Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study

BACKGROUND: Fatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS. METHODS: We evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS ≥ 4) and MS-NoFatigue (MS-NoF, FSS < 4). RESULTS: MS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis. CONCLUSION: Although the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients

AMPA Receptor Activation Causes Silencing of AMPA Receptor-Mediated Synaptic Transmission in the Developing Hippocampus

Agonist-induced internalization of transmembrane receptors is a widespread biological phenomenon that also may serve as a mechanism for synaptic plasticity. Here we show that the agonist AMPA causes a depression of AMPA receptor (AMPAR) signaling at glutamate synapses in the CA1 region of the hippocampus in slices from developing, but not from mature, rats. This developmentally restricted agonist-induced synaptic depression is expressed as a total loss of AMPAR signaling, without affecting NMDA receptor (NMDAR) signaling, in a large proportion of the developing synapses, thus creating AMPAR silent synapses. The AMPA-induced AMPAR silencing is induced independently of activation of mGluRs and NMDARs, and it mimics and occludes stimulus-induced depression, suggesting that this latter form of synaptic plasticity is expressed as agonist-induced removal of AMPARs. Induction of long-term potentiation (LTP) rendered the developing synapses resistant to the AMPA-induced depression, indicating that LTP contributes to the maturation-related increased stability of these synapses. Our study shows that agonist binding to AMPARs is a sufficient triggering stimulus for the creation of AMPAR silent synapses at developing glutamate synapses

Developmental regulation of synaptic function of the hippocampal glutamatergic synapse

The mature mammalian brain and spinal cord contain billions of neurons which are interconnected by means of synapses. The most prevalent type of synapse is excitatory, using the amino acid glutamate as transmitter. The aim of this study was to acquire knowledge of basic synaptic properties at recently formed glutamatergic hippocampal synapses, to help understand how the development of a fully functional mature brain is accomplished. The study was performed in vitro, using slices of hippocampus from rats. Excitatory synaptic transmission between Schaffer collaterals / commissural fibers and pyramidal cells in the hippocampal CA1 region was investigated using standard extra- and intracellular recording techniques.It was shown that some functional properties of the early postnatal synapses differ from properties at more mature synapses. The results can be summarized as follows; i) there is a developmental switch in release properties during the second postnatal week, leading to a lower release probability. However, this change seems to occur only at a small group of synapses with initial high release probability. ii) For the early postnatal synapse, but not for the mature one, low frequency afferent activation could lead to a rapid and total silencing of AMPA receptor-mediated signaling, a previously unrecognized form of synaptic plasticity. Synapses may thus not be formed without functional AMPA receptor-mediated transmission (AMPA-silent), as commonly believed, but with both functional AMPA and NMDA receptors. iii) The early postnatal synapse shows a heightened susceptibility to long-term depression. This developmental form of LTD appears to differ from the more mature form regarding triggering mechanism, synapse specificity, and possibly site of expression. Conclusion: The findings of this study show that synapses during the early postnatal period differ both in release properties and in synaptic plasticity mechanisms, when compared to synapses at around the onset of puberty. It is proposed that the properties of synapses during early development are important for a correct neural circuitry to evolve

Impaired procedural memory in narcolepsy type 1

Objectives Sleep enhances the consolidation of memories. Here, we investigated whether sleep-dependent memory consolidation differs between healthy subjects and narcolepsy type 1 (NT1) patients. Material and Methods We recruited 18 patients with NT1 and 24 healthy controls. The consolidation of spatial (declarative memory; 2-dimensional object location) and procedural (non-declarative memory; finger sequence tapping) memories was examined across one night of at-home sleep. Sleep was measured by an ambulatory sleep recording device. Results The overnight gain in the number of correctly recalled sequences in the finger-tapping test was smaller for NT1 patients than healthy subjects (+8.1% vs. +23.8% from pre-sleep learning to post-sleep recall, p = .035). No significant group differences were found for the overnight consolidation of spatial memory. Compared to healthy subjects, the sleep of NT1 patients was significantly more fragmented and shallow. However, no significant correlations were found between sleep parameters and overnight performance changes on the memory tests in the whole group. Conclusion The sleep-dependent consolidation of procedural but not spatial memories may be impaired among patients with NT1. Therefore, future studies are warranted to examine whether sleep improvement, for example, using sodium oxybate, can aid the sleep-dependent formation of procedural memories among NT1 patients

Extracellular field recordings of AMPA-induced depression.

