Anne Lesemann

Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation

In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen‐directed T lymphocyte‐mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS‐specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35‐55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX)‐positive immature neurons when compared with controls immunized with CNS‐irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro‐neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, β‐catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen‐specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS.

Physical activity and environmental enrichment regulate the generation of neural precursors in the adult mouse substantia nigra in a dopamine-dependent manner

BackgroundParkinson’s disease is characterized by a continuous loss of neurons within the substantia nigra (SN) leading to a depletion of dopamine. Within the adult SN as a non-neurogenic region, cells with mainly oligodendrocytic precursor characteristics, expressing the neuro-glial antigen-2 (NG2) are continuously generated. Proliferation of these cells is altered in animal models of Parkinson’s disease (PD). Exercise and environmental enrichment re-increase proliferation of NG2+ cells in PD models, however, a possible mechanistic role of dopamine for this increase is not completely understood. NG2+ cells can differentiate into oligodendrocytes but also into microglia and neurons as observed in vitro suggesting a possible hint for endogenous regenerative capacity of the SN. We investigated the role of dopamine in NG2-generation and differentiation in the adult SN stimulated by physical activity and environmental enrichment.ResultsWe used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model for dopamine depletion and analysed newborn cells in the SN at different maturation stages and time points depending on voluntary physical activity, enriched environment and levodopa-treatment. We describe an activity- induced increase of new NG2-positive cells and also mature oligodendrocytes in the SN of healthy mice. Running and enriched environment refused to stimulate NG2-generation and oligodendrogenesis in MPTP-mice, an effect which could be reversed by pharmacological levodopa-induced rescue.ConclusionWe suggest dopamine being a key regulator for activity-induced generation of NG2-cells and oliogodendrocytes in the SN as a potentially relevant mechanism in endogenous nigral cellular plasticity.

MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice.

In Parkinsons disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brains capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.

A new case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

Sir, We read with great interest the recent article published in Brain by Pittock and colleagues (2010) describing eight patients with a previously unrecognized distinct brainstem encephalitis named chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Here, we report on what we believe to be another patient with CLIPPERS, lending further support to the concept that CLIPPERS is a novel, definable, inflammatory CNS disease. The patient provided written informed consent for presentation of her case as a report. A 69-year-old female noticed general weakness, dizziness and abnormal fatigue with subacute onset 16 weeks prior to evaluation at the Department of Neurology, Charite, Universitatsmedizin, Berlin. Eleven weeks prior, the patient developed horizontal diplopia and walking difficulties that gradually worsened so that she became unable to walk without assistance. Additionally, she noticed dysarthria and dysphagia as well as facial tingling and paraesthesia in her fingertips. About 4 weeks prior to admission, she developed hyperacusis and a labile affect with involuntary crying. Her past medical history was unremarkable except for arterial hypertension, which was treated with bisoprolol. Her family history was negative. Neurological examination on admission revealed a cerebellar syndrome with limb, gait and stance ataxia, as well as intention tremor on the left, more than on the right-hand side. She had marked cerebellar dysarthria. Her gait …

Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment

Previous studies in older adults suggested beneficial effects of omega-3 fatty acid (FA) supplementation, aerobic exercise, or cognitive stimulation on brain structure and function. However, combined effects of these interventions in patients suffering from mild cognitive impairment (MCI) are unknown. Using a randomized interventional design, we evaluated the effect of combined omega-3 FA supplementation, aerobic exercise and cognitive stimulation (target intervention) versus omega-3 FA supplementation and non-aerobic exercise (control intervention) on cognitive function and gray matter volume in patients with MCI. Moreover, we analyzed potential vascular, metabolic or inflammatory mechanisms underlying these effects. Twenty-two MCI patients (8 females; 60-80years) successfully completed six months of omega-3 FA intake, aerobic cycling training and cognitive stimulation (n=13) or omega-3 FA intake and non-aerobic stretching and toning (n=9). Before and after the interventions, cognitive performance, magnetic resonance imaging of the brain at 3T (n=20), intima-media thickness of the internal carotid artery and serum markers of glucose control, lipid and B-vitamin metabolism, and inflammation were assessed. Intervention-related changes in gray matter volume of Alzheimers disease (AD)-related brain regions, i.e., frontal, parietal, temporal and cingulate cortex were examined using voxel-based morphometry of high resolution T1-weighted images. After the intervention period, significant differences emerged in brain structure between groups: Gray matter volume decreased in the frontal, parietal and cingulate cortex of patients in the control intervention, while gray matter volume in these areas was preserved or even increased after the target intervention. Decreases in homocysteine levels in the target intervention group were associated with increases in gray matter volume in the middle frontal cortex (p=0.010). No significant differences in cognitive performance or other vascular, metabolic and inflammatory parameters were observed between groups. This pilot study provides preliminary evidence that omega-3 FA intake combined with aerobic exercise and cognitive stimulation prevents atrophy in AD-related brain regions in MCI patients, compared to omega-3 FA intake plus the control condition of stretching and toning. These promising findings should now be validated in a larger interventional trial.

