Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non)steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3ß level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1ß and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

Cholinergic modulation of MEG resting-state oscillatory activity in Parkinson's disease related dementia.

OBJECTIVE: EEG and MEG studies in Parkinson's disease (PD) related dementia (PDD) have shown a slowing of resting-state, oscillatory activity compared to non demented PD. Aim of the present MEG study was to determine whether treatment with the cholinesterase inhibitor rivastigmine would reverse this slowing of resting-state activity in PDD patients. METHODS: In eight PDD patients, whole head MEG was recorded in a resting-state condition before and after treatment with rivastigmine. Relative spectral power was calculated in the delta, theta, alpha, beta and gamma frequency bands in fronto-central, parieto-occipital and temporal regions. RESULTS: After treatment with rivastigmine, PDD patients demonstrated an increase in relative power in the alpha range in parieto-occipital and temporal regions together with a diffuse increase in beta power. Furthermore, a decrease of delta power in fronto-central and parieto-occipital regions was found. CONCLUSIONS: Treatment with the cholinesterase inhibitor rivastigmine at least partly counteracts the slowing of resting-state brain activity that is known to occur in PD related dementia. SIGNIFICANCE: Our observations emphasize the prominent role of degeneration of the cholinergic system in the pathophysiology of dementia in PD. In the future, MEG might contribute to the selection of PD patients who may optimally benefit from cholinergic treatment.

Odor recognition memory is not independently impaired in Parkinson's disease.

The results of previous studies in small groups of Parkinson's disease (PD) patients are inconclusive with regard to the presence of an odor recognition memory impairment in PD. The aim of the present study was to investigate odor recognition memory in PD in a larger group of patients. Odor recognition memory and detection thresholds were assessed using components of the "Sniffin' Sticks" test battery in 55 non-demented PD patients (Hoehn and Yahr stages I-III) and 50 control subjects of comparable age and sex. PD patients performed slightly but significantly worse than control subjects on the odor recognition memory task. After correction for odor detection scores, however, the difference in odor recognition memory performance between PD patients and controls was no longer statistically significant. These data indicate that odor recognition memory is not independently impaired in PD patients.

MEG resting state functional connectivity in Parkinson's disease related dementia.

Parkinson's disease (PD) related dementia (PDD) develops in up to 60% of patients, but the pathophysiology is far from being elucidated. Abnormalities of resting state functional connectivity have been reported in Alzheimer's disease (AD). The present study was performed to determine whether PDD is likewise characterized by changes in resting state functional connectivity. MEG recordings were obtained in 13 demented and 13 non-demented PD patients. The synchronization likelihood (SL) was calculated within and between cortical areas in six frequency bands. Compared to non-demented PD, PDD was characterized by lower fronto-temporal SL in the alpha range, lower intertemporal SL in delta, theta and alpha1 bands as well as decreased centro-parietal gamma band synchronization. In addition, higher parieto-occipital synchronization in the alpha2 and beta bands was found in PDD. The observed changes in functional connectivity are reminiscent of changes in AD, and may reflect reduced cholinergic activity and/or loss of cortico-cortical anatomical connections in PDD.

Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: an MEG study.

We set out to determine whether changes in resting-state cortico-cortical functional connectivity are a feature of early-stage Parkinson's disease (PD), explore how functional coupling might evolve over the course of the disease and establish its relationship with clinical deficits. Whole-head magnetoencephalography was performed in an eyes-closed resting-state condition in 70 PD patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) in an "OFF" medication state and 21 controls. Neuropsychological testing was performed in all subjects. Data analysis involved calculation of three synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) measures which reflect functional connectivity within (local) and between (intrahemispheric and interhemispheric) ten major cortical regions in five frequency bands. Recently diagnosed, drug-naive patients showed an overall increase in alpha1 SL relative to controls. Cross-sectional analysis in all patients revealed that disease duration was positively associated with alpha2 and beta SL measures, while severity of parkinsonism was positively associated with theta and beta SL measures. Moderately advanced patients had increases in theta, alpha1, alpha2 and beta SL, particularly with regard to local SL. In recently diagnosed patients, cognitive perseveration was associated with increased interhemispheric alpha1 SL. Increased resting-state cortico-cortical functional connectivity in the 8-10 Hz alpha range is a feature of PD from the earliest clinical stages onward. With disease progression, neighboring frequency bands become increasingly involved. These findings suggest that changes in functional coupling over the course of PD may be linked to the topographical progression of pathology over the brain.

