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Thomas Klockgether

Publications and source records attributed to Thomas Klockgether.

At least 19 recordsLinked to original sources
PubMed2026

Longitudinal progression, metrics, age-dependence, and modifiers of ataxia severity in SCA27B: a multicentre study of 219 patients.

BACKGROUND: Spinocerebellar Ataxia 27B (SCA27B) is a novel, frequent and likely treatable late-onset autosomal-dominant ataxia caused by GAA repeat-expansions in FGF14. For understanding disease evolution and imminent trial planning, metrics of the most widely used clinical outcome assessment (Scale for the Assessment and Rating of Ataxia/SARA), longitudinal progression and modifiers thereof are warranted. METHODS: Multicentre intercontinental observational study (2015-2024) of 661 assessments from 219 patients with SCA27B (age: 68 ± 10 years; SARA: 9 ± 6 points) with item-level distribution-based analyses to characterise SARA metrics relative to ageing-related impairment in 390 healthy controls; and linear mixed-effects modelling to determine longitudinal progression and demographic or genetic modifiers. FINDINGS: Ataxia severity in SCA27B as assessed by SARA was primarily attributable to gait, stance, and lower-limb impairment; other ataxia domains scored ≤1 SARA point in 79-94% of patients. Discrimination of SCA27B motor performance from controls decreased with age due to ageing-related motor variability captured by SARA, thus limiting potential metric response windows for symptomatic treatments. Disease progression was faster in the presence of interfering ageing-related comorbidities in 14 (6%) patients. Overall longitudinal progression of SCA27B was 0.54 SARA points/year [95% CI: 0.37-0.71]. Expansions of (GAA)> 180 repeats were frequent also on the shorter allele (n = 18 (8%), range: 196-348 repeats), and associated with faster progression (+1.6 SARA points/year, [95% CI: 0.9-2.2]), including also otherwise less affected ataxia domains speech and sitting. INTERPRETATION: Disease progression in SCA27B is characterised by mild progression, ageing-related motor variabilities and comorbidities, and associated with repeat size on both alleles. FUNDING: Else-Kröner-Fresenius-Stiftung, EU, DFG, BMBF, CIHR, NAF, Ataxia-UK, CSC.

Humans↗
PubMed2026

Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.

BACKGROUND: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders. METHODS: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2. RESULTS: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement. CONCLUSIONS: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.

Humans↗
PubMed2007

Health-related quality of life in sporadic adult-onset ataxia.

Despite progressive disability in sporadic adult-onset ataxia (SAOA), little is known about patients' assessment of their ataxic disorder and its impact on health-related quality of life (Hr-QoL). This study investigated Hr-QoL by means of the following self-administered scales: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory (BDI), and the Medical Outcome Study Short Form (SF-36). Twenty-two unselected ataxia patients were included. Sleep-related complaints were found in 9 (41%) of 22 and symptoms of depression in 6 (38%) of 16 patients. Compared to a large german control group, SAOA patients had lower scores in all SF-36 dimensions except for bodily pain. The greatest impairment was found in the domain physical functioning, followed by the domains social functioning and role limitations (emotional problems). There was a significant negative correlation of all nonmotor SF-36 dimensions with the BDI score. Walking aid dependency was significantly correlated with poorer health status perception in several motor and nonmotor domains. In addition, impaired sleep quality was correlated with an impaired general health perception and with bodily pain. The study demonstrates a great impact of SAOA on Hr-QoL. Adequate treatment of depression, motor disability, and impaired sleep quality is essential to improve Hr-QoL in ataxic patients.

Adult↗
PubMed2007

Adult index patient with Currarino syndrome due to a novel HLXB9 mutation, c.336dupG (p.P113fsX224), presenting with Hirschsprung's disease, cephalgia, and lumbodynia.

