Publications by authors named "Moritz D Brandt"

28 Publications

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[Insomnia in the context of neurological diseases].

Authors:
Moritz D Brandt

Fortschr Neurol Psychiatr 2021 Jun 18;89(6):314-328. Epub 2021 Jun 18.

This article provides an overview of the prevalence, cause and treatment of insomnia in common neurological diseases (restless legs syndrome, stroke, multiple sclerosis, Parkinson´s disease and Alzheimer´s disease) with an additional focus on the bidirectional relationship between sleep and neurological disorders.Insomnia is prevalent, but frequently unrecognized in the context of neurological diseases. Although it is widely known that sleep has a relevant impact on quality of life in general and cerebral function in particular, sleep disorders receive little attention in the prevention and treatment of neurological diseases.
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http://dx.doi.org/10.1055/a-1309-0793DOI Listing
June 2021

Lithium: A therapeutic option in Alzheimer's disease and its prodromal stages?

Neurosci Lett 2021 Jun 10:136044. Epub 2021 Jun 10.

Department of Psychiatry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.

Experimental data reveal that lithium is capable of attenuating Alzheimer's disease pathology and stimulating adult hippocampal neurogenesis. Clinical studies show procognitive effects in lithium-treated patients with amnestic MCI and Alzheimer's disease. These procognitive effects are associated with changes of CSF biomarkers of Alzheimer's disease. After 3 months of lithium treatment with low lithium levels, a slowing of cognitive decline is observed in patients with Alzheimer's disease. In patients with amnestic MCI with low-dose lithium treatment a trend of a reduced Alzheimer's disease conversion rate and longer cognitive stability was reported. Thus, lithium might be a therapeutic option in the treatment of Alzheimer's disease and its prodromal stages. But its therapeutic efficacy needs further evaluation. Further studies should include head-to-head comparisons with approved dementia treatment options. Due to lithium's therapeutic toxicity a thorough preselection of patients and a closely therapeutic monitoring is necessary. This manuscript is based on a literature review.
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http://dx.doi.org/10.1016/j.neulet.2021.136044DOI Listing
June 2021

Relation of retinal and hippocampal thickness in patients with amnestic mild cognitive impairment and healthy controls.

Brain Behav 2021 05 15;11(5):e02035. Epub 2021 Jan 15.

German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.

Objective: Investigating retinal thickness may complement existing biological markers for dementia and other neurodegenerative diseases. Although retinal thinning is predictive for cognitive decline, it remains to be investigated if and how this feature aligns with neurodegeneration elsewhere in the brain, specifically in early disease stages.

Methods: Using optical coherence tomography and magnetic resonance imaging, we examined retinal thickness as well as hippocampal structure in patients with amnestic mild cognitive impairment and healthy controls.

Results: The groups did not differ in hippocampal and retinal thickness measures. However, we detected a correlation of peripapillary retinal nerve fiber layer thickness and hippocampal thickness in healthy people but not in cognitively impaired patients. The ratio of hippocampus to retina thickness was significantly smaller in patients with mild cognitive impairment and correlated positively with cognitive performance.

Conclusions: Different temporal trajectories of neurodegeneration may disrupt transregional brain structure associations in patients with amnestic mild cognitive impairment.
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http://dx.doi.org/10.1002/brb3.2035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119792PMC
May 2021

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

Front Neurosci 2020 6;14:689. Epub 2020 Aug 6.

Department of Neurology, University of Rostock, Rostock, Germany.

Background: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance.

Objective: This analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD.

Methods: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated.

Results: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, = 0.020, unpaired two-sided -test).

Conclusion: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.
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http://dx.doi.org/10.3389/fnins.2020.00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438827PMC
August 2020

MDS criteria for the diagnosis of progressive supranuclear palsy overemphasize Richardson syndrome.

Ann Clin Transl Neurol 2020 09 31;7(9):1702-1707. Epub 2020 Jul 31.

Department of Neurology, Technische Universität Dresden, Dresden, Germany.

MDS-criteria for clinical diagnosis of progressive supranuclear palsy (PSP) were recently published, their usability in a classical clinical setting is yet unknown. We retrospectively applied the new criteria using PSP patients' case files. Assignment of PSP diagnosis according to the MDS-criteria was possible in 57/80 cases. The main difference to former specialist classification was a lower phenotype diversity and higher representation of PSP-RS. Furthermore, we examined those patients' brain MRIs. While neuroradiologists' reports were suggestive of PSP only in 11/62, the analysis of a blinded rater revealed pathological midbrain-to-pons-ratio in 40/62 implying this imaging feature is often missed.
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http://dx.doi.org/10.1002/acn3.51065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480918PMC
September 2020

Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

Stem Cells 2020 09 25;38(9):1188-1201. Epub 2020 Jun 25.

