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U Rüb,
K Farrag,
K Seidel,
Er Brunt,
H Heinsen,
K Bürk,
B Melegh,
C von Gall,
G Auburger,
J Bohl,
Hw Korf,
F Hoche,
W den Dunnen
[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG-repeat or polyglutamine diseases. Along with a large variety of motor, behavioral and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. Since the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl stained thick tissue sections through the cholinergic basal forebrain nuclei (i.e. medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of eleven control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age and gender matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca; 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.
Neuropathology and Applied Neurobiology 01/2013; · 3.80 Impact Factor
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Udo Rüb,
Franziska Hoche,
Ewout R Brunt,
Helmut Heinsen,
Kay Seidel,
Domenico Del Turco,
Henry L Paulson,
Jürgen Bohl,
Charlotte von Gall,
Jean-Paul Vonsattel,
Horst-Werner Korf,
Wilfred F den Dunnen
[show abstract]
[hide abstract]
ABSTRACT: Huntington's disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo- and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad-based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo-like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD.
Brain Pathology 08/2012; · 3.99 Impact Factor
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W Scherzed,
E R Brunt,
H Heinsen,
R A de Vos,
K Seidel,
K Bürk,
L Schöls,
G Auburger,
D Del Turco,
T Deller,
H W Korf,
W F den Dunnen, U Rüb
[show abstract]
[hide abstract]
ABSTRACT: The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.
The Cerebellum 12/2011; 11(3):749-60. · 3.21 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Recent progress in oculomotor research has enabled new insights into the functional neuroanatomy of the human premotor oculomotor brainstem network. In the present review, we provide an overview of its functional neuroanatomy and summarize the broad range of oculomotor dysfunctions that may occur in Huntington's disease (HD) patients. Although some of these oculomotor symptoms point to an involvement of the premotor oculomotor brainstem network in HD, no systematic analysis of this functional system has yet been performed in brains of HD patients. Therefore, its exact contribution to oculomotor symptoms in HD remains unclear. A possible strategy to clarify this issue is the use of unconventional 100-microm-thick serial tissue sections stained for Nissl substance and lipofuscin pigment (Nissl-pigment stain according to Braak). This technique makes it possible to identify the known nuclei of the premotor oculomotor brainstem network and to study their possible involvement in the neurodegenerative process. Studies applying this morphological approach and using the current knowledge regarding the functional neuroanatomy of this human premotor oculomotor brainstem network will help to elucidate the anatomical basis of the large spectrum of oculomotor dysfunctions that are observed in HD patients. This knowledge may aid clinicians in the diagnosis and monitoring of the disease.
Neuropathology and Applied Neurobiology 03/2009; 35(1):4-15. · 3.80 Impact Factor
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K Gierga,
H J Schelhaas,
E R Brunt,
K Seidel,
W Scherzed,
R Egensperger,
R A I de Vos,
W den Dunnen,
P F Ippel,
E Petrasch-Parwez,
T Deller,
L Schöls, U Rüb
[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive.
We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients.
This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients.
In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.
Neuropathology and Applied Neurobiology 02/2009; 35(5):515-27. · 3.80 Impact Factor
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U Rüb,
E R Brunt,
K Seidel,
K Gierga,
C M Mooy,
M Kettner,
C Van Broeckhoven,
I Bechmann,
A R La Spada,
L Schöls,
W den Dunnen,
R A I de Vos,
T Deller
[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia type 7 (SCA7) represents a rare and severe autosomal dominantly inherited ataxic disorder and is among the known CAG-repeat, or polyglutamine, diseases. In contrast to other currently known autosomal dominantly inherited ataxic disorders, SCA7 may manifest itself with different clinical courses. Because the degenerative changes evolving during these different clinical courses are not well known, many neurological disease symptoms still are unexplained. We performed an initial pathoanatomical study on unconventional thick tissue sections of the brain of a clinically diagnosed and genetically confirmed adult-onset SCA7 patient with progressive visual impairments. In this patient we observed loss of myelinated fibres in distinct central nervous fibre tracts, and widespread degeneration of the cerebellum, telencephalon, diencephalon and lower brainstem. These degenerative changes offer appropriate explanations for a variety of less-understood neurological symptoms in adult-onset SCA7 patients with visual impairments: gait, stance and limb ataxia, falls, dysarthria, dysphagia, pyramidal signs, Parkinsonian features, writing problems, impairments of saccades and smooth pursuits, altered pupillary functions, somatosensory deficits, auditory deficits and mental impairments.
