Lack of muscle stem cell proliferation and myocellular hypertrophy in sIBM patients following blood-flow restricted resistance training

Sporadic inclusion body myositis (sIBM) is characterised by skeletal muscle inflammation, progressive muscle loss and weakness, which is largely refractory to immunosuppressive treatment. Low-load blood-flow restricted (BFR) training has been shown to evoke gains in myofibre cross sectional area (mCSA) in healthy adults. This could partially be due to the activation and integration of muscle satellite cells (SC) resulting in myonuclei addition. Consequently, this study investigated the effect of 12-weeks lower limb low-load BFR resistance training in sIBM patients on SC and myonuclei content, myofibre size and capillarization. Muscle biopsies from sIBM patients randomised to 12-weeks of low-load BFR resistance training (n = 11) or non-exercising controls (CON) (n = 9) were analysed for SC and myonuclei content, myofibre size and capillarization using three-colour immunofluorescence microscopy and computerised quantification procedures. No between-group differences (time-by-group interactions) or within-groups changes were observed for resident SCs (Pax7⁺/Six1⁺), proliferating SCs (Pax7⁺/ Ki67⁺), myonuclei (Six1⁺), type 1 mCSA or capillary number (CD31⁺). However, a time-by-group interaction for type 2 mCSA was observed (p = 0.04). Satellite cell content, myonuclei number, mCSA and capillary density remained unaffected following 12-weeks low-load BFR resistance training, indicating limited myogenic capacity and satellite cell plasticity in long-term sIBM patients.     

Impaired regeneration in LGMD2A supported by increased PAX7‐positive satellite cell content and muscle‐specific microrna dysregulation

Introduction: Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, up‐regulation of miR‐1 and miR‐206 facilitates transition from proliferating SCs to differentiating myogenic progenitors. Methods: We examined the histopathological stages, Pax7 SC content, and muscle‐specific microRNA expression in biopsy specimens from well‐characterized LGMD 2A patients to gain insight into disease pathogenesis. Results: Three distinct stages of pathological changes were identified that represented the continuum of the dystrophic process from prominent inflammation with necrosis and regeneration to prominent fibrosis, which correlated with age and disease duration. Pax7‐positive SCs were highest in the fibrotic group and correlated with down‐regulation of miR‐1, miR‐133a, and miR‐206. Conclusions: These observations, and other published reports, are consistent with microRNA dysregulation leading to inability of Pax7‐positive SCs to transit from proliferation to differentiation. This results in impaired regeneration and fibrosis. Muscle Nerve 47: 731–739, 2013     

Reduced skeletal muscle satellite cell number alters muscle morphology after chronic stretch but allows limited serial sarcomere addition

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. Methods: A transgenic Pax7‐DTA mouse model underwent conditional SC depletion, and their soleii were then stretch‐immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Results: Mice in the SC‐reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross‐sectional area was significantly smaller and was associated with hypertrophic ECM changes, consistent with fibrosis. Conclusions: While a reduced SC population does not hinder serial sarcomere addition, SCs play a role in muscle adaptation to chronic stretch that involves maintenance of both fiber cross‐sectional area and ECM structure. Muscle Nerve 55 : 384–392, 2017     

Hepatocyte growth factor (HGF) and the satellite cell response following muscle lengthening contractions in humans

The time-courses of satellite cell (SC) activation and protein expression of hepatocyte growth factor (HGF), HGF activator (HGFA), HGFA inhibitor-1 (HAI-1), and HGFA inhibitor-2 (HAI-2) in human skeletal muscle, as well as serum HGF following a single bout of muscle lengthening contractions, were determined. Eight recreationally active participants were recruited for the study. Subjects performed 300 lengthening contractions involving the quadriceps femoris muscles of a single leg at a fixed velocity of 180 degrees/s. Percutaneous muscle biopsies were taken before (PRE) and at 4 h (T4), 24 h (T24), 72 h (T72), and 120 h (T120) following the exercise. The protocol resulted in an increase in the number of SCs [neural cell adhesion molecule (NCAM)-labeled cells] expressed relative to total myonuclei, at T24, compared with both PRE and T4 (P<0.05), and peaked at T72 (approximately 80% increase vs. PRE, P<0.05). HGF protein increased significantly in serum from baseline (PRE) to T4 (P<0.05). Active HGF protein was detected in skeletal muscle at rest [14.4+/-1.3 average integrated density value (IDV)/actin average IDV] and tended to increase at early time-points (P=0.12). HGFA protein increased significantly from PRE to T24 (P<0.05). HAI-1 protein increased significantly from PRE to T24 (P<0.05). HAI-2 (32 kDa) increased significantly from baseline (PRE) by T24 (P<0.05), and also by T72 and T120 (P<0.05). We conclude that a single bout of lengthening muscle contractions is sufficient to activate SCs, which may involve both a local and systemic HGF response to contraction-induced injury.     

