To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.
Consecutive patients with sporadic ALS (n = 279) ...underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.
On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.
These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.
Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled ...study was undertaken to address whether IGF-1 benefited patients with ALS.
A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used.
There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period.
Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.
In a large cohort of 1034 patients with the diagnosis of definite or probable amyotrophic lateral sclerosis (ALS), the association of forced vital capacity (FVC) at baseline with (a) time to ...progression of 20 points in Appel ALS (AALS) score or (b) tracheostomy free survival was investigated. The median survival of ALS patients with baseline FVC <75% was 2.91 years, compared with 4.08 years for patients with baseline FVC >75% (p<0.001). Patients with baseline FVC <75% progressed more rapidly (taking 8.0 months to progress 20 AALS points) compared with patients with baseline FVC >75% (10.0 months, p<0.001). Moreover, FVC at first examination was identified as a significant predictor of survival and disease progression in both univariate and multivariate Cox regression models, after adjustment for age, sex, site of onset, diagnostic delay, riluzole therapy, and use of bilateral positive airway pressure and percutaneous endoscopic gastrostomy (p<0.001). We conclude that a single FVC value obtained at an initial visit may serve as a clinically meaningful predictor of survival and disease progression in ALS.
The present study focuses on the beam line optimization from the heavy-ion synchrotron SIS18 to the HADES experiment. BOBYQA (Bound Optimization BY Quadratic Approximation) solves bound constrained ...optimization problems without using derivatives of the objective function. The Bayesian optimization is another strategy for global optimization of costly, noisy functions without using derivatives. A python programming interface to MADX allow the use of the python implementation of BOBYQA and Bayesian method. This gave the possibility to use tracking simulation with MADX to determine the loss budget for each lattice setting during the optimization and compare both optimization methods.
Markers of oxidative stress and immune activation are significantly elevated in postmortem ALS CNS tissue, although the relevance to pathogenesis is unclear.
To determine the degree and distribution ...of oxidative stress and immune activation in living ALS patients and whether these levels correlate with the rate of progression or extent of disease.
Serum and CSF samples from sporadic ALS (sALS) patients were assayed for 4-hydroxy-2,3-nonenal (HNE), a lipid peroxidation product, and monocyte chemoattractant protein-1alpha (MCP-1alpha), a beta-chemokine, by high-performance liquid chromatography and ELISA and compared with levels measured in disease and normal control subjects by one-way analysis of variance. SALS serum levels were analyzed in relation to rate of progression, stage of disease, and drug therapy.
HNE levels were significantly elevated in the sera and spinal fluid of sALS patients compared with control populations and positively correlated with extent of disease but not rate of progression. MCP-1alpha levels were also elevated in the sera of sALS patients, with the exception of the neurodegenerative disease control subjects, but decreased with advancing disease. CSF MCP-1alpha levels were not different between the sampled populations. There was no correlation between serum HNE and MCP-1alpha levels in sALS patients and extent of disease. However, an inverse relationship between HNE and MCP-1alpha was demonstrable in vitro. Low levels of HNE stimulated release of MCP-1alpha from cultured human macrophages, whereas high levels inhibited release of MCP-1alpha.
These data confirm the presence of increased oxidative stress and immune activation in ALS patients. HNE is also suggested as a possible biomarker of disease.
Abstract
The gold-standard treatment for Parkinson’s disease is levodopa (L-DOPA), which is taken orally and absorbed intestinally. L-DOPA must reach the brain intact to exert its clinical effect; ...peripheral metabolism by host and microbial enzymes is a clinical management issue. The gut microbiota is altered in PD, with one consistent and unexplained observation being an increase in
Bifidobacterium
abundance among patients. Recently, certain
Bifidobacterium
species were shown to have the ability to metabolize L-tyrosine, an L-DOPA structural analog. Using both clinical cohort data and in vitro experimentation, we investigated the potential for commensal
Bifidobacteria
to metabolize this drug. In PD patients,
Bifidobacterium
abundance was positively correlated with L-DOPA dose and negatively with serum tyrosine concentration. In vitro experiments revealed that certain species, including
B. bifidum
,
B. breve
, and
B. longum
, were able to metabolize this drug via deamination followed by reduction to the compound 3,4-dihydroxyphenyl lactic acid (DHPLA) using existing tyrosine-metabolising genes
.
DHPLA appears to be a waste product generated during regeneration of NAD +. This metabolism occurs at low levels in rich medium, but is significantly upregulated in nutrient-limited minimal medium. Discovery of this novel metabolism of L-DOPA to DHPLA by a common commensal may help inform medication management in PD.
A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic
defects to the development of hyperglycaemia and type 2 diabetes is ...controversial. Accumulation of excess fat in muscle and
adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation.
The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism
in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function
by 31 P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production
and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle
mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding.
Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat
feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding
increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate
for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development
of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for
insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.
Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, ...harm, do neither, or do both.
Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment.
Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism.
No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS.
This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.
Dendritic cells (DC) are professional antigen‐presenting cells that are capable of both activating immune responses and inducing tolerance. Several studies have revealed efficiency of therapeutic ...vaccination with tolerogenic DC (tolDC) in inhibition of experimental autoimmunity. The purpose of this study was to compare four different protocols for generation of tolDC – the antidiabetic drug troglitazone (TGZ DC), NF‐κB inhibitor BAY 11‐7082 (BAY DC), prostaglandin D2 metabolite 15d‐PGJ2 (PGJ DC) and a combination of dexamethasone and 1α,25‐dihydroxyvitamin D3 (DexVD3 DC) regarding phenotype, cytokine production and T cell stimulatory capacity. TGZ DC and BAY DC had a phenotype comparable to immature DC, while DexVD3 DC were more macrophage like. Analysis of cytokine production using cell culture supernatants from all DC populations revealed that DexVD3 DC were efficient producers of IL‐10 and produced less pro‐inflammatory cytokines. T cells primed with DexVD3 DC showed reduced proliferation, and further analyses of these T cells revealed that functionally effective type 1 regulatory T cells (Tr1) but not FoxP3+ Treg were induced. Furthermore, DexVD3 DC promoted the induction of regulatory B cells (Breg). Together, these results indicate that DexVD3 DC have the best potential to be used in a tolerogenic antigen‐presenting cell‐based immunotherapy setting.
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