Neuropathology and Applied Neurobiology 05/2008; 34(2):155-68. · 3.80 Impact Factor
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F Hoche,
K Seidel,
E R Brunt,
G Auburger,
L Schöls,
K Bürk,
R A de Vos,
W den Dunnen,
I Bechmann,
R Egensperger,
C Van Broeckhoven,
K Gierga,
T Deller, U Rüb
[show abstract]
[hide abstract]
ABSTRACT: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7.
We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients.
Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients.
The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.
Neuropathology and Applied Neurobiology 02/2008; 34(5):479-91. · 3.80 Impact Factor
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U Rüb,
E R Brunt,
E Petrasch-Parwez,
L Schöls,
D Theegarten,
G Auburger,
K Seidel,
C Schultz,
K Gierga,
H Paulson,
C van Broeckhoven,
T Deller,
R A I de Vos
[show abstract]
[hide abstract]
ABSTRACT: Dysphagia, which can lead to nutritional deficiencies, weight loss and dehydration, represents a risk factor for aspiration pneumonia. Although clinical studies have reported the occurrence of dysphagia in patients with spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3), type 6 (SCA6) and type 7 (SCA7), there are neither detailed clinical records concerning the kind of ingestive malfunctions which contribute to dysphagia nor systematic pathoanatomical studies of brainstem regions involved in the ingestive process. In the present study we performed a systematic post mortem study on thick serial tissue sections through the ingestion-related brainstem nuclei of 12 dysphagic patients who suffered from clinically diagnosed and genetically confirmed spinocerebellar ataxias assigned to the CAG-repeat or polyglutamine diseases (two SCA2, seven SCA3, one SCA6 and two SCA7 patients) and evaluated their medical records. Upon pathoanatomical examination in all of the SCA2, SCA3, SCA6 and SCA7 patients, a widespread neurodegeneration of the brainstem nuclei involved in the ingestive process was found. The clinical records revealed that all of the SCA patients were diagnosed with progressive dysphagia and showed dysfunctions detrimental to the preparatory phase of the ingestive process, as well as the lingual, pharyngeal and oesophageal phases of swallowing. The vast majority of the SCA patients suffered from aspiration pneumonia, which was the most frequent cause of death in our sample. The findings of the present study suggest (i) that dysphagia in SCA2, SCA3, SCA6 and SCA7 patients may be associated with widespread neurodegeneration of ingestion-related brainstem nuclei; (ii) that dysphagic SCA2, SCA3, SCA6 and SCA7 patients may suffer from dysfunctions detrimental to all phases of the ingestive process; and (iii) that rehabilitative swallow therapy which takes specific functional consequences of the underlying brainstem lesions into account might be helpful in preventing aspiration pneumonia, weight loss and dehydration in SCA2, SCA3, SCA6 and SCA7 patients.
Neuropathology and Applied Neurobiology 01/2007; 32(6):635-49. · 3.80 Impact Factor
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I Tuin,
U Voss,
J-S Kang,
K Kessler, U Rüb,
D Nolte,
H Lochmüller,
S Tinschert,
D Claus,
K Krakow,
B Pflug,
H Steinmetz,
G Auburger
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant spinocerebellar ataxia type 2 (SCA2) bears clinical and neuropathologic similarities to sporadic multisystem atrophy (MSA) or Parkinson disease, in which sleep pathology is well documented. However, those clinical entities have a marked variability of the reported sleep disturbances, and their etiology is heterogeneous. In contrast, the study of SCA2 provides an opportunity to examine a molecularly homogeneous patient group, in which disease stages can be defined not only based on disease duration and ataxia scores, but also with regard to modulatory effects of mutation size.
To examine the presence and progression of sleep pathology in SCA2.
We analyzed eight patients with disease durations of 3 to 31 years, all with medium size SCA2 expansions (CAG 38 to 49), using clinical scores, sleep interviews, and video-polysomnography (VPSG) recordings.
Almost all patients reported good subjective sleep quality and negated incidents of REM behavior disorder (RBD). At early disease stages, however, REM without atonia in four patients' VPSG suggested subclinical RBD. This was accompanied by a consistent reduction of REM density. In three patients at later SCA2 stages, REM sleep was undetectable, whereas slow wave sleep (SWS) was markedly increased at the cost of light sleep. Periodic leg movements, apnea, or hypopnea were not prominent.
Progressive loss of dream recall in spinocerebellar ataxia type 2 was found and correlated with stages of REM more than non-REM pathology in video-polysomnography. These stages correspond to the progressive atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.
