Mind / Body Blog

Serum homocysteine level is related to cerebral small vessel disease in a healthy population

Prevention is easy and cheap.

Abstract

Objective To evaluate the relationship between serum total homocysteine (tHcy) levels and cerebral small vessel disease (cSVD) in a healthy population.

Methods We included consecutive participants who visited our department for health checkups between 2006 and 2013. We rated white matter hyperintensity volumes using both the Fazekas score and semiautomated quantitative methods. We also evaluated lacunes, cerebral microbleeds, and enlarged perivascular spaces (EPVS), which are involved in cSVD. To assess the dose-dependent relationship between tHcy and cSVD parameters, we scored the burdens of each radiologic marker of cSVD.

Results A total of 1,578 participants were included (age 55 ± 8 years, male sex 57%). In the multivariable analysis, tHcy remained an independent predictor of the white matter hyperintensity volume (B = 0.209; 95% confidence interval [CI] = 0.033–0.385, p = 0.020), presence of cerebral microbleeds (adjusted odds ratio = 2.800; 95% CI = 1.104–7.105, p = 0.030), and moderate to severe EPVS (adjusted odds ratio = 5.906; 95% CI = 3.523–9.901, p < 0.001) after adjusting for confounders. Furthermore, tHcy had positive associations with periventricular Fazekas score (p = 0.001, p for trend <0.001), subcortical Fazekas score (p = 0.003, p for trend = 0.005), and moderate to severe EPVS lesion burden (p < 0.001, p for trend <0.001) in a dose-dependent manner.

Conclusions Serum tHcy level is correlated with cSVD development in a dose-dependent manner. These findings provide us with clues for further studies of the pathophysiology of cSVD.

http://n.neurology.org/content/92/4/e317.abstract?etoc

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Many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline.

Many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline.

Original Investigation
Neurology
November 2, 2018

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical TrialsA Meta-analysis

JAMA Netw Open. 2018;1(7):e184080. doi:10.1001/jamanetworkopen.2018.4080
Key PointsQuestion  Are cholinesterase inhibitors or memantine associated with cognitive outcomes in clinical trials for Alzheimer disease?

Findings  In this meta-analysis, participants receiving cholinesterase inhibitors or memantine had 1.4 points per year difference on the Alzheimer Disease Assessment Scale–cognitive subscale compared with those receiving neither medication, a significant difference that is roughly the same size as the expected effect of new therapeutic drugs being investigated in the clinical trials.

Meaning  Differences in the use of cholinesterase inhibitors and memantine between treatment and placebo groups of clinical trials may lead to the conclusion that a treatment is effective when it is not, or vice versa.

Abstract

Importance  Clinical trials in Alzheimer disease (AD) generally allow participants to continue receiving concomitant medications, including cholinesterase inhibitors (ChEIs) and memantine, if the dose is stable. Previous analysis of observational studies indicates such individuals experience greater rate of decline on cognitive testing than those not receiving such medications.

Objective  To investigate whether concomitant use of ChEIs or memantine is associated with cognitive outcomes in AD clinical trials.

Data Sources  Meta-database of 18 studies from the Alzheimer Disease Cooperative Study and Alzheimer Disease Neuroimaging Initiative.

Study Selection  All studies with data on ChEI and memantine use that included assessment of specified outcome measures.

Data Extraction and Synthesis  The analysis estimated annual rate of decline on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) using linear mixed-effects models, and compared rates for participants receiving ChEIs and memantine, alone and combined, with participants not receiving either medication using random-effects meta-analysis.

Main Outcomes and Measures  Annual rate of change on the ADAS-cog.

Results  Across 10 studies, of 2714 participants, the mean (SD) age was 75.0 (8.2) years, 58% were female, and 9% were racial/ethnic minorities. There were 906 participants (33.4%) receiving ChEIs, 143 (5.3%) receiving memantine, 923 (34.0%) receiving both, and 742 (27.3%) receiving neither. Meta-analysis showed those receiving ChEIs or memantine were associated with significantly greater annual rate of decline on the ADAS-cog than those receiving neither medication (1.4 points/y; 95% CI, 0.1-2.7).

Conclusions and Relevance  Similar to observational studies, many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline. This difference is nearly as large as the hypothesized effect sizes of the treatments investigated in the trials. Concomitant use of ChEIs or memantine may be confounded with outcomes on the ADAS-cog and should be considered in design of clinical trials of potential therapeutic agents for AD. Post hoc analyses stratifying by ChEIs or memantine must be interpreted cautiously given the potential for confounding.

 

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A reminder.. The well-established but under-appreciated dopamine-blocking effect of metoclopramide.

A reminder.. The well-established but under-appreciated dopamine-blocking effect of metoclopramide.

Ned Tijdschr Geneeskd. 2013;157(26):A6037.

Severe parkinsonism due to Reglan (metoclopramide): the importance of early recognition.

[Article in Dutch]

de Ronde MW1, Kingma HJ, Munts AG.