Loss of thalamic serotonin transporters in early drug-naïve Parkinson's disease patients is associated with tremor: an [(123)I]beta-CIT SPECT study.

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson's disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [(123)I]beta-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD(T)) and without tremor (PD(WT)) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [(123)I]beta-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD(T) than in the PD(WT) subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [(123)I]beta-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset.

Observations on the cortical silent period in Parkinson's disease.

Transcranial magnetic stimulation is a tool in the neurosciences to study motor functions and nervous disorders, amongst others. Single pulses of TMS applied over the primary motor cortex lead to a so-called cortical silent period in the recording from the corresponding muscle, i.e. a period of approximately 100ms with no muscle activity. We here show that in Parkinson's disease (PD), this cortical silent period in some cases is interrupted by short bursts of EMG activity. We describe in detail these interruptions in two patients with PD. These interruptions may number up to 3 per cortical silent period and show a consistent frequency across trials and hemispheres within a given patient; the two patients described here do differ, however, in the time-delay of the interruptions and hence the induced frequency. For one patient, the frequency of the interruptions proved to be around 13 Hz, the other patient showed a frequency of around 17 Hz. The results corroborate earlier findings of cortical oscillations elicited by pulses of TMS and may be related to abnormal oscillatory activity found in the cortical-subcortical motor system in PD.

First case of ataxia with isolated vitamin E deficiency in the Netherlands.

We present a 36-year-old Dutch woman who suffered from a progressive form of cerebellar ataxia since school age. In her childhood she was diagnosed with Friedreich's ataxia. Genetic analysis of the frataxin gene at 34 years of age, however, had revealed no abnormal GAA triplet expansion. We identified two point mutations in the alpha-tocopherol transport protein (alpha-TTP) gene on chromosome 8q13, and the diagnosis ataxia with isolated vitamin E deficiency (AVED) was made. This report illustrates the diagnosis AVED and its relation to vitamin E metabolism. It is important to evaluate previously made diagnoses when newly developed tests can be performed for confirmation.

Parkinson's disease: premotor clinico-pathological correlations.

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/ akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuropathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and/or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites, may explain the individually variable expression of this disease.

Resting state oscillatory brain dynamics in Parkinson's disease: an MEG study.

OBJECTIVE: The pathophysiological mechanisms of cognitive dysfunction and dementia in Parkinson's disease (PD) are still poorly understood. Altered resting state oscillatory brain activity may reflect underlying neuropathological changes. The present study using magneto encephalography (MEG) was set up to study differences in the pattern of resting state oscillatory brain activity in groups of demented and non-demented PD patients and healthy, elderly controls. METHODS: The pattern of MEG background oscillatory activity was studied in 13 demented PD patients, 13 non-demented PD patients and 13 healthy controls. Whole head MEG recordings were obtained in the morning in an eyes closed and an eyes open, resting state condition. Relative spectral power was calculated using Fast Fourier Transformation in delta, theta, alpha, beta and gamma frequency bands. RESULTS: In the non-demented PD patients, relative theta power was diffusely increased and beta power concomitantly decreased relative to controls. gamma Power was decreased in central and parietal channels. In the demented PD patients, a diffuse increase in relative delta and to lesser extent theta power and a decrease in relative alpha, beta and to lesser extent gamma power were found in comparison to the non-demented PD group. In addition, reactivity to eye opening was much reduced in the demented PD group. CONCLUSIONS: Parkinson's disease is characterized by a slowing of resting state brain activity involving theta, beta and gamma frequency bands. Dementia in PD is associated with a further slowing of resting state brain activity, additionally involving delta and alpha bands, as well as a reduction in reactivity to eye-opening. SIGNIFICANCE: The differential patterns of slowing of resting state brain activity in demented and non-demented PD patients suggests that, in conjunction with a progression of the pathological changes already present in non-demented patients, additional mechanisms are involved in the development of dementia in PD.

PD-related psychosis: pathophysiology with therapeutical strategies.

