Long-standing multiple sclerosis neurodegeneration: volumetric magnetic resonance imaging comparison to Parkinson's disease, mild cognitive impairment, Alzheimer's disease, and elderly healthy controls.

Multiple sclerosis (MS) exhibits neurodegeneration driven disability progression. We compared the extent of neurodegeneration among 112 long-standing MS patients, 37 Parkinson's disease (PD) patients, 34 amnestic mild cognitive impairment (aMCI) patients, 37 Alzheimer's disease (AD) patients, and 184 healthy controls. 3T MRI volumes of whole brain (WBV), white matter (WMV), gray matter (GMV), cortical (CV), deep gray matter (DGM), and nuclei-specific volumes of thalamus, caudate, putamen, globus pallidus, and hippocampus were derived with SIENAX and FIRST software. Аge and sex-adjusted analysis of covariance was used. WBV was not significantly different between diseases. MS had significantly lower WMV compared to other disease groups (p < 0.021). Only AD had smaller GMV and CV when compared to MS (both p < 0.001). MS had smaller DGM volume than PD and aMCI (p < 0.001 and p = 0.026, respectively) and lower thalamic volume when compared to all other neurodegenerative diseases (p < 0.008). Long-standing MS exhibits comparable global atrophy with lower WMV and thalamic volume when compared to other classical neurodegenerative diseases.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

Treatment of chronic insomnia disorder in menopause: evaluation of literature.

OBJECTIVE: Insomnia both as a symptom and as part of chronic insomnia disorder is quite common in menopause. Comorbid conditions, such as restless legs syndrome and obstructive sleep apnea, occur with high prevalence among perimenopausal women with insomnia. Insomnia in this population group is associated with adverse health outcomes, and there are no clear standards on how to treat it. METHODS: Based on extensive literature search, 76 articles were identified. Two authors independently graded evidence according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. RESULTS: Evaluation and treatment of other comorbid sleep disorders are recommended, as is cognitive-behavioral therapy for insomnia. Hormone therapy, eszopiclone, escitalopram, gabapentin, isoflavones, valerian, exercise, and hypnosis are suggested. Zolpidem, quiteiapine XL, citalopram, mirtazapine followed by long-acting melatonin, ramelteon, Pycnogenol, Phyto-Female Complex, yoga, and massage may be considered. Kampo formulas are not recommended. Acupuncture may not be suggested, and cognitive-behavioral therapy that is not tailored for insomnia probably should not be considered. CONCLUSIONS: Although a variety of interventions are shown to be helpful in improving sleep in menopause, there is a need for well-designed head-to-head trials with uniform outcome measures.

Effective and clinically meaningful non-hormonal hot flash therapies.

Although many non-hormonal compounds have shown statistically significant benefit over placebo in hot flash randomized controlled trials (RCTs), these studies have varied considerably in basic methodology making it challenging to deduce which compounds have the greatest potential to provide clinically meaningful benefit. This review used evidence-based methodology closely mirroring the FDA and EMEA guidelines as a template to identify "well-designed" RCTs from which effective and clinically meaningful non-hormonal hot flash therapies could be identified. In addition, pertinent safety information was reviewed. Out of 3548 MEDLINE citations and abstracts, 51 well-designed hot flash RCTs were identified. From these trials, gabapentin, oxybutynin ER, desvenlafaxine, soy-derived isoflavones and black cohosh each showed a clinically meaningful treatment effect in at least 1 RCT. Among these 5 compounds, only gabapentin demonstrated consistent and statistically significant benefit over placebo in all of its well-designed RCTs. Desvenlafaxine, soy-derived isoflavones, and black cohosh demonstrated statistically significant benefit over placebo in 75%, 21%, and 17% of the well-designed RCTs for each compound, respectively. There was only 1 well-designed RCT using oxybutynin ER, which showed it to have a robust and clinically meaningful benefit. In terms of safety, there have been cardiovascular risks associated with desvenlafaxine use in postmenopausal women with hot flashes. The use of anticonvulsants, in general, has been associated with an absolute 0.21% increase in suicidal thoughts and behavior. Further research is needed with several of these nonhormonal compounds to replicate these findings and to also directly compare their efficacy and tolerability with those of hormone replacement therapy.

Effects of L-isoleucine and L-valine on hot flushes and serum homocysteine: a randomized controlled trial.

OBJECTIVE: To investigate whether L-isoleucine was effective in the treatment of hot flushes and whether L-isoleucine, L-valine, or the combination of both amino acids reduced fasting serum homocysteine. METHODS: After a 1-week baseline period, 100 postmenopausal women experiencing at least five moderate-severe hot flushes per day were randomized with equal probability to one of four groups (phase 1/phase 2): placebo/L-valine, placebo/L-valine and L-isoleucine, L-isoleucine/L-valine, and L-isoleucine/L-valine and L-isoleucine. Phase 1 was 12 weeks long, and phase 2 was 10 weeks long. Patients took five capsules by mouth, twice a day throughout the study, with each capsule containing 500 mg of compound. Data were obtained from daily hot flush diaries, fasting blood work, and several questionnaires. The primary outcome variable was the percent change in hot flush composite score from baseline to week 12. RESULTS: In phase 1 of the study, there were no significant differences between the L-isoleucine and placebo groups for any of the outcome measures. At week 12, there was a mean 13.9% decrease in hot flush composite score compared with baseline in the L-isoleucine group and a mean 25% decrease in the placebo group (P=.28). In phase 2 of the study, there was no significant change in fasting serum homocysteine levels associated with any of the amino acid therapies. CONCLUSION: L-isoleucine therapy appears to be ineffective in the treatment of hot flushes in postmenopausal women. L-isoleucine and L-valine, either alone or in combination, appear to have no effect on fasting serum homocysteine levels. CLINCIAL TRIAL REGISTRATION: ClinicalTrials.gov, (www.clinicaltrials.gov), NCT00081952. LEVEL OF EVIDENCE: I.