Neurology 01/2007; 67(11):1966-72. · 8.31 Impact Factor
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N L Sicotte,
G Salamon,
D W Shattuck,
N Hageman, U Rüb,
N Salamon,
A E Drain,
J L Demer,
E C Engle,
J R Alger,
R W Baloh,
T Deller,
J C Jen
[show abstract]
[hide abstract]
ABSTRACT: Horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging in a patient with HGGPS revealed the absence of major pontine crossing fiber tracts and no decussation of the superior cerebellar peduncles. Mutations in the ROBO3 gene lead to a widespread lack of crossing fibers throughout the brainstem.
Neurology 09/2006; 67(3):519-21. · 8.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia type 4 (SCA4), also known as 'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus, auditory impairments and pathologically altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face, and dysphagia may occur during the course of SCA4. Finally, the results of our immunocytochemical studies support the concept that SCA4 is not a member of the CAG-repeat or polyglutamine diseases.
Acta Neurovegetativa 08/2006; 113(7):829-43. · 2.73 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease (PD) is a multisystem disorder in which predisposed neuronal types in specific regions of the human peripheral, enteric, and central nervous systems become progressively involved. A staging procedure for the PD-related inclusion body pathology (i.e., Lewy neurites and Lewy bodies) in the brain proposes that the pathological process begins at two sites and progresses in a topographically predictable sequence in 6 stages. During stages 1-2, the inclusion body pathology remains confined to the medulla oblongata, pontine tegmentum, and anterior olfactory structures. In stages 3-4, the basal mid- and forebrain become the focus of the pathology and the illness reaches its symptomatic phase. In the final stages 5-6, the pathological process is seen in the association areas and primary fields of the neocortex. To date, we have staged a total of 301 autopsy cases, including 106 cases with incidental pathology and 176 clinically diagnosed PD cases. In addition, 163 age-matched controls were examined. 19 of the 301 cases with PD-related pathology displayed a pathological distribution pattern of Lewy neurites and Lewy bodies that diverged from the staging scheme described above. In these cases, olfactory structures and the amygdala were predominantly involved in the virtual absence of brain stem pathology. Most of the divergent cases (17/19) had advanced concomitant Alzheimer's disease-related neurofibrillary changes (stages IV-VI).
Journal of neural transmission. Supplementum 02/2006; · 1.07 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date 24 different loci have been identified for these conditions. A locus at chromosome 16q22.1 co-segregates with the disease phenotype in families of Scandinavian, Japanese and German origin. The corresponding SCA4 locus was narrowed down to 7.94 Mb for the two European and to 1.25 Mb for Japanese pedigrees. Unfortunately, because of the phenotypic differences between patients from Japan and Europe it is not possible to decide if SCA families linked to chromosome 16q22.1 share a common disease genotype or not. To look for mutations in the German family we screened 34 candidate genes in a 3.69 cM region. With the exception of two cSNPs, no segregation of DNA variations with the disease phenotype was found.
Journal of Neurology 01/2006; 252(12):1472-5. · 3.47 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Parkinson’s disease (PD) is a multisystem disorder in which predisposed neuronal types in specific regions of the human peripheral,
enteric, and central nervous systems become progressively involved. A staging procedure for the PD-related inclusion body
pathology (i.e., Lewy neurites and Lewy bodies) in the brain proposes that the pathological process begins at two sites and
progresses in a topographically predictable sequence in 6 stages. During stages 1–2, the inclusion body pathology remains
confined to the medulla oblongata, pontine tegmentum, and anterior olfactory structures. In stages 3–4, the basal mid- and
forebrain become the focus of the pathology and the illness reaches its symptomatic phase. In the final stages 5–6, the pathological
process is seen in the association areas and primary fields of the neocortex. To date, we have staged a total of 301 autopsy
cases, including 106 cases with incidental pathology and 176 clinically diagnosed PD cases. In addition, 163 age-matched controls
were examined. 19 of the 301 cases with PD-related pathology displayed a pathological distribution pattern of Lewy neurites
and Lewy bodies that diverged from the staging scheme described above. In these cases, olfactory structures and the amygdala
were predominantly involved in the virtual absence of brain stem pathology. Most of the divergent cases (17/19) had advanced
concomitant Alzheimer’s disease-related neurofibrillary changes (stages IV-VI).