Parkinson's disease (PD) is a chronic, neurodegenerative disease with degeneration of the central dopaminergic neurons in the substantia nigra, leading to a depletion of dopamine (DA) in the striatum. This depletion causes the clinical hallmarks of this disease: bradykinesia, hypokinesia, rigidity, tremor and postural instability. Besides these well known motor symptoms, non-motor symptoms may develop, such as hyposmia, sleep disorders, autonomic disturbances, depression, cognitive impairment and psychosis. Pathophysiological mechanisms underlying these symptoms not only comprise Lewy body pathology in the central dopaminergic system, but also in the noradrenergic, serotinergic and cholinergic transmittersystems. Indeed, in Parkinson's disease, about 30-40% of the patients suffers fluctuating psychotic symptoms, mainly paranoid delusions and/or visual or acoustic hallucinations, symptoms considered to represent major contributors to patient and caregiver distress and nursing home placement. Endogenous (related to the disease process itself) as well as exogenous (related to therapeutical interventions) psychotogenic factors may contribute to the development of psychotic symptoms in PD. Therapeutical strategies, therefore, are aimed to reduce both endogenous and exogenous factors. To reduce endogenous psychotogenic factors, cholinesterase inhibitors, suggested to reduce cognitive deterioration, now seem to be the drugs of choice. In exogenously induced psychotic symptoms, atypical antipsychotics are considered the most effective. However, as psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of both strategies may be preferred.

Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Standard therapeutic interventions are aimed at replenishment of empty dopamine stores with levodopa or substitution with dopamine receptor agonists. However, in the long term this symptomatic therapy fails. Currently, various neuroprotective agents are being developed, with the intention to slow down the degeneration of dopaminergic neurons. In this context, the early identification of persons at risk to develop the disease as well as the assessment of the effectiveness of putative neuroprotective agents, are critical issues. Dopamine transporter (DAT) scintigraphy with single photon emission computed tomography (SPECT) has been used to assess the dopaminergic function in PD. Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls. In this paper we review the evidence on the utility of DAT imaging with SPECT in early PD detection as well as in monitoring neurprotection.

Clinical and genetic evaluation of 8 Polish families with levodopa-responsive parkinsonism.

We studied 8 large Polish families with parkinsonism, 6 of which were newly identified. Thirty-six family members had well-documented levodopa-responsive parkinsonism. The phenotype of affected individuals was indistinguishable from that of persons with idiopathic Parkinson disease (PD). The pattern of inheritance in 5 families was consistent with autosomal dominant transmission; in 3 families the mode of inheritance was uncertain. Single photon emission computed tomography (SPECT) studies with the dopamine transporter radioligand [(123)I]FP-CIT were performed in 1 family. The SPECT study showed striatal presynaptic dopaminergic degeneration consistent with sporadic PD in 1 affected family member and no signs of nigrostriatal dopaminergic dysfunction in 5 at-risk individuals. Sequence analysis in all 8 families excluded known genes associated with familial parkinsonism. Genome-wide 2-point linkage studies in the largest 2 families did not identify significant linkage (z > 3.0), although positive scores were obtained for 5q23 (D5S1462 and D5S2501), a locus previously implicated in disease susceptibility.

Cognitive dysfunction and dementia in Parkinson's disease.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia. Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.

Psychotic symptoms in Parkinson's disease: pathophysiology and management.

Parkinson's disease (PD) is a chronic neurodegenerative disease, in which mainly dopaminergic neurons in the substantia nigra in the brain degenerate, leading to a depletion of dopamine (DA) in the striatum. The most important motor disturbances of the disease are bradykinesia (slowing down of movement), hypokinesia (poverty of movement), rigidity (muscle stiffness), tremor and postural instability. Besides these well-known motor symptoms, non-motor symptoms may develop, such as depression, cognitive impairment and psychosis. Psychotic symptoms constitute a relatively common but nevertheless serious complication, with visual hallucinations and paranoid delusions often being most prominent. These symptoms are important contributors to patient and caregiver distress and are often important risk factors for nursing home placement. Exogenous (related to therapeutic interventions) factors are of major importance but endogenous (related to the disease process itself) factors might also contribute to the development of psychotic symptoms in PD. Therapeutic strategies comprise reduction of antiparkinsonian treatment, cholinesterase inhibitors and atypical antipsychotics. As psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of strategies may be chosen.

Deficits on Corsi's block-tapping task in early stage Parkinson's disease.