Impact of tDCS on cerebral autoregulation in aging and in patients with cerebrovascular diseases

Following seminal articles on the technique and underlying mechanisms of transcranial direct current stimulation (tDCS) at the turn of this century,1 tDCS has gained special attention in neurorehabilitative research, given its ability to modulate brain function in a polarity-specific manner in stroke patients together with an excellent safety profile.2 However, an important safety concern emerged recently with regard to its impact on cerebral autoregulation, given a report on decreased autoregulation after 15 minutes anodal tDCS (atDCS) over primary motor cortex (M1) in young healthy subjects.3 Cerebral autoregulation, assessed by vasomotor reactivity (VMR), reflects the autonomic ability of cerebral arterioles to dilate following a vasodilatory stimulus. It is consistently decreased in patients with cerebrovascular diseases,4 and has been linked to stroke risk.5 Thus, a decrease of VMR after atDCS may be harmful to patients with already impaired VMR, such as stroke patients.4 Importantly, >40 ongoing trials with stroke patients and atDCS are registered on www.clinicaltrials.gov as of May 2014. Thus, the concerns raised by Vernieri et al.3 may carry important clinical implications.

Cortical Reorganization Due to Impaired Cerebral Autoregulation in Individuals With Occlusive Processes of the Internal Carotid Artery

BACKGROUND AND PURPOSE To study the impact of impaired cerebral autoregulation on cortical neurophysiology, long term potentiation (LTP)-like plasticity, motor learning and brain structure. METHODS 12 patients with unilateral occlusion or severe stenosis of the internal carotid artery were included. Impairment of cerebral autoregulation was determined by vasomotor reactivity in transcranial Doppler sonography. Corticomotor excitability, cortical silent period and LTP-like plasticity were assessed with transcranial magnetic stimulation, motor learning with a force production task, and brain structure with high-resolution MRI of the brain. RESULTS In the affected hemisphere, corticomotor excitability was significantly higher, cortical silent period and LTP-like plasticity significantly lower, compared to the contralateral side. No significant difference emerged for motor learning, cortical thickness and white matter integrity between the hemispheres. CONCLUSION Despite decreased LTP-like plasticity in the affected hemisphere, motor learning was comparable between hemispheres, possibly due to gamma-aminobutyric-acid (GABA)B-mediated corticomotor excitability changes within the affected hemisphere. Our results may help to develop interventions to beneficially modulate cortical physiology in the presence of cerebral hypoperfusion.

Cerebral autoregulation and brain networks in occlusive processes of the internal carotid artery

Patients with unilateral occlusive processes of the internal carotid artery (ICA) show subtle cognitive deficits. Decline in cerebral autoregulation and in functional and structural integrity of brain networks have previously been reported in the affected hemisphere (AH). However, the association between cerebral autoregulation, brain networks, and cognition remains to be elucidated. Fourteen neurologically asymptomatic patients (65±11 years) with either ICA occlusion or high-grade ICA stenosis and 11 age-matched healthy controls (HC) (67±6 years) received neuropsychologic testing, transcranial Doppler sonography to assess cerebral autoregulation using vasomotor reactivity (VMR), and magnetic resonance imaging to probe white matter microstructure and resting-state functional connectivity (RSFC). Patients performed worse on memory and executive tasks when compared with controls. Vasomotor reactivity, white matter microstructure, and RSFC were lower in the AH of the patients when compared with the unaffected hemisphere and with controls. Lower VMR of the AH was associated with several ipsilateral clusters of lower white matter microstructure and lower bilateral RSFC in patients. No correlations were found between VMR and cognitive scores. In sum, impaired cerebral autoregulation was associated with reduced structural and functional connectivity in cerebral networks, indicating possible mechanisms by which severe unilateral occlusive processes of the ICA lead to cognitive decline.

Using resting-state fMRI to assess the effect of aerobic exercise on functional connectivity of the DLPFC in older overweight adults

&NA; Cardiovascular fitness is thought to exert beneficial effects on brain function and might delay the onset of cognitive decline. Empirical evidence of exercise‐induced cognitive enhancement, however, has not been conclusive, possibly due to short intervention times in clinical trials. Resting‐state functional connectivity (RSFC) has been proposed as an early indicator for intervention‐induced changes. Here, we conducted a study in which healthy older overweight subjects took either part in a moderate aerobic exercise program over 6 months (AE group; n = 11) or control condition of non‐aerobic stretching and toning (NAE group; n = 18). While cognitive and gray matter volume changes were rather small (i.e., appeared only in certain sub‐scores without Bonferroni correction for multiple comparisons or using small volume correction), we found significantly increased RSFC after training between dorsolateral prefrontal cortex and superior parietal gyrus/precuneus in the AE compared to the NAE group. This intervention study demonstrates an exercise‐induced modulation of RSFC between key structures of the executive control and default mode networks, which might mediate an interaction between task‐positive and task‐negative brain activation required for task switching. Results further emphasize the value of RSFC as a sensitive biomarker for detecting early intervention‐related cognitive improvements in clinical trials.