Department of Neurology, University of Rostock, Rostock, Germany.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
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http://dx.doi.org/10.1002/stem.3232DOI Listing
September 2020

Asymmetry of Periodic Leg Movements in Sleep (PLMS) in Parkinson's Disease.

J Parkinsons Dis 2020 ;10(1):255-266

Department of Neurology, University of Rostock, Rostock, Germany.

Background: Periodic limb movements in sleep (PLMS) are repetitive movements usually of the legs strongly associated with Restless-legs syndrome (RLS), which appear more frequently in males, older age and other sleep disturbances, such as sleep-disordered breathing (SDB). Patients with Parkinson's disease (PD) suffer from various sleep disturbances including REM sleep behavior disorder, RLS and PLMS. Although a dopaminergic pathophysiology of PLMS is discussed, no systematic data on PLMS side-to-side distribution in PD and its correlation with asymmetry of motor symptoms are available.

Objective: This study aimed at elucidating PLMS asymmetry in correlation to that of motor symptoms in PD compared to SDB and RLS.

Methods: Cross-sectional, retrospective analysis of two polysomnography (PSG) recordings per patient scoring PLMS separately for both legs.

Results: Of 105 patients (44 PD, 44 age- and sex-matched SDB and 17 RLS patients) PLMS measures (number of PLM, PLM-Index, PLM-arousal index) showed significant side-to-side differences in all disease entities in both PSGs (P < 0.001; Wilcoxon rank test). PLM-Index asymmetry (PLM-I difference of >5/h between both sides) was observed less frequently in PD (34% of patients) compared to RLS (77% , P < 0.05) and SDB (59% , P < 0.05; χ2 test). In asymmetric PD patients, predominant side of PLMS was more stable than in SDB and RLS comparing the two PSGs, but we did not detect an agreement between PLMS predominant side with that of motor symptoms in PD patients.

Conclusions: Only the minority of PD patients shows asymmetric PLMS distribution with relatively high night-to-night stability but no correlation with motor symptom asymmetry.
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http://dx.doi.org/10.3233/JPD-191667DOI Listing
April 2021

Thalamic GABA may modulate cognitive control in restless legs syndrome.

Neurosci Lett 2019 11 11;712:134494. Epub 2019 Sep 11.

Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Technische Universität Dresden, Schubertstr. 42, 01307 Dresden, Germany. Electronic address:

The restless legs syndrome (RLS) has repeatedly, but not exclusively, been associated with functional thalamic changes as well as changes in GABAergic neurotransmission. This has been linked to the well-known sensory-motor symptoms, but it has never been investigated whether those factors also account for potential cognitive changes in RLS, even though they are known to play an important role for cognitive control. To investigate the potential relationship between thalamic GABA concentrations and cognitive control in n = 25 RLS patients; a neuropsychological experimental paradigm was used in combination with magnetic resonance spectroscopy (MRS). Compared to n = 31 healthy controls, RLS patients displayed reduced cognitive control capacities, which were most likely based on working memory deficits. On the neurobiochemical level, (relatively) elevated thalamic GABA levels attenuated control deficits only in the RLS group, even though there were no group differences with respect to overall GABA levels. Given that RLS patients are known to display thalamic hyperactivity and associated thalamic hypoconnectivity, (relatively) higher GABA levels may have helped RLS patients to "compensate" for this pathological factor. Our findings specify the functional relevance of thalamic GABAergic neurotransmission for cognition in RLS, even though changes in GABAergic neurotransmission might not be the ultimate cause of control deficits.
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http://dx.doi.org/10.1016/j.neulet.2019.134494DOI Listing
November 2019

Specific intranasal and central trigeminal electrophysiological responses in Parkinson's disease.

J Neurol 2019 Dec 26;266(12):2942-2951. Epub 2019 Aug 26.

Research Chair in Chemosensory Neuroanatomy, Department of Anatomy, Université du Québec à Trois-Rivières (UQTR), Trois-Rivières, QC, Canada.