Cognitive deficits in Parkinson's disease (PD) include disturbances in working memory. We examined sequential visuo-spatial memory span by means of an adaptation of the Corsi Block-Tapping Task in groups of medicated (n=14) and non-medicated (n=15) patients with early stage PD, and in control subjects (n=22). A deficit in memory span was found in medicated patients with early stage PD relative to controls. There were no differences between non-medicated patients relative to either controls or medicated patients. A decrease in sequential visuo-spatial memory span appears to be a relatively early feature of PD and most likely reflects executive rather than mnemonic dysfunction.

The role of acetylcholine and dopamine in dementia and psychosis in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder in which there is abnormal degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area combined with a varying degree of deterioration of the cholinergic, serotonergic and noradrenergic system, leading to a variety of motor and non-motor abnormalities. Dopamine (DA) depletion in nigrostriatal projections manifests with abnormal spontaneous motor behavior and (subtle) cognitive deficits, whereas more overt cognitive impairment may develop with concomitant DA-deficiency related mesocorticolimbic denervation. In combination with a progressive dysfunction of the ascending neocortical cholinergic (and serotonergic and noradrenergic) projections, mainly due to a loss of cholinergic neurons in the nucleus basalis of Meynert (NbM), these cognitive deficits may proceed into dementia sometimes in combination with psychotic behavior, which might also be associated with dopaminomimetic and/or anticholinergic treatment as well as with cholinergic deficit or dopaminomimetic induced REM sleep disturbances. As these psychiatric symptoms have a substantial negative effect on the patient's quality of life, contribute to caregiver distress and are predictive of nursing home placement, identification and adequate treatment is of great importance. Recent evidence supports a possible role for cholinomimetic therapy in alleviating cognitive dysfunction and psychotic symptoms in PD.

The influence of computer experience on visuo-motor control: implications for visuo-motor testing in Parkinson's disease.

Abnormalities in visuo-motor control have repeatedly been reported in Parkinson's disease (PD) patients. In the more recent studies, tasks measuring visuo-motor performance are usually computerised tasks requiring the use of a mouse-like manipulandum. In healthy subjects, previous computer mouse experience can influence performance in computerised visuo-motor tasks. We, therefore, investigated the potential confounding effect of mouse experience in a visuo-motor task used in PD patients, the visuo-motor testing (VMT) system, and its concurrent usefulness in the diagnosis of PD. Our study population included 49 early PD patients and 31 controls. The VMT system involves moving a pointer over a sinusoidal path displayed on a computer screen by moving an unseen digitiser mouse over a tablet. In both PD patients and controls, subjects with low mouse experience scored worse than subjects with high mouse experience on variables measuring movement accuracy, direction and speed. After correction for mouse experience the aforementioned deficits were still present in PD patients with low mouse experience. However, PD patients with high mouse experience only showed deficits in movement accuracy. It would seem that previous mouse experience can at least partly compensate for deficits in directional control and speed in PD patients, implying a possible role for training in the treatment of functional motor impairments in PD. Future studies using computerised psychomotor tasks should take sufficient precautions to avoid potential confounding effects of mouse experience. The present data further suggest that only accuracy of visuo-motor control might be a useful parameter in the (early) diagnosis of PD.

[Presymptomatic detection of Parkinson's disease]. / Presymptomatische detectie van de ziekte van Parkinson.

Parkinson's disease (PD) is characterized by a progressive degeneration of mesencephalic dopaminergic neurons. More than half of these neurons are lost in a presymptomatic phase of an estimated 4-6 years duration. It is obvious that any type of treatment aimed at slowing down the disease process should preferably be applied in this presymptomatic phase. Presymptomatic detection of PD has therefore become an important goal. In a recent study in a population of 361 asymptomatic first degree relatives of PD patients, we were able to demonstrate that presymptomatic detection is possible by means of a combination of three olfactory processing tasks and [123l] beta-CIT single photon emission computed tomography (SPECT) scanning of the nigrostriatal dopaminergic system. These results are a first step towards the development of a screening strategy that may be applied in the general population. Impairments of olfactory function, however, are not specific to PD but are also associated with other neurodegenerative disorders (e.g. Alzheimer's disease) and certain lifestyle characteristics (e.g. smoking). In the next few years our research efforts will focus on two different approaches to develop a more specific screening strategy. First, olfactory processing tasks will be combined with tasks aimed at detecting subtle (visuo)motor disturbances and early cognitive impairments. In parallel, an effort will be made to define disease-specific patterns of olfactory dysfunction in neurodegenerative disorders.