12/2005: pages 89-97;
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U Rüb,
K Gierga,
E R Brunt,
R A I de Vos,
M Bauer,
L Schöls,
K Bürk,
G Auburger,
J Bohl,
C Schultz,
M Vuksic,
G J Burbach,
H Braak,
T Deller
[show abstract]
[hide abstract]
ABSTRACT: The pre-cerebellar nuclei act as a gate for the entire neocortical, brainstem and spinal cord afferent input destined for the cerebellum. Since no pathoanatomical studies of these nuclei had yet been performed in spinocerebellar ataxia type 2 (SCA2) or type 3 (SCA3), we carried out a detailed postmortem study of the pre-cerebellar nuclei in six SCA2 and seven SCA3 patients in order to further characterize the extent of brainstem degeneration in these ataxic disorders. By means of unconventionally thick serial sections through the brainstem stained for lipofuscin pigment and Nissl material, we could show that all of the pre-cerebellar nuclei (red, pontine, arcuate, prepositus hypoglossal, superior vestibular, lateral vestibular, medial vestibular, interstitial vestibular, spinal vestibular, vermiform, lateral reticular, external cuneate, subventricular, paramedian reticular, intercalate, interfascicular hypoglossal, and conterminal nuclei, pontobulbar body, reticulotegmental nucleus of the pons, inferior olive, and nucleus of Roller) are among the targets of both of the degenerative processes underlying SCA2 and SCA3. These novel findings are in contrast to the current neuropathological literature, which assumes that only a subset of pre-cerebellar nuclei in SCA2 and SCA3 may undergo neurodegeneration. Widespread damage to the pre-cerebellar nuclei separates all three phylogenetically and functionally defined regions of the cerebellum, impairs their physiological functions and thus explains the occurrence of gait, stance, limb and truncal ataxia, dysarthria, truncal and postural instability with disequilibrium, impairments of the vestibulo-ocular reaction and optokinetic nystagmus, slowed and saccadic smooth pursuits, dysmetrical horizontal saccades, and gaze-evoked nystagmus during SCA2 and SCA3.
Acta Neurovegetativa 12/2005; 112(11):1523-45. · 2.73 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The spinocerebellar
ataxias (SCAs) with autosomal
dominant inheritance are a clinically
and genetically heterogeneous
group of neurodegenerative disorders.
To date 24 different loci have
been identified for these conditions.
A locus at chromosome
16q22.1 co–segregates with the disease
phenotype in families of Scandinavian,
Japanese and German
origin. The corresponding SCA4
locus was narrowed down to 7.94
Mb for the two European and to
1.25 Mb for Japanese pedigrees.
Unfortunately, because of the phenotypic
differences between patients
from Japan and Europe it is
not possible to decide if SCA families
linked to chromosome 16q22.1
share a common disease genotype
or not. To look for mutations in the
German family we screened 34
candidate genes in a 3.69 cM region.
With the exception of two
cSNPs, no segregation of DNA variations
with the disease phenotype
was found.
Journal of Neurology 11/2005; 252(12):1472-1475. · 3.47 Impact Factor
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U Rüb,
E R Brunt,
K Gierga,
K Seidel,
C Schultz,
L Schöls,
G Auburger,
H Heinsen,
P F Ippel,
W F Glimmerveen,
D Wittebol-Post,
K Arai,
T Deller,
R A I de Vos
[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia type 7 (SCA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (ADCA). It belongs to the group of CAG-repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12-p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late-onset SCA7 patient with a very short CAG-repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti-polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well-preserved brain regions and retina of SCA7 patients.
Brain Pathology 11/2005; 15(4):287-95. · 3.99 Impact Factor
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U. Rüb,
K. Gierga,
E. R. Brunt,
R. A. I. de Vos,
M. Bauer,
L. Schöls,
K. Bürk,
G. Auburger,
J. Bohl,
C. Schultz,
M. Vuksic,
G. J. Burbach,
H. Braak,
T. Deller
[show abstract]
[hide abstract]
ABSTRACT: The precerebellar nuclei act as a gate for the entire neocortical, brainstem and spinal cord afferent input destined for the
cerebellum. Since no pathoanatomical studies of these nuclei had yet been performed in spinocerebellar ataxia type 2 (SCA2)
or type 3 (SCA3), we carried out a detailed postmortem study of the precerebellar nuclei in six SCA2 and seven SCA3 patients
in order to further characterize the extent of brainstem degeneration in these ataxic disorders. By means of unconventionally
thick serial sections through the brainstem stained for lipofuscin pigment and Nissl material, we could show that all of the
precerebellar nuclei (red, pontine, arcuate, prepositus hypoglossal, superior vestibular, lateral vestibular, medial vestibular,
interstitial vestibular, spinal vestibular, vermiform, lateral reticular, external cuneate, subventricular, paramedian reticular,
intercalate, interfascicular hypoglossal, and conterminal nuclei, pontobulbar body, reticulotegmental nucleus of the pons,
inferior olive, and nucleus of Roller) are among the targets of both of the degenerative processes underlying SCA2 and SCA3.
