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Biomedical subjects

G Auburger

Publications and source records attributed to G Auburger.

At least 19 recordsLinked to original sources
PubMed2006

Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2).

BACKGROUND: 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. OBJECTIVE: To examine the presence and progression of sleep pathology in SCA2. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adolescent↗
PubMed2006

The role of protein aggregates in neuronal pathology: guilty, innocent, or just trying to help?

Protein aggregates such as Lewy bodies have done much for the scientists in the field of neurodegenerative diseases: They have highlighted the affected cell populations and they have trapped the mutant disease protein. Instead of a good reputation, however, protein aggregates have received incriminations, because they are consistently seen at the site of crime. Reviewing the arguments, crucial evidence has become known that (a) the specific neuronal pathology precedes the appearance of protein aggregates in mouse models of disease, (b) the neurodegenerative disease in patients occurs with comparable severity when visible protein aggregates remain absent, (c) the neurotoxicity in vitro is best reproduced by oligomers, not polymers of the mutant disease protein. Is it feasible that protein aggregates are inert byproducts of the disease protein malconformation, or that they even represent beneficial cellular efforts to sequestrate the soluble toxic disease protein, together with normal or aberrant interactor proteins? Whatever the answer will be, one positive role of protein aggregates seems clear: In contrast to earlier speculations that random cytoplasmic proteins are trapped within the aggregates, scientists now believe that the composition of the Lewy body reflects the network of interactions between crucial players in disease pathogenesis, such as the PARK1, PARK2 and PARK5 protein.

Alzheimer Disease↗
PubMed2006

Degeneration of ingestion-related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7.

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.

Adult↗
PubMed2005

Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2).

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.

Adolescent↗
PubMed2005

Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson's syndrome.

A G309D mutation in the PINK1 gene in a consanguineous Spanish kindred with seven siblings, three of whom are clinically affected, has recently been shown to be a cause of the PARK6 form of autosomal-recessive Parkinson's syndrome. In this family, we studied pre- and postsynaptic dopaminergic function using 123I-FP-CIT- and 123I-iodobenzamide-SPECT to determine binding to the presynaptic dopamine transporter (DAT) and postsynaptic D2 receptors respectively. All three PARK6 patients showed reduced striatal DAT binding with posterior preponderance similar to sporadic idiopathic PD, but only one patient showed significant striatal asymmetry. In two of the siblings, DAT binding was markedly increased. IBZM-SPECT was normal in both patients and sibs. Our findings indicate that 123I-FP-CIT-SPECT shows similar DAT binding in PARK6 patients compared to idiopathic Parkinson's disease. The increased DAT binding in heterozygous PARK6 carriers may be a new very early preclinical finding, but its significance is still unclear.

Adult↗
PubMed2005

Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum.

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.

Adolescent↗
PubMed2005

[HERNS. A rare, hereditary, multisystemic disease with cerebral microangiopathy].

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomally dominant inherited, multisystemic disease presenting with leukoencephalopathy, progressive visual loss, and nephropathy. Furthermore, psychiatric symptoms and migraine may occur. Magnetic resonance imaging has identified contrast-enhancing cerebral lesions with surrounding vasogenic edema. Electron microscopy has shown alterations in the arterioles and capillaries consisting of multilayered basement membranes in brain, kidney, and skin biopsies. Linkage analysis has mapped the disease locus to chromosome 3p21. At the present time, no effective treatment is known. This article gives a summary of the clinical, morphological, genetical, and pathological characteristics of HERNS.

Brain↗
PubMed2005

Extended pathoanatomical studies point to a consistent affection of the thalamus in spinocerebellar ataxia type 2.

The involvement of the thalamus during the course of the currently known polyglutamine diseases is still a matter of debate. While it is well-known that this diencephalic nuclear complex undergoes neurodegeneration in some polyglutamine diseases such as Huntington's disease (HD), it has remained unclear whether and to what extent the thalamus is also involved in spinocerebellar ataxia type 2 (SCA2) patients. Encouraged by our recent post-mortem findings in one German SCA2 patient and the results of a recent nuclear magnetic resonance (NMR) study, we extended our pathoanatomical analysis to serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of four additional German and Cuban SCA2 patients. According to this analysis the thalamus is consistently affected by the destructive process of SCA2. In particular, during our study we observed a consistent involvement of the lateral geniculate body, the lateral posterior, ventral anterior, ventral lateral, ventral posterior lateral, and ventral posterior medial thalamic nuclei as well as the extraterritorial reticular nucleus. In four of the SCA2 cases studied additional damage was seen in the inferior and lateral nuclei of the pulvinar, whereas in the minority of the patients a subset of the limbic nuclei of the thalamus (i.e. anterodorsal, anteroprincipal, laterodorsal, fasciculosus, mediodorsal, central lateral, central medial, cucullar, and paracentral nuclei, medial nucleus of the pulvinar) underwent neurodegeneration. These interindividual differences in the distribution pattern of thalamic neurodegeneration indicate that the thalamic nuclei differ in their proclivities to degenerate in SCA2 and may suggest that they become involved at different phases in the evolution of the underlying degenerative process.

