Subthalamic nucleus but not entopeduncular nucleus deep brain stimulation enhances neurogenesis in the SVZ-olfactory bulb system of Parkinsonian rats.

Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease.

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

Comorbid cerebral amyloid angiopathy in dementia and prodromal stages-Prevalence and effects on cognition.

OBJECTIVES: To determine the contribution of cerebral amyloid angiopathy to cognitive impairment in MCI and dementia. METHODS: Patients with subjective memory impairment (SMI), amnestic and non-amnestic mild cognitive impairment ((n)aMCI), Alzheimer's disease (AD), mixed and vascular dementia (MD/VD) from our memory clinic were included in this retrospective analysis. Patients underwent neuropsychological testing and cranial magnetic resonance imaging (MRI). Magnetic resonance imaging data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. ANOVAs were used to investigate the contribution of CAA to cognitive impairment within diagnostic groups and to determine whether differences in cognitive test performance between the diagnostic groups are mediated by total CAA burden. RESULTS: 475 patients (222 male, 253 female) with SMI (n = 47), naMCI (n = 41), aMCI (n = 189), early AD (n = 9), AD (n = 114), MD (n = 71) and VD (n = 4) were included. Mean age was 73.2 (9.9) years. CAA prevalence was 14.9% in SMI, 14.6% in naMCI, 24.3% in aMCI, 22.2% in early onset AD, 18.4% in late onset AD, 46.5% in MD and 25% in VD. Patients with possible and probable CAA were older than patients without CAA. In particular, diagnosis of aMCI, early onset AD, MD and VD showed high CAA prevalence. In AD but not in aMCI, CAA diagnosis significantly influenced test performance in the CERAD word list recall (F (1,78) = 4505; p = 0.037; partial eta-square = 0.055). Differences in cognitive test performance between the diagnostic groups of naMCI, aMCI, AD and MD were mediated by total CAA burden within AAT simply nouns subtest (F (2,39) = 4059; p = 0.025; partial eta-square = 0.172) and in CERAD verbal fluency test (F (3,129) = 3533; p = 0.017; partial eta-square = 0.076). CONCLUSION: This retrospective analysis demonstrates high prevalence rates of CAA in cognitive diagnoses. Our data suggest that comorbid CAA independently impacts cognitive test performance in the course of AD with presumably stage-dependent effects. Especially in patients with AD comorbid CAA additionally impairs memory function. Total CAA small vessel disease burden further modulates psychometric differences in cognitive test performance between diagnostic groups regarding word finding and word fluency capabilities.

[Coincidence of normal pressure hydrocephalus and Alzheimer`s disease: therapeutic implications and open questions]. / Zur Koinzidenz von Normaldruckhydrocephalus und Alzheimer-Demenz: therapeutische Implikationen und offene Fragen.

Normal pressure hydrocephalus (NPH) is prevalent in aging patient populations. Despite its clinical relevance, many patients with NPH may not receive adequate treatment. Because of the frequency of Alzheimer`s disease in these patients, there could be overlapping pathophysiological mechanisms that are as yet incompletely understood. Cerebral comorbidities seem to have negative effects on therapeutic response to ventriculoperitoneal shunting. In order to avoid unnecessary and unsuccessful surgery in highly vulnerable elderly patients, they have to be taken into consideration in the diagnostic process.

A pragmatic methodical framework for the user-centred development of an electronic process support for the sleep laboratory patients' management.

Objective: Limited capacities and ineffective care pathways result in long waiting times for patients and sporadic treatment controls in sleep medicine. As one objective of the 'Telesleep Medicine' project, a portal should be developed, which supports sleep specialists in an efficient and resource-saving patient management. On account of the limited project timeframe, the 'classical' user-centred design and evaluation methods could not be comprehensively implemented. Therefore, a pragmatic methodical framework was developed. Methods: For the iterative development of the portal, a combination of low-cost and quick-to-implement methods was used. In chronological order, these were: context interviews, personas, the development of an as-is model, a web search of design standards and good design aspects of similar systems, the development of a to-be model, the creation of an overarching mind map, and the iterative creation of mockups with simplified usability walkthroughs. Results: The feasibility of the pragmatic methodological framework for the development of a prototype for the portal was demonstrated. The used method combination resulted in a prototype based on the needs and requirements of the sleep specialists, taking into account their specific workflow and the technical implementation conditions. Conclusions: The presented pragmatic methodological framework can be a valuable resource for developers of comparable projects. The combination of methods worked well together regarding the limited timeframe and resources for concept development. For the future, we plan to implement and test the portal in the clinical field and thus enrich our framework with additional methods.

Training with Odors Impacts Hippocampal Thickness in Patients with Mild Cognitive Impairment.

