Brain, Vol. 125, No. 11, 2558-2566,
November 2002
© 2002 Oxford University Press
Clinical findings in sporadic Creutzfeldt–Jakob disease correlate with thalamic pathology
1 Departments of Neuropathology and 2 Neurology, Georg-August University, Goettingen, 3 Department of Neuropathology, Ludwig-Maximilians Universität, München and 4 Epilepsy Centre Kork, Kehl-Kork, Germany
Correspondence to: Prof. Dr Hans A. Kretzschmar, Institut für Neuropathologie, Ludwig-Maximilians Universität, Marchioninistrasse 17, D-81377 München, Germany E-mail: hans.kretzschmar{at}inp.med.uni-muenchen.de
Received December 28, 2001. Revised June 6, 2002. Accepted June 10, 2002.
 |
Summary |
|---|
 Top Summary IntroductionMaterial and methodsResultsDiscussionReferences |
|---|
The pathogenesis underlying the typical findings in Creutzfeldt–Jakob disease (CJD) such as periodic EEG changes or myoclonus is not fully understood. The thalamus possesses a high density of inhibitory neurones and serves as a crucial pacemaker of rhythmic EEG activity. As inhibitory neurones expressing parvalbumin (PV) are reduced in the cerebral cortex and hippocampus in sporadic CJD (sCJD), we studied the distribution and number of PV-immunoreactive neurones in sCJD thalami in order to determine whether damage to them could account for certain clinical findings. Immuno histochemical analysis was performed on the thalami from 21 sCJD patients and five controls. The number of PV+ neurones was counted in the thalamic nuclei and compared with clinical and molecular findings. In sCJD patients, PV+ neurones were significantly reduced in the ventrolateral posterior (VLp), ventrolateral anterior (VLa), anteroventral (AV), lateral dorsal (LD), mediodorsal (MD) and reticular (Re) thalamic nuclei (P < 0.05). The VLp was especially damaged in sCJD patients with homozygosity for methionine at codon 129 and scrapie prion protein (PrPSc) type 1. Patients with typical EEG changes [periodic sharp wave complexes (PSWCs)] and myoclonus had a predominant loss of PV+ cells in the reticular thalamic nucleus. In conclusion, our data support the hypothesis that the damage to PV-immunoreactive neurones determines the generation of certain typical clinical features of CJD, i.e. PSWCs associated with myoclonus.
Keywords: Creutzfeldt–Jakob disease; parvalbumin; periodic sharp wave complexes; thalamus
Abbreviations: AV = anteroventral thalamic nucleus; CM = centre médian (centromedian) thalamic nucleus; EEG = electroencephalogram; LD = lateral dorsal thalamic nucleus; MD = mediodorsal thalamic nucleus; PRNP = human prion protein gene; PrPSc = scrapie prion protein; PSWCs = periodic sharp wave complexes; PV = parvalbumin; Re = reticular thalamic nucleus; sCJD = sporadic Creutzfeldt–Jakob disease; VA = ventral anterior thalamic nucleus; VLa = ventral lateral anterior thalamic nucleus; VLp = ventral lateral posterior thalamic nucleus; VPL= ventral posterior lateral thalamic nucleus
|
Introduction |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
It has recently become apparent that clinical and neuropathological characteristics of sporadic Creutzfeldt–Jakob disease (sCJD) correlate with genetic and molecular determinants (Parchi et al., 1999
). These molecular determinants are a polymorphism for methionine/valine at codon 129 of the human prion protein gene (PRNP), and two isoforms of PrPSc that can be distinguished by their different glycosylation and proteinase K digestion patterns. The subtypes are characterized clinically by a combination of features such as duration of disease, EEG changes, age at onset and predominant neurological signs, especially myoclonus. Neuropatho logically they are defined by associations of certain morphological changes such as small or confluent vacuoles, and synaptic, pericellular, perivacuolar, plaque-like scrapie prion protein (PrPSc) deposition or kuru plaques in anatomically defined areas of the CNS. The pathogenesis underlying typical clinical findings such as myoclonus or periodic sharp wave complexes (PSWCs) in the EEG is still largely unknown.