Olfactory dysfunction is a frequent early non-motor symptom of Parkinson's disease (PD). There is evidence that with regard to trigeminal perception, PD-related olfactory dysfunction is different from other olfactory disorders. More specifically, trigeminal sensitivity, when measured behaviorally, was unimpaired in PD patients as opposed to patients with non-Parkinsonian olfactory dysfunction (NPOD). We sought to investigate the trigeminal pathway by measuring electrophysiological recordings from the nasal epithelium and EEG-derived event-related potentials in response to a specific trigeminal stimulus in 21 PD patients and compare them to 23 patients with NPOD and 25 controls (C). The peripheral trigeminal response, as measured by the negative-mucosa potential, showed no difference between patients with PD and controls whereas PD patients showed faster responses than patients with NPOD, the latter having shown slower and larger responses than controls (18 PD, 14 NPOD, 20 C). The central trigeminal response, as measured by event-related potentials, revealed larger early component response in PD patients compared to patients with NPOD (15 PD, 21 NPOD, 23 C). As expected, psychophysical olfactory testing showed impaired olfactory function in both groups of patients as opposed to controls. Discriminant analysis revealed a model that could predict group membership for 80% of participants based on the negative-mucosa potential latency, olfactory threshold and discrimination tests. These results provide novel insights into the pattern of trigeminal activation in PD which will help to differentiate PD-related olfactory loss from NPOD, a crucial step towards establishing early screening batteries for PD including smell tests.
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http://dx.doi.org/10.1007/s00415-019-09517-4DOI Listing
December 2019

Cognitive impairment and medial temporal lobe structure in young adults with a depressive episode.

J Affect Disord 2018 09 24;237:112-117. Epub 2018 May 24.

Department of Psychiatry, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Neurology (Neustadt/Trachau), Städtisches Klinikum Dresden, Industriestr. 40, 01129 Dresden, Germany.

Background: Cognitive deficits are common in patients with a depressive episode although the predictors for their development and severity remain elusive. We investigated whether subjective and objective cognitive impairment in young depressed adults would be associated with cortical thinning in medial temporal subregions.

Methods: High-resolution magnetic resonance imaging, cortical unfolding data analysis, and comprehensive assessments of subjective and objective cognitive abilities were performed on 27 young patients with a depressive episode (mean age: 29.0 ± 5.8 years) and 23 older participants without a history of a depressive disorder but amnestic mild cognitive impairment (68.5 ± 6.6 years) or normal cognition (65.2 ± 8.7 years).

Results: Thickness reductions in parahippocampal, perirhinal and fusiform cortices were associated with subjective memory deficits only among young patients with a depressive episode and a measurable cognitive impairment.

Limitations: Long-term longitudinal data would be desirable to determine the trajectories of cognitive impairment associated with depression in patients with or without cortical structure changes.

Conclusions: The presence of clinically significant cognitive deficits in young people with a depressive episode may identify a patient population with extrahippocampal cortical thinning.
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http://dx.doi.org/10.1016/j.jad.2018.05.015DOI Listing
September 2018

RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming.

Clin Neurophysiol 2018 01 6;129(1):112-121. Epub 2017 Nov 6.

Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Schubertstr. 42, 01307 Dresden, Germany.

Objective: The restless legs syndrome (RLS) is characterized by sensory-motor symptoms which usually occur predominantly at rest in the evening and at night. It is assumed that this circadian rhythm is caused by low dopamine levels in the evening. Yet, it has never been investigated whether RLS patients show diurnal variations in cognitive functions modulated by dopamine and what neurophysiological and functional neuroanatomical processes underlie such modulations.

Methods: We used a Simon task combined with EEG and source localization to investigate whether top-down response selection and/or automatic visuo-motor priming are subject to diurnal changes in RLS patients, as compared to matched healthy controls.

Results: We found that RLS patients showed better task performance due to reduced visuo-motor priming in the evening, as reflected by smaller early lateralized readiness potential (e-LRP) amplitudes and decreased activation of the superior parietal cortex and premotor cortex. Top-down response selection and early attentional processing were unaffected by RLS.

Conclusions: Counterintuitively, RLS patients show enhanced task performance in the evening, i.e. when experiencing dopaminergic deficiency. Yet, this may be explained by deficits in visuo-motor priming that lead to reduced false response tendencies.

Significance: This study reveals a counterintuitive circadian variation of cognitive functions in RLS patients.
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http://dx.doi.org/10.1016/j.clinph.2017.10.022DOI Listing
January 2018

Early Postnatal but Not Late Adult Neurogenesis Is Impaired in the Pitx3-Mutant Animal Model of Parkinson's Disease.

Front Neurosci 2017 24;11:471. Epub 2017 Aug 24.

German Center for Neurodegenerative Diseases RostockRostock, Germany.

The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinson's disease (PD). As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN) in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ) and dentate gyrus (DG). Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD ( mice), which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA). Proliferating cells were labeled with BrdU in mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8-42 weeks) indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN), which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running) almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old mice to a number comparable to that of wild-type mice, abolishing the slight reduction of baseline neurogenesis at this age. The described age-dependent susceptibility of adult neurogenesis to PD-like dopaminergic degeneration and its responsiveness to physical activity might have implications for the understanding of the pathophysiology and treatment of non-motor symptoms in PD.
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http://dx.doi.org/10.3389/fnins.2017.00471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573808PMC
August 2017

Neurophysiological mechanisms of circadian cognitive control in RLS patients - an EEG source localization study.