Skeletal muscle satellite cells: Mediators of muscle growth during development and implications for developmental disorders

Satellite cells (SCs) are the muscle stem cells responsible for longitudinal and cross‐sectional postnatal growth and repair after injury and which provide new myonuclei when needed. We review their morphology and contribution to development and their role in sarcomere and myonuclear addition. SCs, similar to other tissue stem cells, cycle through different states, such as quiescence, activation, and self‐renewal, and thus we consider the signaling mechanisms involved in maintenance of these states. The role of the SC niche and their interactions with other cells, such as fibroblasts and the extracellular matrix, are all emerging as major factors that affect aging and disease. Interestingly, children with cerebral palsy appear to have a reduced SC number, which could play a role in their reduced muscular development and even in muscular contracture formation. Finally, we review the current information on SC dysfunction in children with muscular dystrophy and emerging therapies that target promotion of myogenesis and reduction of fibrosis. Muscle Nerve 50 : 723–732, 2014     

Matters of fiber size and myonuclear domain: Does size matter more than age?

Introduction: The relationship between fiber size and myonuclear content is poorly understood. Methods: Biopsy cross‐sections from young and old trained and untrained healthy individuals were analyzed for fiber area and myonuclei, and 2 fiber‐size‐dependent cluster analyses were performed. Results: When comparing fibers of similar size, no effect of training or age was found for myonuclear domain. There was a linear relationship between fiber area and myonuclei per fiber (r = 0.99; P < 0.001) and a non‐linear relationship between fiber area and domain (r = 0.97–0.99; P < 0.0001), with a markedly smaller domain in fibers <3,000 µm². A higher proportion of type II fibers <3,000 µm² was observed in the old subjects. Conclusions: These findings suggest that age‐related reductions in myonuclear domain size could be explained by the greater proportion of small fibers. The data also highlight the usefulness of determining fiber‐size‐based clusters for gaining mechanistic insight into the relationship between skeletal muscle fiber size and myonuclear content. Muscle Nerve 52 : 1040–1046, 2015     

Serum brain‐derived neurotrophic factor and interleukin‐6 response to high‐volume mechanically demanding exercise

Introduction: The aim of this study was to follow circulating brain‐derived neurotrophic factor (BDNF) and interleukin‐6 (IL‐6) levels in response to severe muscle‐damaging exercise. Methods: Young healthy men (N = 10) performed a bout of mechanically demanding stretch–shortening cycle exercise consisting of 200 drop jumps. Voluntary and electrically induced knee extension torque, serum BDNF levels, and IL‐6 levels were measured before and for up to 7 days after exercise. Results: Muscle force decreased by up to 40% and did not recover by 24 hours after exercise. Serum BDNF was decreased 1 hour and 24 hours after exercise, whereas IL‐6 increased immediately and 1 hour after but recovered to baseline by 24 hours after exercise. IL‐6 and 100‐Hz stimulation torque were correlated (r = ?0.64, P < 0.05) 24 hours after exercise. Discussion: In response to acute, severe muscle‐damaging exercise, serum BDNF levels decrease, whereas IL‐6 levels increase and are associated with peripheral fatigue. Muscle Nerve 57 : E46–E51, 2018     

GABAA‐benzodiazepine receptor availability in smokers and nonsmokers: Relationship to subsyndromal anxiety and depression