A disturbance of inhibitory GABAergic mechanisms in prion diseases has been postulated by various authors (Ferrer et al., 1993; Guentchev et al., 1997, 1998, 1999; Macchi et al., 1997; Belichenko et al., 1999). Parvalbumin (PV) is a cytosolic calcium (Ca2+)-binding protein (Berchtold et al., 1985; Baimbridge et al., 1992), which is implicated in the buffering and transport of Ca2+ as well as in the regulation of various enzyme systems. In the cerebral cortex and hippocampus it is predominantly expressed in a subset of fast-spiking, inhibitory GABAergic interneurones (Celio, 1986). Because of its capacity to regulate Ca2+ homeostasis by reducing the Ca2+-dependent K+ outward current (Celio, 1986), PV is thought to have a neuroprotective function against neurotoxic insults (Sloviter, 1989).
In sCJD, a marked reduction of PV+ cells and morphological changes of the remaining PV+ neurones in the cerebral cortex (Ferrer et al., 1993) and the hippocampus (Guentchev et al., 1997) have been reported. A test of correlation with clinical or molecular data has not yet been undertaken.
According to Jones (Jones, 1985, 1998; Hirai and Jones, 1989), the thalamus serves as a relay site for incoming and outgoing information. There is a complex network of synaptic interactions between the thalamic nuclei and, additionally, the thalamus is connected to the cerebral cortex in almost every brain area. There is electrophysiological evidence that the thalamus, especially the reticular thalamic nucleus, serves as a pacemaker, generating highly synchronous electric activity (Steriade et al., 1987; Avanzini et al., 1993; Contreras and Steriade, 1995; Huguenard, 1998; Jones, 1998; Mihaly et al., 1998; Seidenbecher et al., 1998; Steriade and Contreras, 1998). The thalamus always shows pathological changes in patients with CJD (Parchi et al., 1999), and the appearance of periodic sharp and slow waves in the EEG is one of the key features of clinical presentation (Steinhoff et al., 1996). For a better understanding of a possible relationship, we studied the thalamus of sCJD patients and correlated our results with molecular and clinical data.
|
Material and methods |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Study population
We studied 21 confirmed sCJD patients whose brains had been sent to the German Reference Center for Spongiform Encephalopathies, which is now located at the University of München. Formalin-fixed material from the entire thalamus was available for all patients. All of the study patients had been examined as suspected CJD cases during their lifetimes by a neurologist of the German CJD Surveillance Unit, and EEG tracings close to the patients’ deaths were available. The age at death of the study patients (six females, 15 males) ranged from 25 to 77 years (mean 62.7 years, SD 11.3 years).
Five brains of two women and three men (age range 48–77 years; mean age 58.6 years; SD 11.5 years) from patients without any evidence of neurological disorders and with normal neuropathological findings at autopsy served as a control group. Causes of death in the control patients were left ventricular failure from pre-existing cardiovascular disease (four cases) or pulmonary embolism (one case) (see Table 1 for details).
|
Determination of molecular and genetic subtype
Western blot analysis was carried out in all cases in which unfixed brain tissue was available (n = 17), as described previously (Parchi et al., 1996
, 1999; Zerr et al., 2000). For the determination of PrPSc type, we used cerebellum (17 out of 17 cases) and frontal cortex (16 out of 17 cases, not available in case No. 18), and in eight out of 17 cases we also used the occipital cortex. The thalamus was available in one of the valine homozygote (V/V) cases with PrPSc type 1 (patient 16). In none of the cases did we find diverging results if two or more areas were studied.
PrPSc was classified as type 1 (unglycosylated PrPSc of 20–21 kDa) or type 2 (unglycosylated PrPSc of 18–19 kDa), according to the electrophoretic mobility in the immunoblot after proteinase K digestion (Parchi et al., 1996). Analysis of the prion protein gene (PRNP) was performed using single-strand conformation polymorphism (SSCP) analysis or direct DNA sequence analysis (Windl et al., 1999). Patients with PRNP mutations were excluded from further analysis (see Table 1 for results).