BACKGROUND: The symptom triad of autosomal dominant Currarino syndrome (CS; MIM #176450) consists of anorectal malformation, a sacral bone defect, and presacral masses. Mutations in the homeoboxHLXB9 gene have already been described in a subset of sacrococcygeal anomalies characterized by partial sacral agenesis. CASE: We report a 28-year-old male patient with Currarino syndrome due to a heterozygous novel frame-shift mutation c.336dupG (p.P113fsX224) in the homeoboxHLXB9 gene. CONCLUSIONS: Molecular diagnostics may be helpful in cases of Hirschsprung's disease accompanied by other symptoms suggestive for Currarino syndrome, since it can lead to major complications such as perianal sepsis, meningitis, and malignant transformation.

Abnormalities, Multiple↗
PubMed2006

Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation.

Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with the ubiquitin-proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 (MMP-2) gene promoter and represses transcription by recruitment of the histone deacetylase 3 (HDAC3), the nuclear receptor corepressor (NCoR), and deacetylation of histones bound to the promoter. Both normal and expanded AT3 physiologically interacted with HDAC3 and NCoR in a SCA3 cell model and human pons tissue; however, normal AT3-containing protein complexes showed increased histone deacetylase activity, whereas expanded AT3-containing complexes had reduced deacetylase activity. Consistently, histone analyses revealed an increased acetylation of total histone H3 in expanded AT3-expressing cells and human SCA3 pons. Expanded AT3 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of HDAC3, NCoR, and deacetylation of the promoter, allowing aberrant MMP-2 transcription via the transcription factor GATA-2. For transcriptional repression normal AT3 cooperates with HDAC3 and requires its intact ubiquitin-interacting motifs (UIMs), whereas aberrant transcriptional activation by expanded AT3 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain. These findings demonstrate that normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function. Expanded AT3 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions.

Amino Acid Motifs↗
PubMed2006

Homocysteine and carotid intima-media thickness in a german population: lack of clinical relevance.

BACKGROUND AND PURPOSE: Common carotid artery intima-media thickness (CCA IMT) is a predictor of stroke. This study aimed to analyze whether homocysteine (Hcys) metabolism influences CCA IMT. METHODS: We analyzed the association of personal, clinical, and biochemical data (multivariate analysis) and of 9 polymorphisms involved in Hcys metabolism (ANOVA) with CCA IMT in 714 individuals of 187 families. RESULTS: CCA IMT was significantly predicted by age, sex, creatinine levels, lipoprotein(a) levels, pack-years of smoking, the presence of hypertension, and the presence of diabetes mellitus but not by Hcys levels. Homozygosity for the T allele of the polymorphism methylenetetrahydrofolate reductase c.677C>T was significantly associated with higher Hcys levels but not with a higher CCA IMT. CONCLUSIONS: These data do not support the thesis that elevated Hcys levels are causally involved in cerebrovascular disease.

Aged↗
PubMed2006

Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells.

Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu(2+), and Cu(2+) supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu(2+) chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu(2+).

Animals↗
PubMed2006

Restricted ocular exploration does not seem to explain simultanagnosia.

One major function of parietal cortex is to direct our attention towards salient stimuli. The present data suggest that it also plays an important role in visual gestalt perception. Patients with simultanagnosia following lesions in this area are not able to extract the meaning of a visual scene whereas being perfectly able to recognise individual objects of this scene. We tested two patients with simultanagnosia with hierarchical Navon figures combined with eye movements recordings. The patients' performance allowed us to compare directly the scan paths in trials in which the global letter shape was recognised with trials in which the global letter shape was not recognised. We did not find any obvious differences in the eye movement pattern related to the two perceptual situations. The two patients did not show a significant problem in shifting their eyes (and thus possibly also their attentional focus) to all aspects of the complex visual stimulus when attempting to bind together the different elements of spatially distributed information. The results demonstrate that restricted ocular exploration cannot be the reason for the patients' inability to recognise the global shape of stimuli. Our data rather suggest a role of parietal cortex in visual gestalt perception that is beyond its role of directing attention towards relevant objects.