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid_A‐benzodiazepine receptor (GABA_A‐BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA_A‐BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex‐matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [¹²³I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State‐Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES‐D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA_A‐BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA_A‐BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA_A‐BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = ?0.47, P = 0.03), frontal (r = ?0.46, P = 0.03), anterior cingulate (r = ?0.47, P = 0.04), temporal (r = ?0.47, P = 0.03), occipital (r = ?0.43, P = 0.05) cortices, and cerebellum (r = ?0.46, P = 0.04)], trait anxiety [parietal (r = ?0.72, P = 0.02), frontal (r = ?0.72, P = 0.02), and occipital (r = ?0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = ?0.68; P = 0.02), frontal (r = ?0.65; P = 0.03), anterior cingulate (r = ?0.61; P = 0.04), and temporal (r = ?0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA_A‐BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA_A‐BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA_A‐BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA_A‐BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression. Synapse 63:1089–1099, 2009. © 2009 Wiley‐Liss, Inc.     

Purinergic signaling mediated by P2X7 receptors controls myelination in sciatic nerves

Adenosine‐5′‐triphosphate, the physiological ligand of P2X receptors, is an important factor in peripheral nerve development. P2X₇ receptor is expressed in Schwann cells (SCs), but the specific effects of P2X₇ purinergic signaling on peripheral nerve development, myelination, and function are largely unknown. In this study, sciatic nerves from P2X₇ knockout mice were analyzed for altered expression of myelin‐associated proteins and for alterations in nerve morphology. Immunohistochemical analyses revealed that, in the wild‐type peripheral nerves, the P2X₇ receptor was localized mainly in myelinating SCs, with only a few immunopositive nonmyelinating SCs. Complete absence of P2X₇ receptor protein was confirmed in the sciatic nerves of the knockout mice by Western blot and immunohistochemistry. Western blot analysis revealed that expression levels of the myelin proteins protein zero and myelin‐associated glycoprotein are reduced in P2X₇ knockout nerves. In accordance with the molecular results, transmission electron microscopy analyses revealed that P2X₇ knockout nerves possess significantly more unmyelinated axons, contained in a higher number of Remak bundles. The myelinating/nonmyelinating SC ratio was also decreased in knockout mice, and we found a significantly increased number of irregular fibers compared with control nerves. Nevertheless, the myelin thickness in the knockout was unaltered, suggesting a stronger role for P2X₇ in determining SC maturation than in myelin formation. In conclusion, we present morphological and molecular evidence of the importance of P2X₇ signaling in peripheral nerve maturation and in determining SC commitment to a myelinating phenotype. © 2014 Wiley Periodicals, Inc.     

Aerobic training in patients with anoctamin 5 myopathy and hyperckemia

Introduction: Anoctamin 5 deficiency has recently been defined to cause limb‐girdle muscular dystrophy type 2L (LGMD2L) with pronounced hyperCKemia. No treatment interventions have been made so far in this condition. Methods: In 6 patients with LGMD2L, we studied the effect of home‐based, pulse‐watch monitored, moderate‐intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly, for 10 weeks. Plasma creatine kinase (CK) was assessed before, during, and after the program as a marker of muscle damage. Primary outcome measures were maximum oxygen uptake (VO_2max) and time in the 5‐repetitions‐sit‐to‐stand test (FRSTST). Results: Training resulted in improvements in VO_2max (27 ± 7%; P = 0.0001) and FRSTST time (35 ± 12%; P = 0.007). Improvements in physiologic and functional muscle testing were accompanied by stable CK levels and no reports of adverse effects. Conclusions: These findings suggest that supervised aerobic exercise training is safe and effective in improving oxidative capacity and muscle function in patients with anoctamin 5 deficiency. Muscle Nerve 50 : 119–123, 2014     

Schwann cell dedifferentiation‐associated demyelination leads to exocytotic myelin clearance in inflammatory segmental demyelination

