout the basal ganglia, it appears that convergence of these segregated nigral and pallidal loops must occur at the cortical level where prefrontal and premotor targets of the basal ganglia are interconnected via corticocortical projections (Selemon and Goldman-Rakic, '88).     

Neuroradiological studies of Wilson's disease by computed tomography and magnetic resonance imaging

Three cases of Wilson's disease were imaged by computed tomography and magnetic resonance. They were characterized by common findings. CT scan showed atrophy of cerebral cortex, caudate head, midbrain and cerebellum, and areas of low absorption in the caudate head, putamen, globus pallidus, posterior limb of internal capsule, thalamus and midbrain. The T2-weighted MRI imaging demonstrated marked hyperintensity in the putamen, retrolenticular part of internal capsule, thalamus and midbrain. In 2 patients, these high intensity areas were decreased by chelating therapy. Improvement of the increased intensity on T2-weighted images led to the suggestion that the area of marked hyperintensity area might be edema or demyelination rather than neuronal loss or cavitation.