Agnosia↗
PubMed2006

Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-3. There is growing evidence that neuronal electrophysiological properties are altered in a variety of polyglutamine diseases such as Huntington's disease and SCA1 and that these alterations may contribute to disturbances of neuronal function prior to neurodegeneration. To elucidate possible electrophysiological changes in SCA3, we generated a stable PC12 cell model with inducible expression of normal and mutant human full-length ataxin-3 and analyzed the electrophysiological properties after induction of the recombinant ataxin-3 expression. Neuronally differentiated PC12 cells expressing the expanded form of ataxin-3 showed significantly decreased viabilities and developed ultrastructural changes resembling human SCA3. Prior to neuronal cell death, we found a significant reduction of the resting membrane potential and a hyperpolarizing shift of the activation curve of the delayed rectifier potassium current. These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3.

Analysis of Variance↗
PubMed2006

Higher sensitivity in the detection of inflammatory brain lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis using high field MRI: an intraindividual comparison of 1.5 T with 3.0 T.

The purpose of this study was to determine the sensitivities in the detection of inflammatory lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis at 3.0 T and 1.5 T. MR imaging of 40 patients at both field strengths was performed in separate sessions including contiguous axial slices of T2 turbo spin-echo (T2 TSE), fluid-attenuated-inversion-recovery (FLAIR) and pre- and postcontrast T1 spin-echo (T1 SE). Inflammatory lesions > 3 mm in size were counted and categorized according to their anatomic location. Lesion conspicuity was assessed on a five-point scale. At 3.0 T, 13% more white matter lesions could be identified on the FLAIR sequence and on the T2 TSE sequence. Compared to 1.5 T 7.5% more contrast-enhancing lesions were detected at 3.0 T. The higher detection rate at 3.0 T was significant for the infratentorial (p = 0.02) and juxtacortical (p < 0.01) region on the FLAIR as well as for the infratentorial (p = 0.03), juxtacortical (p = 0.02) and periventricular (p = 0.03) region on the T2 TSE sequence. The lesion conspicuity was significantly better at 3.0 T for FLAIR and T2 TSE sequences (p<0.01; p=0.01). In conclusion, high-field MRI at 3.0 T provides a significantly higher detection rate of inflammatory brain lesions especially in the infratentorial, juxtacortical and periventricular anatomic region.

Adolescent↗
PubMed2006

Transcriptional changes in multiple system atrophy and Parkinson's disease putamen.

Multiple system atrophy (MSA) and sporadic, non-mendelian Parkinson's disease (PD) are progressive neurodegenerative disorders with overlapping clinical symptoms and pathology. The etiology of both disorders is unknown, and complex combinations of multiple susceptibility genes and environmental factors are thought to be involved. Both disorders are characterized by ubiquitous alpha-synuclein aggregates in distinct regions and cell types of the central nervous system. In PD, alpha-synuclein-positive aggregates appear to be largely neuronal while in MSA oligodendroglial inclusions prevail. In PD patients, the alpha-synuclein pathology is thought to evolve in a rather regular pattern, starting in the brainstem and olfactory bulb and extending gradually onto the substantia nigra and ultimately the cerebral cortex while the cerebellum is largely spared. MSA pathology has not been graded in a similar way yet; neuropathological analyses revealed neurodegeneration and gliosis primarily in the brainstem, midbrain and basal ganglia and the cerebellum, while the cortex is largely spared. To identify disease-specific transcriptional patterns in MSA, we chose CNS regions differentially affected in MSA and PD for comparative gene expression profiling: putamen, cerebellum and occipital cortex. Four genes were regulated in both MSA and PD putamen and twelve in MSA and PD cerebellum. Regulated transcripts were validated using real-time quantitative RT-PCR, and immunohistochemistry was performed for the most significantly downregulated transcripts in MSA and PD putamen, GPR86 and RGS14, associated with G protein signaling and transcriptional regulation.

Aged↗
PubMed2006

Serial MRI of limbic encephalitis.