<p><b>A</b> and <b>C</b>, Extracellular field recordings showing depression of AMPAR-mediated synaptic transmission in developing (<b>A</b>, <i>n</i> = 17), but not in mature (<b>C</b>, <i>n</i> = 8) synapses. <b>B</b> and <b>D</b>, Brief application of AMPA (5 µM, 30 s) results in depression of AMPAR-mediated synaptic transmission in developing (<b>B</b>, <i>n</i> = 7), but not in mature (<b>D</b>, <i>n</i> = 6) synapses. Three synaptic stimuli were applied before the application of AMPA and the synaptic stimulation was interrupted for 10 minutes during the agonist application. <b>E</b>, Stimulus-induced depression (120 stimuli at 0.2 Hz) is followed by a brief application of AMPA (5 µM, 30 s) in acute slices from P7–13 day-old rats using extracellular field recordings (<i>n</i> = 7). All data are means ± s.e.m. Scale bars represent 200 µV and 20 ms. Representative fEPSPs are shown superimposed above the graphs. In <b>A</b>–<b>D</b>, thick traces are averages taken during the first three stimuli and thin traces are averages during the last minute of recordings, as indicated in the figure. In <b>E</b>, fEPSPs from indicated time points are shown.</p

Reversibility and LTP after agonist-induced depression.

<p><b>A</b>, Summary data for reversibility experiments in which AMPA-induced depression was followed by a pause of stimulation for 30 minutes (<i>n</i> = 6), showing reversal of synaptic signaling to the initial (100%) level. <b>B</b>, Summary data for LTP experiments (<i>n</i> = 6) in which AMPA was applied 10 min after five trains of high-frequency stimulation (HFS, each consisting of 20 stimuli at 50 Hz, 20 s intertrain interval), showing that further agonist-induced depression was prevented. <b>C</b>, Summary of stimulus and agonist-induced depression in extracellular field recordings. All data are means ± s.e.m. Scale bars represent 200 µV and 20 ms. Representative fEPSPs are shown superimposed above the graphs as indicated in the figure.</p

Selective decrease in the frequency of miniature AMPAR-mediated EPSCs after application of AMPA.

<p><b>A</b>, Continuous recording of AMPAR mEPSCs in the presence of 500 nM TTX before and after application of AMPA. 5 µM AMPA was applied for 30 s as indicated. <b>B</b>, Effects of AMPA application on cumulative distribution of mEPSC amplitude and inter event-interval (<i>n</i> = 8). Scale bars represent 10 pA and 10 ms. Representative traces recorded at −70 mv and +40 mV are shown on top. <b>C</b>, Bar graph summarizing the effect of AMPA application on AMPAR and NMDAR mEPSCs (*** <i>P</i><0.001). All data are means ± s.e.m.</p

AMPA-induced depression exclusively at developing synapses.

<p><b>A</b> and <b>C</b>, Whole-cell recordings from CA1 pyramidal cells in acute slices from P7–13 day-old rats (<b>A</b>) and >P26 day-old rats (<b>C</b>). Synaptic stimulation (0.2 Hz) results in depression of AMPAR-mediated synaptic transmission in developing (<b>A</b>, <i>n</i> = 16), but not in mature (<b>C</b>, <i>n</i> = 8) synapses. <b>B</b> and <b>D</b>, Brief application of AMPA (5 µM, 30 s) results in depression of AMPAR-mediated synaptic transmission in developing (<b>B</b>, <i>n</i> = 7), but not in mature (<b>D</b>, <i>n</i> = 6) synapses. Three synaptic stimuli were applied before the application of AMPA and the synaptic stimulation was interrupted for 10 minutes during the agonist application. <b>E</b>, Whole-cell currents evoked by bath application of AMPA (5 µM, 30 s) were larger in mature pyramidal cells (P7–13, <i>n</i> = 7; >P26, <i>n</i> = 8). <b>F</b>, Effects of AMPA application on NMDAR-mediated synaptic transmission in developing synapses (<i>n</i> = 5). <b>G</b>, Summary of stimulus and agonist-induced depression using the whole-cell patch clamp configuration. All data are means ± s.e.m. Scale bars represent 200 pA and 20 ms. Representative EPSCs are shown superimposed above the graphs. Thick traces are averages taken during the first three stimuli. Thin traces are averages during the last minute of recordings, as indicated in the figure.</p

Tactile direction discrimination in humans after stroke

Sensing movements across the skin surface is a complex task for the tactile sensory system, relying on sophisticated cortical processing. Functional MRI has shown that judgements of the direction of tactile stimuli moving across the skin are processed in distributed cortical areas in healthy humans. To further study which brain areas are important for tactile direction discrimination, we performed a lesion study, examining a group of patients with first-time stroke. We measured tactile direction discrimination in 44 patients, bilaterally on the dorsum of the hands and feet, within 2 weeks (acute), and again in 28 patients 3 months after stroke. The 3-month follow-up also included a structural MRI scan for lesion delineation. Fifty-nine healthy participants were examined for normative direction discrimination values. We found abnormal tactile direction discrimination in 29/44 patients in the acute phase, and in 21/28 3 months after stroke. Lesions that included the opercular parietal area 1 of the secondary somatosensory cortex, the dorsolateral prefrontal cortex or the insular cortex were always associated with abnormal tactile direction discrimination, consistent with previous functional MRI results. Abnormal tactile direction discrimination was also present with lesions including white matter and subcortical regions. We have thus delineated cortical, subcortical and white matter areas important for tactile direction discrimination function. The findings also suggest that tactile dysfunction is common following stroke.Funding Agencies|Svenska Strokeforbundet and Sahlgrenska Universitetssjukhusets fonder</p