Neuropathological evaluation
Brains from patients and controls were fixed in formalin for at least 14 days. Representative blocks were cut from standardized brain regions for the histopathological diagnosis. Additionally, two to four serial sections were cut through the thalamus in the coronal plane. The anterior sections showed the subthalamic nucleus (STN; Fig. 1A), and more posterior sections showed the lateral geniculate body (LGB; Fig. 1B). The thalamus of one hemisphere was examined in all cases (10 out of 21 right thalamus, 11 out of 21 left thalamus), depending on the material provided to the Reference Center for Spongiform Encephalopathies. The blocks, including the control cases, were decontaminated for 1 h in formic acid (Brown et al., 1990) and embedded in paraffin. The diagnosis of prion disease was made as described previously (Kretzschmar et al., 1996). Microtome sections were cut serially at 2 µm (2 x 10–6m) from the thalamus blocks and mounted on silanized slides. The sections were deparaffinized and boiled in citric buffer (pH 6.0) for 5x 3 min. After blocking with 3% H2O2 at 4°C, and pre-treatment with foetal calf serum (FCS), adjacent sections were incubated for 4 h at room temperature with a monoclonal antibody against PV (PA-235, 1 : 1000; Sigma, Saint Louis, MO, USA). For visualization, the avidin–biotin–peroxidase complex (ABC; Vectastatin Peroxidase PK-400 Vector) was used. Slides were then developed in AEC (3-amino-9-ethylcarbazole; Sigma A575; in dimethylformamide and acetate buffer) and counterstained with haematoxylin.
|
Quantification of neurones
According to Aherne, a random distribution of cells can be assumed in the thalamus (Aherne, 1975
). We therefore used the classical method of counting the number of cells per area. Neurones were included in the evaluation if the cell nucleus was in the plane of the section. Immunohistochemistry with PV yielded reliable staining results with little background. Only those sections were included in the study in which the neurones were unequivocally identifiable. Quantification of neurones was performed by two blinded investigators (H.J.T. and J.W.H.), whose results were very similar [intraclass correlation coefficient 0.81, according to Bartko (1994)].
The classification of Hirai and Jones was used for identification of thalamic nuclei (Hirai and Jones, 1989). Immunoreactive neurones were counted in the following nuclei in four fields with a 22x objective using a graticule (SQ515 eyepiece micrometer; Olympus, Japan) (Aherne, 1975): anteroventral nucleus (AV), lateral dorsal nucleus (LD), mediodorsal nucleus (MD), centre médian (centromedian) nucleus (CM), ventral anterior nucleus (VA), ventral lateral posterior nucleus (VLp), ventral lateral anterior nucleus (VLa) and ventral posterior lateral nucleus (VPL). In the reticular nucleus (Re) cells lie in groups, so that no random distribution can be assumed. Therefore we counted the total number of immunoreactive cells in the Re using a 10x objective (Aherne, 1975).
EEG analysis
The original EEG tracings were provided by the notifying hospitals. All EEG tracings were evaluated by a certified investigator (B.J.S.) using standardized criteria (Steinhoff et al., 1996) and without knowledge of clinical data (see Table 1 for results).
Statistical analysis
After counting four fields in each thalamic nucleus or all PV+ cells in the Re, the mean number of immunoreactive cells was calculated in each nucleus. In most cases, two or more sections (mean 2.32, SD 0.63) through the thalamus were available for study. The mean number of cells per nucleus was calculated for all sections and used for further analysis.
To test for differences in the number of cells in the thalamic nuclei under distinct clinical conditions, the two-tailed unpaired t-test was used. Correlation of the results with age was tested using the Spearman rank correlation with a two-tailed P value. P < 0.05 was considered significant.
|
Results |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Clinical features
The clinical data are summarized in Table 1.
General brain pathology
The brains of all control patients were normal upon neuropathological, macroscopic and histological examination. Brain atrophy with widening of sulci (11 out of 21 cases) was a common feature in sCJD patients. We detected atrophy of the thalamus macroscopically in two patients. Associated pathology consisted of arteriosclerosis (none in three, mild in four, moderate in eight and severe in two cases). Two patients presented with dilated perivascular spaces in the putamen, and in one of these an old cavitary infarct (size 3 mm) was found occipitally. Histology yielded senile plaques in one patient, with amyloid and tau pathology corresponding to CERAD B and Braak & Braak I–II, respectively.