INTRODUCTION: The aim of the study was to analyze serial magnetic resonance imaging (MRI) scans in patients with various forms of limbic encephalitis (LE) in order to evaluate whether, and at what time point, MRI findings support the diagnosis of LE. METHODS: Serial MRI scans (1 day to 15 years after the onset of symptoms) of 20 patients with LE were retrospectively evaluated. Of these 20 patients, 16 had definite LE (histopathological limbic inflammation, n=6; onconeural antibodies, n=5; voltage-gated potassium channel antibodies, n=3; malignant tumors, n=5), and 4 possible LE because they met the clinical criteria but had no typical antibodies or tumors. RESULTS: Of 13 patients who were studied with MRI within 3 months after the onset of symptoms, 11 had swollen temporomesial structures (unilateral, n=7; bilateral, n=4). After up to 9 months, the swelling had resolved in nine of ten re-evaluated patients. Of seven patients who were initially studied with MRI more than 3 months after disease onset, three had swollen temporomesial structures, one had a hyperintense, normal-sized hippocampus, and three had hyperintense and atrophic temporomesial structures. CONCLUSION: LE starts as an acute disease with uni- or bilateral swollen temporomesial structures that are hyperintense on fluid attenuation inversion recovery and T2-weighted sequences. Swelling and hyperintensity may persist over months to years, but in most cases progressive temporomesial atrophy develops.

Adult↗
PubMed2006

Imaging of inflammatory lesions at 3.0 Tesla in patients with clinically isolated syndromes suggestive of multiple sclerosis: a comparison of fluid-attenuated inversion recovery with T2 turbo spin-echo.

The aims of this study were to determine and compare the sensitivity of T2 turbo spin-echo (T2 TSE) and fluid-attenuated inversion recovery (FLAIR) sequences at 3.0 T in the detection of inflammatory lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis. Forty-nine patients were examined with a 3.0 T MRI system using 5 mm axial sections of T2 TSE (2:19 min), FLAIR (4:00 min) and pre- and postcontrast T1 spin-echo sequences (3:37 min). Brain lesions were counted and categorized according to their anatomic location. Patients were classified according to Barkhof MRI criteria for FLAIR and T2 TSE sequences. The FLAIR sequence detected more lesions in every anatomic region except for the infratentorial region. The higher sensitivity was significant for the total number of lesions (p<0.01), the juxtacortical (p<0.01), and the periventricular (p=0.01) region. A 9% increase of infratentorial lesions using the T2 TSE sequence was not significant. The higher sensitivity using the FLAIR sequence resulted in one additional MRI criterion in nine patients, whereas the better detection of infratentorial lesions using the T2 TSE sequence resulted in additional MRI criteria in three patients. In conclusion, FLAIR provides the highest sensitivity when compared with the T2 TSE, although T2 TSE still has a diagnostic relevance in terms of MRI criteria classification.

Adolescent↗
PubMed2006

Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms.

There is compelling evidence that Alzheimer's disease (AD) amyloid-beta (Abeta) deposition is associated with a local inflammatory response, which is initiated by the activation of microglia and the recruitment of astrocytes. These cells secrete a number of cytokines and neurotoxic products that may contribute to neuronal degeneration and cell death. It has been documented that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk for developing AD and delay the onset of the disease. The mechanism behind these NSAIDs is still controversial and several hypotheses have been raised, including changes in the amyloid precursor protein (APP) metabolism, in Abeta aggregation and a decrease in inflammatory mediators. Recently, it was proposed that some NSAIDs might activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma belongs to a family of nuclear receptors that are able to regulate the transcription of pro-inflammatory molecules, such as iNOS. The activation of PPAR-gamma has been recently reported to reduce Abeta levels in cell culture and AD animal models. The implication of PPAR-gamma in the control of Abeta-induced inflammation suggests a new target for AD therapy and emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.

Alzheimer Disease↗
PubMed2006

Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

Alzheimer Disease↗
PubMed2006

Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.

Aged↗