Neuroimage Clin 2017 15;15:644-652. Epub 2017 Jun 15.

Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Schubertstr. 42, 01307 Dresden, Germany.

The circadian variation of sensory and motor symptoms with increasing severity in the evening and at night is a key diagnostic feature/symptom of the restless legs syndrome (RLS). Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, it has remained unclear whether cognitive performance of RLS patients declines in the evening and which neurophysiological mechanisms are affected by the circadian variation. In the current study, we examined daytime effects (morning vs. evening) on cognitive performance in RLS patients (n = 33) compared to healthy controls (n = 29) by analyzing flanker interference effects in combination with EEG and source localization techniques. RLS patients showed larger flanker interference effects in the evening than in the morning (p = .023), while healthy controls did not display a comparable circadian variation. In line with this, the neurophysiological data showed smaller N1 amplitudes in RLS patients compared to controls in the interfering task condition in the evening (p = .042), but not in the morning. The results demonstrate diurnal cognitive changes in RLS patients with intensified impairments in the evening. It seems that not all dopamine-regulated cognitive processes are altered in RLS and thus show daytime-dependent impairments. Instead, the daytime-related cognitive impairment emerges from attentional selection processes within the extra-striate visual cortex, but not from later cognitive processes such as conflict monitoring and response selection.
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http://dx.doi.org/10.1016/j.nicl.2017.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480014PMC
April 2018

MAPT mutation associated with frontotemporal dementia and parkinsonism (FTDP-17).

Int Psychogeriatr 2017 05 1;29(5):869-871. Epub 2016 Dec 1.

Department of Psychiatry,University Hospital Carl Gustav Carus,Technische Universität Dresden,Dresden,Germany.

We present a 56-year-old patient suffering from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The history included a three-generation pedigree and the patient was found to be a mutation carrier. The diagnosis was hindered by late appearance of the hypokinetic movement disorder. For clinicians, it is important to consider rare neurodegenerative disease variants in early-onset familial dementia syndromes with behavioral, cognitive, and motor symptoms.
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http://dx.doi.org/10.1017/S1041610216002192DOI Listing
May 2017

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity.

Front Neurosci 2016 3;10:362. Epub 2016 Aug 3.

Genomics of Regeneration, Center for Regenerative Therapies Dresden (CRTD), Technische Universität DresdenDresden, Germany; Genomics of Regeneration, German Center for Neurodegenerative Diseases (DZNE) DresdenDresden, Germany.

The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. Evidence exists for several mechanisms including cell cycle shortening, reduced cell death and stem cell recruitment, but as yet no model can account for all observations. An appreciation of how the cells proliferate, however, is crucial to our ability to model the neurogenic process and predict its behavior in response to pro-neurogenic stimuli. In a recent study, we addressed modulation of the cell cycle length as one possible mode of regulation of precursor cell proliferation in running mice. Our results indicated that the observed increase in number of proliferating cells could not be explained through a shortening of the cell cycle. We must therefore consider other mechanisms by which physical activity leads to enhanced precursor cell proliferation. Here we review the evidence for and against several different hypotheses and discuss the implications for future research in the field.
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http://dx.doi.org/10.3389/fnins.2016.00362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971098PMC
August 2016

Reduced intraepidermal nerve fiber density in patients with REM sleep behavior disorder.

Parkinsonism Relat Disord 2016 08 6;29:10-6. Epub 2016 Jun 6.

Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; Jülich Aachen Research Alliance (JARA) BRAIN Institute II, Research Center Jülich GmbH and RWTH Aachen, Germany. Electronic address:

Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) has been increasingly acknowledged to be an initial specific manifestation of alpha-synucleinopathies such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Recent findings suggest that cutaneous abnormalities like small fiber neuropathy and alpha-synuclein deposition might reflect brain pathology and might function as early biomarkers in PD. This is the first study to elucidate whether iRBD patients already suffer from distinctive cutaneous features.

Methods: We examined skin punch biopsies from the distal leg of 18 iRBD patients and 22 age- and sex-matched controls using immunohistochemistry and microscopy. Further clinical evaluation included structured interviews, clinical motor and non-motor questionnaires and rating scales (e.g. Unified Parkinson's disease rating scale [UPDRS], non-motor symptoms questionnaire [NMS-Quest] and Beck Depression Inventory, Epworth Sleepiness Scale, evaluation of cognitive and olfactory functioning as well as blood samples.