These novel findings are in contrast to the current neuropathological literature, which assumes that only a subset of precerebellar
nuclei in SCA2 and SCA3 may undergo neurodegeneration. Widespread damage to the precerebellar nuclei separates all three phylogenetically
and functionally defined regions of the cerebellum, impairs their physiological functions and thus explains the occurrence
of gait, stance, limb and truncal ataxia, dysarthria, truncal and postural instability with disequilibrium, impairments of
the vestibulo-ocular reaction and optokinetic nystagmus, slowed and saccadic smooth pursuits, dysmetrical horizontal saccades,
and gaze-evoked nystagmus during SCA2 and SCA3.
Acta Neurovegetativa 10/2005; 112(11):1523-1545. · 2.73 Impact Factor
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K Gierga,
K Bürk,
M Bauer,
G Orozco Diaz,
G Auburger,
C Schultz,
M Vuksic,
L Schöls,
R A I de Vos,
H Braak,
T Deller, U Rüb
[show abstract]
[hide abstract]
ABSTRACT: Although the cranial nerves, their nuclei and related fiber tracts are crucial for a variety of oculomotor, somatomotor, somatosensory, auditory, vestibular-related, autonomic and ingestion-related functions, knowledge regarding the extent of their involvement in spinocerebellar ataxia type 2 (SCA2) patients is incomplete. Accordingly, we performed a pathoanatomical analysis of these structures in six clinically diagnosed SCA2 patients. Unconventionally thick serial sections through the brainstem stained for lipofuscin pigment (aldehyde-fuchsin) and Nissl material (Darrow red) showed that all oculomotor, somatomotor, somatosensory, auditory, vestibular and autonomic cranial nerve nuclei may undergo neurodegeneration during SCA2. Similarly, examination of myelin-stained thick serial sections revealed that nearly all cranial nerves and associated fiber tracts may sustain atrophy and myelin loss in SCA2 patients. In view of the known functional role of the affected cranial nerves, their nuclei and associated fiber tracts, the present findings provide appropriate pathoanatomical explanations for some of the disease-related and unexplained symptoms seen in SCA2 patients: double vision, gaze palsy, slowing of saccades, ptosis, ingestion-related malfunctions, impairments of the optokinetic nystagmus and the vestibulo-ocular reaction, facial and tongue fasciculation-like movements, impaired centripetal transmission of temperature-related information from the face, dystonic posture of the neck, as well as abnormalities of the brainstem auditory evoked potentials.
Acta Neuropathologica 07/2005; 109(6):617-31. · 9.32 Impact Factor
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ABSTRACT: To study the association of cognitive status with the stages of a published neuropathologic staging procedure for sporadic Parkinson disease (PD) in a cohort of 88 patients with PD from a single neurologic unit. None had received the clinical diagnosis of dementia with Lewy bodies (DLB).
The authors assessed Lewy neurites/bodies (LNs/LBs) immunoreactive for alpha-synuclein semiquantitatively in sections from 18 brain regions. In silver-stained sections and sections immunostained for tau and beta-amyloid protein, the authors semiquantitatively evaluated comorbidities potentially contributing to cognitive decline, e.g., Alzheimer disease (AD), argyrophilic grain disease (AGD), and cerebral vascular disease. The authors analyzed four Mini-Mental State Examination (MMSE) subgroups ranging from marginally impaired cognition to severe dementia using nonparametric tests.
It was possible to assign all patients to one of the PD stages. MMSE scores correlated with neuropathologic stages (p < 0.005) and this association showed a linear trend (p < 0.025). Median MMSE test scores for women were lower than those for men. Cognitively impaired individuals displayed higher stages of AD-related neurofibrillary pathology (p < 0.05) and beta-amyloid deposition (p < 0.05) than cognitively unimpaired persons. MMSE scores did not correlate significantly with AGD, disease duration, age at disease onset, or age at death. Hoehn and Yahr scores, however, correlated with PD stages (p < 0.0005) and MMSE scores (p < 0.0005).
The decrease in median Mini-Mental State Examination scores between PD stages 3 to 6 indicates that the risk of developing dementia increases with disease progression. In some individuals, however, cognitive decline can develop in the presence of mild Parkinson disease-related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline.
Neurology 05/2005; 64(8):1404-10. · 8.31 Impact Factor