PV immunoreactivity
Overall staining with the antibody against PV was strong in the controls, clearly delineating the different thalamic nuclei. As shown in Fig. 1A and B, the nuclei of the ventral nuclear group, including the ventral anterior (VA), the ventral lateral anterior (VLa), the ventral lateral posterior (VLp) and the ventral posterior lateral (VPL) nuclei, showed the most intense PV staining. Particularly large, oval-to-round neurones with their proximal dendrites were strongly positive for PV. The VA, VLa, VLP and VPL nuclei appeared striped (Fig. 1A, B, G and H) due to unstained fibre bundles traversing the nuclei frontolaterally to caudomedially. The mediodorsal nucleus (MD) showed moderately PV-stained cells, which were distributed in clusters. The reticular nucleus (Re) was clearly identifiable, as it covers the ventral nuclear group like a shell. The PV+ cells in the Re had an oval shape and lay in clusters in a moderately stained neuropil. The AV and the LD showed a moderate to weak PV staining with a more intensely stained neuropil. Our staining results are in accordance with those of Munkle et al. (2000).
PV+ cells in patients versus controls
In general, PV immunoreactivity in sCJD patients was more heterogeneous than in controls. Staining intensity in some sCJD patients was comparable to controls, with clear delineation of thalamic nuclei. In other sCJD patients, staining was weaker but cells were still clearly identifiable. This was probably due to differences in the processing of the material in the referring institutes. In some sCJD patients, a few neurones appeared shrunken (Fig. 1J).
Compared with the controls, sCJD patients showed a significant reduction of PV-positive neurones in most thalamic nuclei. This was most severe in the Re (164.7 ± 15.3 in controls compared with 99.3 ± 9.1 in patients; P = 0.0035), but also significant in the VLa (P = 0.029), VLp (P = 0.0052), AV (P = 0.019) and LD (P = 0.01) thalamic nuclei (Table 2). In the CM, sCJD patients had insignificantly more PV+ neurones than controls [5.3 ± 0.8 compared with 4.0 ± 0.8, respectively; P = not significant (NS)].
|
Atrophy of the thalamus was observed macroscopically in two sCJD patients. In one of these, the number of cells per thalamic nucleus was in the upper range, and in the other it was in the lower range compared with the other sCJD patients.
PV+ cells and clinical findings
The number of PV+ cells per thalamic nucleus was correlated with clinical data (see Fig. 2 and Table 3 for details): The VLp showed a significant reduction of PV+ cells in sCJD patients with PrPSc type 1 (Fig. 1H) compared with PrPSc type 2 (Fig. 1G), and in those homozygous for methionine at codon 129 (M/M1) compared with those homozygous for valine (V/V2) (P < 0.05).
|
|
In the Re there was a reduction of PV+ cells in sCJD patients with PSWCs compared with patients without typical EEG changes (no PSWCs: 109.9 ± 14.5; PSWCs: 87.7 ± 10.0; P = NS) (Table 3; Fig. 1D and E).
Patients exhibiting myoclonus and PSWCs had significantly fewer PV-immunoreactive cells in the Re than patients with myoclonus but without periodic EEGs (myoclonus and PSWCs: 92.7 ± 9.7; myoclonus, no PSWCs: 130.9 ± 11.1; P = 0.02).
In the AV, patients whose disease had lasted >6 months showed significantly less PV immunoreactivity than patients with a shorter duration of disease (4.3 ± 0.7 and 6.4 ± 0.6, respectively; P = 0.045). The absence of PSWCs (no PSWCs: 4.0 ± 0.7; PSWCs: 6.1 ± 0.6) (Fig. 1J and K) and even more so the absence of PSWCs in combination with the presence of myoclonus correlated with a reduction of PV+ cells in the AV (myoclonus and PSWCs: 6.1 ± 0.6; myoclonus, no PSWCs 2.8 ± 0.3; P = 0.04). There were no differences in the number of PV+ neurones in the LD in various clinical conditions.
Sporadic CJD patients without myoclonus had more PV+ cells in the CM than those with myoclonus (no myoclonus: 6.1 ± 2.1; myoclonus: 4.9 ± 0.6; P = NS); this finding was not statistically significant. Independent of the presence or absence of myoclonus, sCJD patients had more PV+ cells in the CM than controls.
There was no correlation between the patients’ ages and the number of PV+ cells in the different thalamic nuclei.
|
Discussion |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
In sporadic CJD, there are variations in the degree of thalamic pathology (Macchi et al., 1997
; Parchi et al., 1999) that are likely to be related to the molecular subtype.
According to functional and morphological studies carried out by Jones (Jones, 1985, 1998), the integration between the thalamus and the cerebral cortex is due to subsets of thalamic neurones immunoreactive for different calcium-binding proteins (calbindin D28K, PV). While calbindin D28K+ cells constitute a matrix of diffusely projecting cells, PV+ cells connect the thalamus with the cortex in a highly ordered fashion (Jones, 1998).