Results: Intraepidermal nerve fiber density (IEFND) was reduced in iRBD patients compared to controls (p = 0.037), whereas the axon swelling ratio did not differ between groups. Patients with iRBD reported non-motor symptoms more frequently than controls (UPDRS I, NMS-Quest). Olfaction and daytime sleepiness differed between both groups, whereas there were no differences regarding cognition.

Conclusions: These in vivo findings demonstrate small fiber neuropathy in iRBD patients that are associated with non-motor symptoms indicating that peripheral abnormalities may occur early in iRBD. However, the prognostic value has to be further investigated in longitudinal studies.
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http://dx.doi.org/10.1016/j.parkreldis.2016.06.003DOI Listing
August 2016

The nonmotor features of Parkinson's disease: pathophysiology and management advances.

Curr Opin Neurol 2016 Aug;29(4):467-73

Department of Neurology, Technical University Dresden, Dresden, Germany.

Purpose Of Review: In recent years progress has been made in the detection and evaluation of nonmotor symptoms in Parkinson's disease. The pathophysiology is better understood and new treatment is available, which will be discussed in this review.

Recent Findings: The most intriguing recent finding is the fact that Parkinson's disease may be a spreading disease. From the environment a toxin, bacteria, or virus may start in genetically susceptible patients a cascade of α-synuclein aggregation which reaches via the olfactory and the enteric system of the gut the brain where further spreading causes symptoms, such as sleep disturbances, motor impairment, and neuropsychiatric symptoms. New treatment should address the abnormal α-synuclein folding. If this would be achieved premotor signs, such as hyposmia, rapid eye movement-sleep behavior disorder, constipation, or depression may be a kind of biomarkers which allow together with other diagnostic tools, such as parenchymal sonography, iodobenzamide-scintigraphy and dopamine transporter scans the prediction whether somebody might be under way to develop the full-blown Parkinson's disease syndrome.

Summary: Parkinson's disease seems to be a spreading disease which causes not only a dopaminergic deficit as major cause for the movement disorder but also impairs function of many other brain centers which leads to a multitransmitter malfunction.
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http://dx.doi.org/10.1097/WCO.0000000000000348DOI Listing
August 2016

Preventive brain radio-chemotherapy alters plasticity associated metabolite profile in the hippocampus but seems to not affect spatial memory in young leukemia patients.

Brain Behav 2015 Sep 14;5(9):e00368. Epub 2015 Jul 14.

Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden 01307, Dresden, Germany ; German Center for Neurodegenerative Diseases (DZNE) Dresden 10307, Dresden, Germany ; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden 01307, Dresden, Germany.

Background: Neuronal plasticity leading to evolving reorganization of the neuronal network during entire lifespan plays an important role for brain function especially memory performance. Adult neurogenesis occurring in the dentate gyrus of the hippocampus represents the maximal way of network reorganization. Brain radio-chemotherapy strongly inhibits adult hippocampal neurogenesis in mice leading to impaired spatial memory.

Methods: To elucidate the effects of CNS radio-chemotherapy on hippocampal plasticity and function in humans, we performed a longitudinal pilot study using 3T proton magnetic resonance spectroscopy ((1)H-MRS) and virtual water-maze-tests in 10 de-novo patients with acute lymphoblastic leukemia undergoing preventive whole brain radio-chemotherapy. Patients were examined before, during and after treatment.

Results: CNS radio-chemotherapy did neither affect recall performance in probe trails nor flexible (reversal) relearning of a new target position over a time frame of 10 weeks measured by longitudinal virtual water-maze-testing, but provoked hippocampus-specific decrease in choline as a metabolite associated with cellular plasticity in (1)H-MRS.

Conclusion: Albeit this pilot study needs to be followed up to definitely resolve the question about the functional role of adult human neurogenesis, the presented data suggest that (1)H-MRS allows the detection of neurogenesis-associated plasticity in the human brain.
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http://dx.doi.org/10.1002/brb3.368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589814PMC
September 2015

Acute effects of wheel running on adult hippocampal precursor cells in mice are not caused by changes in cell cycle length or S phase length.

Front Neurosci 2014 6;8:314. Epub 2014 Oct 6.

Genomics of Regeneration, CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden Dresden, Germany ; Genomics of Regeneration, German Center for Neurodegenerative Diseases (DZNE) Dresden Dresden, Germany.