Schwann cells (SCs), which form the peripheral myelin sheath, have the unique ability to dedifferentiate and to destroy the myelin sheath under various demyelination conditions. During SC dedifferentiation‐associated demyelination (SAD) in Wallerian degeneration (WD) after axonal injury, SCs exhibit myelin and junctional instability, down‐regulation of myelin gene expression and autophagic myelin breakdown. However, in inflammatory demyelinating neuropathy (IDN), it is still unclear how SCs react and contribute to segmental demyelination before myelin scavengers, macrophages, are activated for phagocytotic myelin digestion. Here, we compared the initial SC demyelination mechanism of IDN to that of WD using microarray and histochemical analyses and found that SCs in IDN exhibited several typical characteristics of SAD, including actin‐associated E‐cadherin destruction, without obvious axonal degeneration. However, autophagolysosome activation in SAD did not appear to be involved in direct myelin lipid digestion by SCs but was required for the separation of SC body from destabilized myelin sheath in IDN. Thus, lysosome inhibition in SCs suppressed segmental demyelination by preventing the exocytotic myelin clearance of SCs. In addition, we found that myelin rejection, which might also require the separation of SC cytoplasm from destabilized myelin sheath, was delayed in SC‐specific Atg7 knockout mice in WD, suggesting that autophagolysosome‐dependent exocytotic myelin clearance by SCs in IDN and WD is a shared mechanism. Finally, autophagolysosome activation in SAD was mechanistically dissociated with the junctional destruction in both IDN and WD. Thus, our findings indicate that SAD could be a common myelin clearance mechanism of SCs in various demyelinating conditions.     

Estimation of skeletal muscle energy metabolism in Machado‐Joseph disease using 31P‐MR spectroscopy

The aim of this study was to determine if muscle energy metabolism, as measured by ³¹P‐magnetic resonance spectroscopy (MRS), is a metabolic marker for the efficacy of treatment of Machado‐Joseph disease (MJD). We obtained ³¹P‐MRS in the calf muscle of 8 male patients with MJD and 11 healthy men before, during, and after a 4 minute plantar flexion exercise in a supine position. The data showed that there was a significant difference between the groups in terms of the PCr/(Pi + PCr) ratio at rest (P = 0.03) and the maximum rate of mitochondrial ATP production (V_max) (P < 0.01). In addition, V_max was inversely correlated with the scale for the assessment and rating of ataxia score (r = ?0.34, P = 0.04). The MJD group also showed a reduction in V_max over the course of 2 years (P < 0.05). These data suggest that this noninvasive measurement of muscle energy metabolism may represent a surrogate marker for MJD. © 2010 Movement Disorder Society     

Proteomics and transcriptomics of peripheral nerve tissue and cells unravel new aspects of the human Schwann cell repair phenotype

The remarkable feature of Schwann cells (SCs) to transform into a repair phenotype turned the spotlight on this powerful cell type. SCs provide the regenerative environment for axonal re‐growth after peripheral nerve injury (PNI) and play a vital role in differentiation of neuroblastic tumors into a benign subtype of neuroblastoma, a tumor originating from neural crest‐derived neuroblasts. Hence, understanding their mode‐of‐action is of utmost interest for new approaches in regenerative medicine, but also for neuroblastoma therapy. However, literature on human SCs is scarce and it is unknown to which extent human SC cultures reflect the SC repair phenotype developing after PNI in patients. We performed high‐resolution proteome profiling and RNA‐sequencing on highly enriched human SC and fibroblast cultures, control and ex vivo degenerated nerve explants to identify novel molecules and functional processes active in repair SCs. In fact, we found cultured SCs and degenerated nerves to share a similar repair SC‐associated expression signature, including the upregulation of JUN, as well as two prominent functions, i.e., myelin debris clearance and antigen presentation via MHCII. In addition to myelin degradation, cultured SCs were capable of actively taking up cell‐extrinsic components in functional phagocytosis and co‐cultivation assays. Moreover, in cultured SCs and degenerated nerve tissue MHCII was upregulated at the cellular level along with high expression of chemoattractants and co‐inhibitory rather than ‐stimulatory molecules. These results demonstrate human SC cultures to execute an inherent program of nerve repair and support two novel repair SC functions, debris clearance via phagocytosis‐related mechanisms and type II immune‐regulation. GLIA 2016;64:2133–2153     