Ferrer and colleagues were the first to study PV immunoreactive neurones in brain biopsies from the frontal lobes of three CJD patients (Ferrer et al., 1993), and they found a marked reduction of PV+ cells. Studies on the hippocampus of CJD patients (Guentchev et al., 1997) as well as in experimentally infected mice confirmed that PV+ cells are selectively damaged in prion disease (Guentchev et al., 1999), without affecting calbindin D28K+ or calretinin+ neurones (Guentchev et al., 1998). There is only one published morphometric investigation (Macchi et al., 1997) examining the thalami of two sCJD patients using Nissl-stained sections, and a significant reduction of neurones in nearly all thalamic nuclei was described.
The present study shows a reduction of PV-immunoreactive cells in sCJD patients, which was particularly marked in the VLp and Re (Fig. 1A–H; Table 2), and was also significant in the VLa, AV and LD (P < 0.05). The VLp and VLa belong to the ventral nuclear group, which also includes the VPL and VA. The ventral nuclear group generally stains densely for PV and it is part of the motor thalamus (Jones, 1985; Macchi and Jones, 1997). PV+ cells in the VLp receive afferents from the cerebellum and project to the motor cortex (Jones, 1998). The VLa connects the pallidum with the supplementary motor cortex (Macchi and Jones, 1997). We therefore hypothesized that a reduction of inhibitory PV+ cells in the ventral nuclear group would show a relationship with the occurrence of excitatory motor symptoms such as myoclonus (Ferrer et al., 1993; Guentchev et al., 1997, 1998). Nevertheless, the reduction of PV+ cells in the ventral nuclear group in sCJD did not correlate with the occurrence of myoclonus.
However, the pathology in the ventral nuclear group was related to the molecular sCJD subtype: comparing patients with PrPSc type 1 to PrPSc type 2 and those homozygous for methionine at Codon 129 and PrPSc type 1 (M/M1) with patients homozygous for valine and PrPSc type 2 (V/V2), there was a significant loss of PV+ cells in the VLp in PrPSc type 1 patients (P = 0.001) and the subset of M/M1 patients (P = 0.003). Parchi and colleagues studied the MD in the sCJD subtypes and found mild to moderate pathological changes (neuronal loss, astrogliosis and spongiosis) in M/M1 patients and moderate to severe changes in V/V2 patients (Parchi et al., 1999). There was no difference in the MD between M/M1 and V/V2 patients in our study. PV+ cells were most severely damaged in the Re in sCJD, showing a 40% reduction in PV+ cells compared with controls (P < 0.005) (see Table 2 and Fig. 2).
The Re has been studied extensively in epilepsy and sleep models using electrophysiological experiments (Steriade et al., 1985, 1987; Avanzini et al., 1993; Contreras and Steriade, 1995; Mihaly et al., 1998; Seidenbecher et al., 1998; Steriade and Contreras, 1998). Steriade and colleagues presented the hypothesis that the reticular thalamic nucleus is a pacemaker for spindle rhythms present in natural sleep (Steriade et al., 1985). The Re is the interface between thalamocortical and corticothalamic systems as it receives collaterals from corticothalamic neurones and is connected to thalamocortical cells in most thalamic nuclei. Thus, the synchronized activity generated by GABAergic inhibitory neurones in the Re would be distributed to the thalamic nuclei and consecutively to the cortex (Steriade et al., 1985). Avanzini and colleagues showed that in rats suffering from genetic absence epilepsy, the spike and wave discharges typical for absence epilepsy are abolished after lesioning the Re neurones (Avanzini et al., 1993). Other investigators (Mihaly et al., 1998) demonstrated that the number of PV+ cells in the Re decreases after experimentally induced epileptic activity in a rat model. According to Huntsman and colleagues, in normal rats a recurrent inhibition in the Re reduces the genuine synchronicity and thus prevents seizures (Huntsman et al., 1999). In summary, it is widely accepted that the Re plays an important role in the generation and maintenance of synchronous electric activity (Steriade et al., 1985, 1987; Avanzini et al., 1993; Contreras and Steriade, 1995; Mihaly et al., 1998; Seidenbecher et al., 1998; Steriade and Contreras, 1998).