Adult↗
PubMed2005

Spinocerebellar ataxia type 7 (SCA7): first report of a systematic neuropathological study of the brain of a patient with a very short expanded CAG-repeat.

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.

Aged↗
PubMed2004

Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3.

BACKGROUND: The reticulotegmental nucleus of the pons (RTTG) is among the precerebellar nuclei of the human brainstem. Although it represents an important component of the oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuits, the RTTG has never been considered in CAG repeat or polyglutamine diseases. METHODS: Thick serial sections through the RTTG of 10 patients with spinocerebellar ataxias (SCAs) assigned to the CAG repeat or polyglutamine diseases (2 SCA-1 patients, 4 SCA-2 patients, and 4 SCA-3 patients) were stained for neuronal lipofuscin pigment and Nissl material. RESULTS: The unconventionally thick tissue sections revealed the hitherto overlooked involvement of the RTTG in the degenerative processes underlying SCA-1, SCA-2, and SCA-3, whereby in one of the SCA-1 patients, in two of the SCA-2 patients, and in all of the SCA-3 patients, the RTTG underwent a conspicuous loss of its nerve cells. CONCLUSIONS: Neurodegeneration may not only affect the cranial nerve nuclei (i.e., oculomotor and abducens nuclei) of SCA-1, SCA-2 and SCA-3 patients integrated into the circuits, subserving accuracy of horizontal saccades and the generation of horizontal smooth pursuits, but likewise involves the premotor networks of these circuits. This may explain why the SCA-1, SCA-2, and SCA-3 patients in this study with a heavily damaged reticulotegmental nucleus of the pons developed dysmetric horizontal saccades and impaired smooth pursuits during the course of the disease.

Adolescent↗
PubMed2004

Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance.

Although the vestibular complex represents an important component of the neural circuits crucial for the maintenance of truncal and postural stability, and it is integrated into specialized oculomotor circuits, knowledge regarding the extent of the involvement of its nuclei and associated fibre tracts in cases with spinocerebellar ataxia type 3 (SCA3) is incomplete. Accordingly, we performed a pathoanatomical analysis of the vestibular complex and its associated fibre tracts in four clinically diagnosed and genetically confirmed SCA3 patients with the aim of providing more exact information as to the involvement of the vestibular system in this disorder. By means of unconventionally thick serial sections through the vestibular nuclei stained for lipofuscin pigment and Nissl material, we could show that all five nuclei of this complex (interstitial, lateral, medial, spinal, and superior vestibular nuclei) are subject to neurodegenerative processes in SCA3, whereby examination of thick serial sections stained for myelin revealed that all associated fibre tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the eighth cranial nerve) underwent atrophy and demyelinization in all four of the patients studied. The reported lesions can help to explain the truncal and postural instability as well as the impaired optokinetic nystagmus, vestibulo-ocular reaction, and horizontal gaze-holding present in SCA3 cases.

Age of Onset↗
PubMed2003

Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance.

In spite of the considerable progress in clinical and molecular research, knowledge regarding brain damage in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) still is limited and the extent to which the thalamus is involved in both diseases is uncertain. Accordingly, we performed a pathoanatomical analysis on serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of two genetically confirmed cases: one an SCA2 patient, the other an SCA3 patient. During this systematic study, we detected severe destruction of the reticular (RT), fasciculosus (FA), ventral anterior (VA), ventral lateral (VL), ventral posterior lateral (VPL), ventral posterior medial (VPM), cucullar (CU) and mediodorsal thalamic nuclei (MD), the lateral geniculate body (LGB) and inferior nucleus of the pulvinar (PU i) in the SCA2 case, and a severe neuronal loss in the RT, FA, VA and PU i of the SCA3 case. In the SCA2 patient, additional obvious neuronal loss was observed in all nuclei of the anterior and rostral intra laminar groups, in the lateral posterior nucleus (LP), the lateral (PU l) and the medial subnuclei of the pulvinar (PU m), whereas in the SCA3 patient only two of the nuclei that belong to the anterior thalamic group, the VL, VPL, VPM, LP, LGB, PU l and PU m, displayed marked neurodegeneration. These novel findings indicate that thalamic involvement in SCA2 and SCA3 patients has been underestimated in the past. In view of what is known about the functions of the affected thalamic nuclei, the present findings provide an appropriate pathoanatomical explanation for some of the disease-related symptoms seen in both of our and other SCA2 and SCA3 patients: gait, stance, truncal and limb ataxia, dysarthria or anarthria, falls, dysdiadochokinesia and bradykinesia, problems with writing, somatosensory deficits, saccadic dysfunctions, executive dysfunctions and abnormalities of visual evoked potentials.