BACKGROUND: The olfactory system is affected early in Alzheimer's disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. OBJECTIVE: The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. METHODS: A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. RESULTS: After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. CONCLUSION: Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.

Predictors of subjective cognitive deficits in patients with mild cognitive impairment.

BACKGROUND: Detailed examination of cognitive deficits in patients with mild cognitive impairment (MCI) yields substantial diagnostic and prognostic value, specifically with respect to memory. Magnitude and characteristics of subjective cognitive deficits, however, often receive less attention in this population at risk for developing dementia. METHODS: We investigated predictors of subjective cognitive deficits in patients with MCI, using a detailed assessment for such impairments associated with different cognitive domains, as well as demographic and clinical variables including magnetic resonance imaging data. RESULTS: The strongest predictor for subjective memory deficits was depressed mood, whereas subjective performance issues associated with attention or executive functions also corresponded to measurable impairments in the respective cognitive domains. Reduced hippocampal thickness and hemispheric entorhinal cortex thickness asymmetry were associated with objective memory impairment but not with subjective deficits or symptoms of depression. CONCLUSIONS: Whereas low objective memory performance and reduced cortical thickness within medial temporal lobe subregions could be associated with neurodegeneration, greater subjective memory deficits in patients with MCI may indicate psychological burden.

Adult Neural Stem Cells from Midbrain Periventricular Regions Show Limited Neurogenic Potential after Transplantation into the Hippocampal Neurogenic Niche.

The regulation of adult neural stem or progenitor cell (aNSC) proliferation and differentiation as an interplay of cell-intrinsic and local environmental cues remains in part unclear, impeding their role in putative regenerative therapies. aNSCs with all major properties of NSCs in vitro have been identified in a variety of brain regions beyond the classic neurogenic niches, including the caudal periventricular regions (PVRs) of the midbrain, though active neurogenesis is either limited or merely absent in these regions. To elucidate cell-intrinsic properties of aNSCs from various PVRs, we here examined the proliferation and early differentiation capacity of murine aNSCs from non-neurogenic midbrain PVRs (PVRMB) compared to aNSCs from the neurogenic ventricular-subventricular zone (PVRV-SVZ) 7 days after transplantation into the permissive pro-neurogenic niche of the dentate gyrus (DG) of the hippocampus in mice. An initial in vitro characterization of the transplants displayed very similar characteristics of both aNSC grafts after in vitro expansion with equal capacities of terminal differentiation into astrocytes and Tuj1+ neurons. Upon the allogenic transplantation of the respective aNSCs into the DG, PVRMB grafts showed a significantly lower graft survival and proliferative capacity compared to PVRV-SVZ transplants, whereby the latter are exclusively capable of generating new neurons. Although these differences might be-in part-related to the transplantation procedure and the short-term study design, our data strongly imply important cell-intrinsic differences between aNSCs from neurogenic compared to non-neurogenic PVRs with respect to their neurogenic potential and/or their sensitivity to neurogenic cues.

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

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.

[Insomnia in the context of neurological diseases]. / Insomnie im Rahmen neurologischer Erkrankungen.

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.

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

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.

Cognitive profile in Restless Legs Syndrome: A signal-to-noise ratio account.

Restless legs syndrome (RLS) is a common neurological disorder characterized by a sensorimotor condition, where patients feel an uncontrollable urge to move the lower limbs in the evening and/or during the night. RLS does not only have a profound impact on quality of life due to the disturbed night-time sleep, but there is growing evidence that untreated or insufficiently managed RLS might also cause cognitive changes in patients affected by this syndrome. It has been proposed that RLS is caused by alterations in the signal-to-noise ratio (SNR) and in dopamine (DA) neurotransmission in the nervous system. Based on this evidence, we propose the "SNR-DA hypothesis" as an explanation of how RLS could affect cognitive performance. According to this hypothesis, variations/reductions in the SNR underlie RLS-associated cognitive deficits, which follow an inverted U-shaped function: In unmedicated patients, low dopamine levels worsen the SNR, which eventually impairs cognition. Pharmacological treatment enhances DA levels in medicated patients, which likely improves/normalizes the SNR in case of optimal doses, thus restoring cognition to a normal level. However, overmedication might push patients past the optimal point on the inverted U-shaped curve, where an exaggerated SNR potentially impairs cognitive performance relying on cortical noise such as cognitive flexibility. Based on these assumptions of SNR alterations, we propose to directly measure neural noise via "1/f noise" and related metrics to use transcranial random noise stimulation (tRNS), a noninvasive brain stimulation method which manipulates the SNR, as a research tool and potential treatment option for RLS.

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

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 post hoc 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, P = 0.020, unpaired two-sided t-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.

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

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.

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

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.

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

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.

Thalamic GABA may modulate cognitive control in restless legs syndrome.

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.

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

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.