In our study, patients with CJD-typical periodic sharp wave complexes (PSWCs) and myoclonus had a predominant reduction of PV+ cells in the Re. In view of this connection we hypothesize that in CJD there is an electrophysiological relation between the generation of PSWCs and the PV+ neurones in the Re. Assuming that the Re controls the genuine electric activity of the thalamus by PV+ inhibitory neurones (Steriade and Contreras, 1998), damage to the PV+ Re cells would reduce inhibition. A reduction of inhibition would thus result in increased synchronicity and generation of the PSWCs. While the Re and VLp demonstrated the most pronounced reduction of PV+ neurones when comparing patients and controls, the AV was the only thalamic nucleus exhibiting significant cell loss if the disease lasted for >6 months (Table 3). In addition, it showed a significant preservation of cells in patients with PSWCs (Fig. 1J and K). The main afferent and efferent projections of the AV are from the limbic system, especially the cingulate area, and from the Re (Jones, 1985). An implication of the AV in the generation of PSWCs has not been postulated. Although the hippocampus is part of the limbic system and is usually involved in the creation of seizures, its role in the generation of PSWCs is not yet clear.
In summary, we have shown that PV-positive neurones are reduced in the majority of thalamic nuclei in sCJD patients compared with controls. A particularly high loss of PV+ cells was found in the Re in sCJD patients with myoclonus and PSWCs. This relationship will be elucidated further, as our knowledge of the functional anatomy of the thalamus and the pathogenesis of prion diseases is evolving.
|
Acknowledgements |
|---|
The authors wish to thank all physicians who referred suspect patients to the German Reference Center for Spongiform Encephalopathies, for providing necropsy brains and clinical data. They also wish to express their thanks to the physicians of the CJD Surveillance Unit, as well as to Dorothea Hause-Reitner, Christina Oberdieck, Wolfgang Dröse and Maja Schneider-Dominco for their excellent technical assistance. This study was supported by a grant from the Bundesministerium für Gesundheit, Bonn, Germany, to H.A.K. and to S.P. (BMG Gz 325-4471-02/15).
|
References |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Aherne W. Some morphometric methods for the central nervous system. J Neurol Sci 1975; 24: 221–41.[Web of Science][Medline]
Avanzini G, Vergnes M, Spreafico R, Marescaux C. Calcium-dependent regulation of genetically determined spike and waves by the reticular thalamic nucleus of rats. Epilepsia 1993; 34: 1–7.[Web of Science][Medline]
Baimbridge KG, Celio MR, Rogers JH. Calcium-binding proteins in the nervous system. [Review]. Trends Neurosci 1992; 15: 303–8.[Web of Science][Medline]
Bartko JJ. Measures of agreement: a single procedure. Stat Med 1994; 13: 737–45.[Web of Science][Medline]
Belichenko PV, Miklossy J, Belser B, Budka H, Celio MR. Early destruction of the extracellular matrix around parvalbumin-immunoreactive interneurons in Creutzfeldt–Jakob disease. Neurobiol Dis 1999; 6: 269–79.[Web of Science][Medline]
Berchtold MW, Celio MR, Heizmann CW. Parvalbumin in human brain. J Neurochem 1985; 45: 235–9.[Web of Science][Medline]
Brown P, Wolff A, Gajdusek DC. A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt–Jakob disease. Neurology 1990; 40: 887–90.
Celio MR. Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex. Science 1986; 231: 995–7.
Contreras D, Steriade M. Cellular basis of EEG slow rhythms: a study of dynamic corticothalamic relationships. J Neurosci 1995; 15: 604–22.[Abstract]
Ferrer I, Casas R, Rivera R. Parvalbumin-immunoreactive cortical neurons in Creutzfeldt–Jakob disease. Ann Neurol 1993; 34: 864–6.[Web of Science][Medline]
Guentchev M, Hainfellner JA, Trabattoni GR, Budka H. Distribution of parvalbumin-immunoreactive neurons in brain correlates with hippocampal and temporal cortical pathology in Creutzfeldt–Jakob disease. J Neuropathol Exp Neurol 1997; 56: 1119–24.[Web of Science][Medline]
Guentchev M, Groschup MH, Kordek R, Liberski PP, Budka H. Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies. Brain Pathol 1998; 8: 615–23.[Web of Science][Medline]
Guentchev M, Wanschitz J, Voigtlander T, Flicker H, Budka H. Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am J Pathol 1999; 155: 1453–7.