Duodenal levodopa/carbidopa infusion therapy in patients with advanced Parkinson’s disease leads to improvement in caregivers’ stress and burden

Background: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson’s disease (PD). However, the impact of DLI on caregivers’ stress and burden has not been reported. Methods: We evaluated prospectively open‐label seven advanced PD patients (65.7 ± 9.6 years, 71.4% men) treated with DLI. Schwab & England Activities of Daily Living Scale (ADLS), 39‐item Parkinson’s disease QoL Questionnaire Summary Index score (PDQ‐39SI), Zarit Caregiver Burden Interview (ZCBI), and Caregiver Strain Index (CSI) were used. Comparisons were made between scores obtained at baseline and those at a mean follow‐up of 31.4 ± 7.9 months (range, 23–42). Results: In patients, mean ± SD ADLS was increased from 50 ± 8.2 to 80 ± 11.6 (P = 0.014), and mean ± SD PDQ‐39SI was decreased from 53.7 ± 11.9 to 33.6 ± 12.8 (P = 0.018). In caregivers, ZCBI decreased from 43 ± 13.3 to 20.7 ± 12.1 (P = 0.018) and CSI from 6.3 ± 2.5 to 1.6 ± 0.9 (P = 0.018). At baseline, 57.1% of caregivers reported moderate to severe burden (ZCBI 41–88) compared to 28.6% at the end of the follow‐up (P = 0.015); at that time, no caregiver reported high level of stress (CSI ≥ 7) compared to 57.1% at baseline (P = 0.046). There were significant correlations between ZCBI and CSI improvement (r = 0.813, P = 0.026), ZCBI and PDQ‐39SI (r = 0.875, P = 0.01), and ZCBI and ADLS (r = 0.813, P = 0.026). Conclusions: Duodenal levodopa infusion‐related clinical improvement in patients with advanced PD leads to substantial reductions in caregivers’ stress and burden.     

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study

Abstract Gastric emptying (GE) may be driven by tonic contraction of the stomach (‘pressure pump’) or antral contraction waves (ACW) (‘peristaltic pump’). The mechanism underlying GE was studied by contrasting the effects of clonidine (α₂‐adrenergic agonist) and sumatriptan (5‐HT₁ agonist) on gastric function. Magnetic resonance imaging provided non‐invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min^?1 IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r² = 49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r² = 15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the ‘pressure pump’ mechanism.     

A novel protocol for assessing exercise performance and dystropathophysiology in the mdx mouse

Introduction: Dystrophinopathy in the young mdx mouse model of Duchenne muscular dystrophy is comparatively mild, requires induction, and is rarely assessed with tests of systemic muscle function in whole animals. Methods: A modified TREAT‐NMD induction protocol was used to evaluate respiratory and exercise performance, starting and ending with maximum oxygen consumption (VO _2max) tests. Results: The initial and/or final VO _2max, time to exhaustion, speed at exhaustion, and total expended calories were significantly lower in mdx mice. Episodic VO ₂ and VCO ₂ fluctuations occurred during training and resulted in dissociated patterns of VO ₂ and respiratory exchange ratio (RER). These fluctuations further resulted in significantly greater VO ₂ coefficient of variation and RER values and lower minimal VO ₂ values. Conclusions: Quantifying respiratory performance during exercise is a potentially useful means for studying pathophysiology in mdx mice, as it assesses intact animals over time, is more sensitive than some histological markers, and assesses systemic muscle function. Muscle Nerve 50: 541–548, 2014     

Nonmotor symptoms are independently associated with impaired health‐related quality of life in Chinese patients with Parkinson's disease