Exercise stimulates cellular brain plasticity by extending the pool of proliferating neural precursor cells in the adult hippocampus. This effect has been investigated extensively, but the most immediate cellular effect induced by exercise that results in this acute increase in the number of cycling cells remained unclear. In the developing brain as well as adult pathological models, cell cycle alterations have a major influence on the balance between proliferative and neurogenic divisions. In this study we investigated whether this might also apply to the acute physiological pro-neurogenic stimulus of physical exercise in adulthood. Do changes in cell cycle precede the measurable increase in proliferation? After 5 days of voluntary wheel running, however, we measured only a very small, statistically not significant acceleration in cell cycle, which could not quantitatively explain the observed increase in proliferating cells after exercise. Thus, at this acute stage, changes at the level of cell cycle control is not the primary causal mechanism for the expansion of the precursor cell population, although with time after the stimulus changes in cell cycle of the entire population of labeled cells might be the result of the expanded pool of cells that have progressed to the advanced neurogenic stages with shorter cell cycle length.
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http://dx.doi.org/10.3389/fnins.2014.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186268PMC
October 2014

Sleep disorders in Parkinson's disease.

J Parkinsons Dis 2014 ;4(2):211-21

Department of Neurology, Dresden University of Technology, Dresden, Germany.

Sleep disorders in patients with Parkinson's disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD.
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http://dx.doi.org/10.3233/JPD-130301DOI Listing
December 2014

Brief report: Adult hippocampal precursor cells shorten S-phase and total cell cycle length during neuronal differentiation.

Stem Cells 2012 Dec;30(12):2843-7

Division of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.

Cell cycle analyses of adult hippocampal neural stem and precursor cells in vivo are challenging, as there is no temporal or local discrimination of different precursor cell populations. All commonly used techniques to determine the cell cycle length of proliferating cells in the adult hippocampus do not allow discrimination between different cell types. Here, we introduce a novel procedure to precisely calculate cell cycle phase lengths of distinct precursor cell populations in vivo and thereby demonstrate a large heterogeneity of cell cycle kinetics within the pool of adult hippocampal precursor cells. Proliferating NeuroD1(+) cells exhibited a significantly faster S-phase progression (T(s) = 10.1 ± 0.6 hours) and shorter total cell cycle length (T(c) = 22.6 ± 0.1 hours) than NeuroD1(-) cells (T(s) = 13.5 ± 0.8 hours, T(c) = 27.0 ± 0.5 hours; p < .05). Dividing glial fibrillary acidic protein (GFAP(+)) cells also showed significantly shorter mean T(s) of 9.7 ± 0.6 hours and T(c) of 22.8 ± 0.5 hours compared to the rest of uncommitted NeuroD1(-) precursors (p < .01). Together, NeuroD1(+) neuronal progenitors and mitotic GFAP(+) radial glia-like cells divide significantly faster than amplifying neural progenitor cells by accelerating their S-phase. S-phase duration seems to determine cell cycle length in the adult hippocampus.
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http://dx.doi.org/10.1002/stem.1244DOI Listing
December 2012

Adult hippocampal neurogenesis and plasticity in the infrapyramidal bundle of the mossy fiber projection: I. Co-regulation by activity.

Front Neurosci 2011 27;5:107. Epub 2011 Sep 27.

Genomics of Regeneration, Center for Regenerative Therapies Dresden Dresden, Germany.

BESIDES THE MASSIVE PLASTICITY AT THE LEVEL OF SYNAPSES, WE FIND IN THE HIPPOCAMPUS OF ADULT MICE AND RATS TWO SYSTEMS WITH VERY STRONG MACROSCOPIC STRUCTURAL PLASTICITY: adult neurogenesis, that is the lifelong generation of new granule cells, and dynamic changes in the mossy fibers linking the dentate gyrus to area CA3. In particular the anatomy of the infrapyramidal mossy fiber tract (IMF) changes in response to a variety of extrinsic and intrinsic stimuli. Because mossy fibers are the axons of granule cells, the question arises whether these two types of plasticity are linked. Using immunohistochemistry for markers associated with axonal growth and pro-opiomelanocortin (POMC)-GFP mice to visualize the post-mitotic maturation phase of adult hippocampal neurogenesis, we found that newly generated mossy fibers preferentially but not exclusively contribute to the IMF. The neurogenic stimulus of an enriched environment increased the volume of the IMF. In addition, the IMF grew with a time course consistent with axonal outgrowth from the newborn neurons after the induction of neurogenic seizures using kainate. These results indicate that two aspects of plasticity in the adult hippocampus, mossy fiber size and neurogenesis, are related and may share underlying mechanisms. In a second part of this study, published separately (Krebs et al., 2011) we have addressed the question of whether there is a shared genetics underlying both traits.
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http://dx.doi.org/10.3389/fnins.2011.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180604PMC
November 2011

Adult Hippocampal Neurogenesis and Plasticity in the Infrapyramidal Bundle of the Mossy Fiber Projection: II. Genetic Covariation and Identification of Nos1 as Linking Candidate Gene.

Front Neurosci 2011 21;5:106. Epub 2011 Sep 21.

Genomics of Regeneration, Center for Regenerative Therapies Dresden Dresden, Germany.