Adolescent↗
PubMed2003

Anatomically based guidelines for systematic investigation of the central somatosensory system and their application to a spinocerebellar ataxia type 2 (SCA2) patient.

Dysfunctions of the somatosensory system are among the clinical signs that characterize a variety of polyglutamine or CAG-repeat diseases. Deficits within this system may hinder the perception of potential threats, be detrimental to somatomotor functions, and result in uncoordinated movements, ataxia, and falls. Despite the considerable clinical relevance of such deficits, however, no systematic pathoanatomical studies of the central somatosensory system in polyglutamine diseases are currently available. The present paper has two goals: (1) recommendation of an economical tissue sampling method and optimized histological processing of this tissue to allow rapid and reliable evaluation of the structural integrity of all known relay stations and interconnecting fibre tracts within this complex system, and (2) the proposal of guidelines for a rapid and detailed pathoanatomical investigative procedure of the human central somatosensory system. In so doing, we draw on the current state of neuroanatomic research and apply the methods and guidelines proposed here to a 25-year-old female patient with spinocerebellar ataxia type 2 (SCA2). The use of 100 microm serial sections through the SCA2 patient's central somatosensory components showed that obvious neuronal loss occurred in nearly all of the relay stations of this system (Clarke's column; cuneate, external cuneate and gracile nuclei; spinal, principal and mesencephalic trigeminal nuclei; ventral posterior lateral and ventral posterior medial nuclei of the thalamus), whereas the majority of interconnecting fibre tracts (dorsal spinocerebellar tract; cuneate and gracile fascicles; medial lemniscus; spinal trigeminal tract, trigeminal nerve and mesencephalic trigeminal tract) displayed signs of atrophy accompanied by demyelinization. These pathological findings suffice to explain the patient's impaired senses of vibration, position and temperature. Moreover, together with the lesions seen in the motor cerebellothalamocortical feedback loop (pontine nuclei, deep cerebellar nuclei and cerebellar cortex, ventral lateral nucleus of the thalamus), they also account for the somatomotor deficits that were observed in the young woman (gait, stance, and limb ataxia, falls, and impaired writing). In proposing these new guidelines, we hope to enable others to study the hitherto unknown morphological counterparts of somatosensory dysfunctions in additional CAG-repeat disease patients.

Adult↗
PubMed2002

Chances and shortcomins of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats.

BACKGROUND & AIMS: Wilson disease (WD) is an autosomal recessively inherited copper storage disease due to mutations in the ATP7B gene. It results in impaired biliary copper excretion followed by liver injury leading to cirrhosis. In parallel, copper accumulates in other tissues e. g. basal ganglia of the brain inducing motoric disorders. Phenotypical cure of Wilson disease by liver transplantation raised the question whether gene therapy may represent a successful alternative treatment procedure. To examine the principle feasibility of this approach we investigated the effects of gene transfer using an adenoviral vector construct expressing the human ATP7B cDNA in an established rodent model for WD, the Long-Evans Cinnemon rat (LEC). METHODS: Transduction efficiency was assessed by RT-PCR, Western blot and immunofluorescence analysis. The therapeutic effect was estimated by analyzing holoceruloplasmin and its ferroxidase activity in serum, and the copper content of excrements. Changes in copper homeostasis were determined by positron emission tomography (PET). RESULTS: Successful, but temporary gene transfer was clearly detectable on RNA and protein levels. In parallel the temporary therapeutic effect was documented by restoration of serum holoceruloplasmin and of its ferroxidase activity. Additionally the Ad-ATP7B treated LEC rat revealed a higher (64)Cu content in stool. PET was able to visualize differences in (64)Cu distribution between wild type and LEC rats, indicating its principle usefulness as analytical tool. CONCLUSION: The data demonstrate proof of principle of successful gene therapy in an experimental model of WD. As a consequence of successful but only transient therapeutic effect of adenoviral gene transfer we can now focus more efficient and permanent gene transfer strategies.

Adenosine Triphosphatases↗
PubMed2001

Saturating density of STSs (1/6 kb) in a 1.1 Mb region on 3q28-q29: a valuable resource for cloning of disease genes.

We have fine mapped 29 ESTs of Genemap'99 to YACs and radiation hybrids covering 8 cM of the chromosomal region of 3q28-q29. Focusing on the genetic interval of approximately 1 Mb between markers D3S3669 and D3S3562 we established a sequence-ready PAC contig which covers the OPA1 locus containing the gene causing autosomal dominant optic atrophy (ADOA; OMIM*165500). The fidelity of the contig was increased by the generation of 181 PAC end sequences, 84 of which resulted in PCR-able STSs. Sequence content evaluation of the PAC ends by BLAST analysis identified two novel ESTs localising to the OPA1 crucial interval.

Chromosome Mapping↗