Hirai T, Jones EG. A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res Brain Res Rev 1989; 14: 1–34.[Medline]
Huguenard JR. Anatomical and physiological considerations in thalamic rhythm generation. J Sleep Res 1998; 7 (Suppl 1): 24–9.
Huntsman MM, Porcello DM, Homanics GE, DeLorey TM, Huguenard JR. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 1999; 283: 541–3.
Jones EG. The thalamus. New York: Plenum Press; 1985.
Jones EG. Viewpoint: the core and matrix of thalamic organization. [Review]. Neuroscience 1998; 85: 331–45.[Web of Science][Medline]
Kretzschmar HA, Ironside JW, DeArmond SJ, Tateishi J. Diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Arch Neurol 1996; 53: 913–20.
Macchi G, Jones EG. Toward an agreement on terminology of nuclear and subnuclear divisions of the motor thalamus. [Review]. J Neurosurg 1997; 86: 670–85.[Web of Science][Medline]
Macchi G, Rossi G, Abbamondi AL, Giaccone G, Mancia D, Tagliavini F, et al. Diffuse thalamic degeneration in fatal familial insomnia. A morphometric study. Brain Res 1997; 771: 154–8.[Web of Science][Medline]
Mihaly A, Szente M, Dobo E, Por I. Early activation of inhibitory neurons in the thalamic reticular nucleus during focal neocortical seizures. Acta Histochem 1998; 100: 383–93.[Web of Science][Medline]
Munkle MC, Waldvogel HJ, Faull RL. The distribution of calbindin, calretinin and parvalbumin immunoreactivity in the human thalamus. J Chem Neuroanat 2000; 19: 155–73.[Web of Science][Medline]
Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 1996; 39: 767–78.[Web of Science][Medline]
Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al. Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224–33.[Web of Science][Medline]
Seidenbecher T, Staak R, Pape HC. Relations between cortical and thalamic cellular activities during absence seizures in rats. Eur J Neurosci 1998; 10: 1103–12.[Web of Science][Medline]
Sloviter RS. Calcium-binding protein (calbindin-D28k) and parvalbumin immunocytochemistry: localization in the rat hippocampus with specific reference to the selective vulnerability of hippocampal neurons to seizure activity. J Comp Neurol 1989; 280: 183–96.[Web of Science][Medline]
Steinhoff BJ, Racker S, Herrendorf G, Poser S, Grosche S, Zerr I, et al. Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt–Jakob disease. Arch Neurol 1996; 53: 162–6.
Steriade M, Contreras D. Spike–wave complexes and fast components of cortically generated seizures. I. Role of neocortex and thalamus. J Neurophysiol 1998; 80: 1439–55.
Steriade M, Deschenes M, Domich L, Mulle C. Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol 1985; 54: 1473–97.
Steriade M, Domich L, Oakson G, Deschenes M. The deafferented reticular thalamic nucleus generates spindle rhythmicity. J Neurophysiol 1987; 57: 260–73.
Windl O, Giese A, Schulz-Schaeffer W, Zerr I, Skworc K, Arendt S, et al. Molecular genetics of human prion diseases in Germany. Hum Genet 1999; 105: 244–52.[Web of Science][Medline]
Zerr I, Schulz-Schaeffer WJ, Giese A, Bodemer M, Schroter A, Henkel K, et al. Current clinical diagnosis in Creutzfeldt–Jakob disease: identification of uncommon variants. Ann Neurol 2000; 48: 323–9.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Lee, H. Rosenmann, J. Chapman, P. B. Kingsley, C. Hoffmann, O. S. Cohen, E. Kahana, A. D. Korczyn, and I. Prohovnik Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers Brain, March 24, 2009; (2009) awp064v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pocchiari, M. Puopolo, E. A. Croes, H. Budka, E. Gelpi, S. Collins, V. Lewis, T. Sutcliffe, A. Guilivi, N. Delasnerie-Laupretre, et al. Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies Brain, October 1, 2004; 127(10): 2348 - 2359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Rub, D. Del Turco, K. Del Tredici, R. A. I. de Vos, E. R. Brunt, G. Reifenberger, C. Seifried, C. Schultz, G. Auburger, and H. Braak Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance Brain, October 1, 2003; 126(10): 2257 - 2272. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||