The hippocampus of adult rodents harbors two systems exhibiting structural plasticity beyond the level of synapses and dendrites. First, the persistent generation of granule cells (adult neurogenesis); second, dynamic changes in the mossy fibers (MF), in particular in the infrapyramidal mossy fiber (IMF) tract. Because MFs are the axons of granule cells, the question arises whether these two types of plasticity are linked. In the first part of this study (Römer et al., 2011) we have asked how both traits are regulated in relation to each other. In the present part, we asked whether, besides activity-dependent co-regulation, there would also be signs of genetic co-regulation and co-variance. For this purpose we used the BXD panel of recombinant inbred strains of mice, a unique genetic reference population that allows genetic association studies. In 31 BXD strains we did not find correlations between the traits describing the volume of the MF subfields and measures of adult neurogenesis. When we carried out quantitative trait locus mapping for these traits, we found that the map for IMF volume showed little overlap with the maps for the other parts of the projection or for adult neurogenesis, suggesting that to a large degree the IMF is regulated independently. The highest overlapping peak in the genome-wide association maps for IMF volume and the number of new neurons was on distal chromosome 5 (118.3-199.2 Mb) with an LRS score of 5.5 for IMF and 6.0 for new neurons. Within this interval we identified Nos1 (neuronal nitric oxide synthase) as a cis-acting (i.e., presumably autoregulatory) candidate gene. The expression of Nos1 is has been previously linked with both IMF and adult neurogenesis, supporting our findings. Despite explaining on its own very little of the variance in the highly multigenic traits studied, our results suggest Nos1 may play a part in the complex genetic control of adult neurogenesis and IMF morphology.
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http://dx.doi.org/10.3389/fnins.2011.00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177083PMC
November 2011

Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis.

Eur J Neurosci 2010 Oct 8;32(8):1256-64. Epub 2010 Oct 8.

Department of Neurology, Dresden University of Technology, Dresden, Germany.

In adult hippocampal neurogenesis of mice, the proliferation of precursor cells can be stimulated by voluntary exercise (wheel-running). Physical activity has an additional effect on late progenitor cells (type-3) by promoting cell survival and further maturation. Notch1 is a key regulator of various steps in neuronal development, including the inhibition of cell cycle exit and neuronal differentiation of neural stem cells, as well as promoting the survival and dendritic branching of newborn neurons. We here report that physical activity increased the proportion and absolute number of doublecortin(+) (DCX) type-2b and type-3 progenitor cells that showed an activated Notch1 pathway. In contrast, the fraction of dividing cells with nuclear Notch intracellular domain expression indicating an activated Notch pathway was not affected by physical exercise. We used double labeling with two halogenated thymidine analogs, iododeoxyuridine and chlorodeoxyuridine, to distinguish between cell cycle exit and continued division at the progenitor cell level. After 7 days of physical exercise, the proliferative activity of precursor cells was increased, whereas the proportion of type-2b/3 cells re-entering S-phase was reduced. Consistent with this observation, the proportion of DCX(+) cells that expressed the marker of postmitotic immature granule cells (calretinin) was enhanced. Running promotes both the proliferation and cell cycle exit of DCX(+) type-3 precursors, possibly by preferentially stimulating a last neurogenic cell division. These pro-proliferative effects are independent of Notch1, whereas the running-induced survival and cell cycle exit of type-3 progenitor cells might by mediated by Notch1 activity.
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http://dx.doi.org/10.1111/j.1460-9568.2010.07410.xDOI Listing
October 2010

"Silenced" polydendrocytes: a new cell type within the oligodendrocyte progenitor cell population?

Cell Tissue Res 2010 Apr 9;340(1):45-50. Epub 2010 Mar 9.

Department of Neurology and Center for Regenerative Therapies Dresden, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany.

Oligodendrocyte progenitor cells (OPCs) were first described more than two decades ago. Novel labeling techniques have shown them to be cells with more than just progenitor functions, with their classification as a fourth glial cell type in addition to astrocytes, oligodendrocytes, and microglial cells. Another term used for this cell type is polydendrocytes, owing to both their morphology and to the evolving knowledge about their diverse functions. Recently, an exclusive hallmark of neurons--the generation of action potentials--became debatable, because a subset of polydendrocytes was reported to generate action potentials in response to adequate stimuli. The new technique of inducible reporter gene expression has brought new insights into the fate and function of polydendrocytes. In recent studies, so-called "silenced" OPCs were detected in cortical tissue, and which underwent proliferation with subsequent cell cycle exit, but without any signs of differentiation. Within this review, we focus on the identification of this new subset of polydendrocytes and their possible functions within cortical networks.
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http://dx.doi.org/10.1007/s00441-010-0940-5DOI Listing
April 2010

Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice.