We performed a cross‐sectional study of 82 Chinese patients with Parkinson's disease (PD) enrolled during an 18‐month period using a clinical interview to assess the prevalence of nonmotor symptoms (NMS), the association with disease severity and motor status, and the impact on patients' health‐related quality of life (Hr‐QoL). The patients' NMS, Hr‐QoL, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), the 39‐item Parkinson's Disease Questionnaire (PDQ‐39), the modified Hoehn and Yahr staging scale (H&Y) and the Unified Parkinson's Disease Rating Scale part III (UPDRS III), respectively. We found that 100% of patients with PD presented with NMS. The NMSS significantly correlated with disease duration (Spearman's r_S = 0.276, P = 0.012), H&Y (r_S = 0.230, P = 0.038), and UPDRS III (r_S = 0.350, P = 0.001). Similarly, the PDQ‐39 SI significantly associated with the disease duration (r_S = 0.258, P = 0.019), H&Y (r_S = 0.340, P = 0.002), and UPDRS III (r_S = 0.453, P < 0.001). NMS domains that influenced the PDQ‐39 SI were sleep/fatigue, mood, gastrointestinal, urinary, and miscellaneous symptoms. This strongly suggested that the five domains played a key role in the manifestation of Hr‐QoL. NMSS explains more of the variability in Hr‐QoL than UPDRS III, when both are the model (stepwise multiple linear regression analysis R² change, 47.8% vs. 5.87%, respectively). Therefore, these findings demonstrate that NMS are independently and negatively associated with Hr‐QoL in PD and that improving NMS should be viewed as an important part in the management of PD. © 2010 Movement Disorder Society     

Regulation of central muscarinic receptors after cholinesterase inhibition: Effect of clonidine

In rats, the injection of soman (70 μg/kg, SC) resulted in a 90% inhibition of the cholinesterase (ChE) activities in three brain regions. The density (B_max) for muscarinic acetylcholine receptors (mAChRs) following a single injection of soman was significantly reduced at 2 h after injection in the cortex and hindbrain. B_max values, however, returned to baseline within 24 h. Subacute (repeated injection every 15 min) treatment with a sublethal dose of soman over 2 h also decreased the density of mAChRs. In both cases the density of mAChRs was reduced by about 15% for the cortex and 17% for the hindbrain (the midbrain was also reduced by 18% for subacute injections). Chronic administration (once daily for 7 days) of soman (20 μg/kg, SC) produced maximal inhibition of ChE activity but did not significantly downregulate mAChRs. Clonidine pretreatment reversed the soman-induced mAChR downregulation in cortex and hindbrain produced by acute soman administration. Thus, marked reduction in the levels of brain ChE is not the only factor involved in the production of mAChR downregulation to cholinesterase inhibitors.     

CSF total and phosphorylated tau protein,regional glucose metabolism and dementia severity in Alzheimer’s disease

Background and purpose: We investigated associations between severity of cognitive impairment, cerebrospinal fluid (CSF) concentrations of total‐tau (t‐tau) protein and tau phosphorylated at threonin 181 (p‐tau₁₈₁) and regional glucose metabolism measured with 18F‐fluorodeoxyglucose‐positron emission tomography (18F‐FDG‐PET) in patients with probable Alzheimer’s disease (AD). Methods: In 38 patients (mean age 66.5 ± 8.0 years) with AD, Mini‐Mental State Examination (MMSE) scores were evaluated and CSF levels of t‐tau and p‐tau₁₈₁ measured. All patients underwent an 18F‐FDG‐PET scan. Image analysis including correlation analysis and principal component analysis (PCA) were performed using SPM5 and VINCI. Results: Dementia severity (MMSE 21.2 ± 4.9) correlated well with metabolic impairment especially in left hemisphere association areas that are typically affected in patients with AD (e.g. inferior parietal lobule, r = 0.512; medial temporal gyrus, r = 0.478; inferior temporal gyrus, r = 0.488; precuneus, r = 0.468; PCA: r = 0.639, F = 7.751; all P < 0.001). There were no associations between t‐tau and p‐tau₁₈₁ with dementia severity and only weak correlations between t‐tau and cerebral glucose metabolism (superior parietal gyrus, r = ?0.325, P < 0.05; precentral gyrus r = ?0.418, P < 0.01; amygdala r = ?0.362, P < 0.05). No correlations were found between p‐tau₁₈₁ and regional hypometabolism in FDG‐PET. Conclusion: MMSE and CSF t‐tau represent different aspects of disease severity. Whilst MMSE is closely related to impaired cerebral glucose metabolism, CSF t‐tau is less closely related and appears to be less well suited for assessment of disease progression.