Glia 2004 Apr;46(1):41-52

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Berlin, Germany.

In adult hippocampal neurogenesis, new neurons appear to originate from a cell with astrocytic properties expressing glial fibrillary acidic protein (GFAP). Also, new astrocytes are generated in the adult dentate gyrus. Whereas the putative astrocyte-like progenitor cells are consistently S-100beta-negative, many new astrocytes are S-100beta-positive. Thus, it is unclear whether the GFAP-positive progenitor cells are astrocytes in a general sense or rather neural progenitor cells with certain astrocytic characteristics. We therefore investigated the development of GFAP-expressing cells in the context of adult hippocampal neurogenesis. Proliferating cells could be either GFAP-positive or doublecortin-positive (DCX), but never both, indicating two independent populations of dividing cells in the glial and neuronal lineages. Two distinct populations of cells with astroglial properties were detected-one expressing GFAP, the other co-expressing GFAP and S-100beta. We never found S-100beta-cells to be in S-phase. No overlap between neuronal and glial markers was seen at any time point. Thus, astrogenesis occurred in parallel and to some degree independent of adult neurogenesis. The uninterrupted GFAP expression in this lineage, and neuronal markers in the other lineage, argue against a late common precursor for neurogenesis and gliogenesis in the adult hippocampus. Very few newly generated microglia and no new oligodendrocytes were detected. Environmental enrichment and voluntary wheel running-two experimental paradigms with robust stimulatory effects on adult hippocampal neurogenesis-affected hippocampal astrogenesis differentially: Running, but not enrichment, strongly induced net astrogenesis (GFAP/S-100beta), but also GFAP-positive S-100beta-negative cells, which thus appear to be a transiently amplifiable intermediate population within the glial lineage.
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http://dx.doi.org/10.1002/glia.10337DOI Listing
April 2004

Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.

Mol Cell Neurosci 2003 Nov;24(3):603-13

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

We here show that the early postmitotic stage of granule cell development during adult hippocampal neurogenesis is characterized by the transient expression of calretinin (CR). CR expression was detected as early as 1 day after labeling dividing cells with bromodeoxyuridine (BrdU), but not before. Staining for Ki-67 confirmed that no CR-expressing cells were in cell cycle. Early after BrdU, CR colocalized with immature neuronal marker doublecortin; and later with persisting neuronal marker NeuN. BrdU/CR-labeled cells were negative for GABA and GABAA1 receptor, but early on expressed granule cell marker Prox-1. After 6 weeks, no new neurons expressed CR, but all contained calbindin. Stimuli inducing adult neurogenesis have limited (enriched environment), strong (voluntary wheel running), and very strong effects on cell proliferation (kainate-induced seizures). In these models the induction of cell proliferation was paralleled by an increase of CR-positive cells, indicating the stimulus-dependent progression from cell division to a postmitotic stage.
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http://dx.doi.org/10.1016/s1044-7431(03)00207-0DOI Listing
November 2003

Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.

J Comp Neurol 2003 Dec;467(4):455-63

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, 13125 Berlin, Germany.

To study how adult hippocampal neurogenesis might originate from the proliferation of stem or progenitor cells in vivo, we have used transgenic mice expressing green fluorescent protein (GFP) under the nestin promoter to identify these cells. Having described an astrocyte-like type 1 cell with low proliferative activity, a characteristic morphology, vascular end feet, and passive electrophysiological properties, we focused here on the large population of nestin-GFP-expressing type 2 cells, which lack all these features. Type 2 cells were highly proliferative and showed signs suggestive of their involvement in the neuronal lineage. They could be subclassified by the absence (type 2a) or presence (type 2b) of a coexpression of the early neuronal marker doublecortin. A third type of proliferating cells was doublecortin positive but nestin-GFP negative (type 3). We believe that type 2a, 2b, and 3 cells mirror a marker progression during earliest neuronal development. This view is supported by the increasing coexpression of the early granule cell-specific marker Prox-1. The low proliferative activity of type 1 cells showed little change over time or under "neurogenic interventions," such as a challenge by environmental complexity (ENR) or voluntary physical activity (RUN). However, RUN led to a significant increase of type 2 cells labeled with the proliferation marker bromodeoxyuridine (BrdU). ENR did not cause increased cell proliferation or an increased number of BrdU-labeled type 2 cells, but both ENR and RUN resulted in more newly generated cells lacking nestin-GFP immunoreactivity and expressing Prox-1. These findings allow us to break down what was broadly perceived as "proliferation" in earlier experiments into the relative contribution of several cell types, representing the earliest steps of neuronal development.
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http://dx.doi.org/10.1002/cne.10945DOI Listing
December 2003
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