Author information

1Kennemer Gasthuis, afd. Neurologie, Haarlem, the Netherlands. mwjderonde@gmail.com

Abstract

In this article, we present 3 women aged 73, 85 and 88 years who developed metoclopramide-induced parkinsonism. Shortly after starting metoclopramide, bradykinesia and rigidity developed in all 3 patients; tremor and postural instability in 2 of them. We discontinued the metoclopramide after 3-6 months; 2 of the patients had fully recovered 4-6 months later. The 3rd patient died from pneumonia, however, 2 months after discontinuation. Metoclopramide, a dopamine D2-antagonist, is a frequently prescribed anti-emetic drug; however, evidence of its efficacy is limited. In many patients, domperidone, another dopamine D2-antagonist, seems to be a better alternative. Movement disorders due to domperidone are uncommon, presumably because it does not cross the blood-brain barrier. It is likely that metoclopramide-induced parkinsonism is not uncommon; however, it is under-recognized. Risk factors are female sex, advanced age, diabetes mellitus and polypharmacy. Follow-up on patients using metoclopramide is advised.

Zhonghua Nei Ke Za Zhi. 1988 Jun;27(6):358-60, 390.

Adverse neurologic effects of Reglan (metoclopramide). Report of 60 cases.

[Article in Chinese]

Sun B, Cao QL, Ou XR.

Am J Gastroenterol. 2013 Jun;108(6):866-72. doi: 10.1038/ajg.2012.300.

The metoclopramide black box warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug lawsuits.

Ehrenpreis ED1, Deepak P, Sifuentes H, Devi R, Du H, Leikin JB.

Author information

1Department of Gastroenterology, Evanston Hospital, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. ehrenpreis@gipharm.net

Abstract

OBJECTIVES: We examined the effects of the black box warning about the risk of tardive dyskinesia (TD) with chronic use of metoclopramide on management of gastroparesis within a single clinical practice, and on reporting of adverse events.

METHODS: Medical records of gastroparesis patients were evaluated for physician management choices. The FDA Adverse Event Reporting System (FAERS) was analyzed for event reports, and for lawyer-initiated reports, with metoclopramide from 2004 to 2010. Google Scholar was searched for court opinions against metoclopramide manufacturers.

RESULTS: Before the black box warning, 69.8% of patients received metoclopramide for gastroparesis, compared with 23.7% after the warning. Gastroenterologists prescribed domperidone more often after than before the warning. Metoclopramide prescriptions decreased after 2008. Adverse event reporting increased after the warning. Only 3.6% of all FAERS reports but 70% of TD reports were filed by lawyers, suggesting a distortion in signal. Forty-seven legal opinions were identified, 33 from 2009-2010.

CONCLUSIONS: The black box warning for metoclopramide has decreased its usage and increased its rate of adverse event reporting. Lawyer-initiated reports of TD hinder pharmacovigilance.

Ned Tijdschr Geneeskd. 2002 Jan 26;146(4):175-7.

Severe parkinsonism due to Reglan (metoclopramide) in a patient with polypharmacy.

[Article in Dutch]

Hoogendam A1, Hofmeijer J, Frijns CJ, Heeringa M, Schouten-Tjin a Tsoi SL, Jansen PA.

Author information

1Afd. Klinische Geriatrie, Universitair Medisch Centrum, Utrecht. hoogendam-dekkers@zonnet.nl

Abstract

A 73-year-old woman, with tuberculosis of the large intestine, developed nausea as a side effect of the antituberculosis drugs. The nausea was treated with metoclopramide. Subsequently she developed severe medication-induced parkinsonism. As her symptoms initially mimicked a depressive disorder, drug-induced parkinsonism was only considered at a later stage. Due to drug-induced impaired function of the liver and kidney the patient had received a toxic dose of metoclopramide. Treatment with biperiden and withdrawal of the metoclopramide resulted in a reduction of the complaints within 3 months, after which the anti-tuberculosis medication could be reintroduced. Adjusting the dose of metoclopramide could possibly have prevented this severe side effect.

 

Psychiatry Clin Neurosci. 2007 Apr;61(2):193-5.

Persistent generalized anxiety after brief exposure to the dopamine antagonist Reglan (metoclopramide).

Kluge M1, Schüssler P, Steiger A.

Author information

1Max Planck Institute of Psychiatry, Munich, Germany. kluge@mpipsykl.mpg.de

Abstract

The authors describe a 31-year-old woman who developed persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Independently of that, she had experienced a panic attack followed by dystonias, shortly after a single dose of that drug, 17 years before. Both temporal association and recurrence of anxiety symptoms after re-challenge with metoclopramide suggest a causal relationship. The case might provide an initial piece of evidence that dopaminergic neurotransmission can be involved in the pathogenesis of generalized anxiety disorder.

 

See comment in PubMed Commons below

Ceylon Med J. 1996 Sep;41(3):125.

Parkinsonism: an under-recognised complication of Reglan (metoclopramide) use.

[No authors listed

Acta Neurol (Napoli). 1992 Apr;14(2):130-3.

Reglan (Metoclopramide)-induced parkinsonism and depression.

Jibiki I1, Maeda T, Yamaguchi N.

Author information

1Department of Neuropsychiatry, Kanazawa University School of Medicine, Japan.

Abstract

A 46-year-old female patient with metoclopramide-induced parkinsonism and depression was reported in view of the rarity of the concurrent development of these side effects. A risk of metoclopramide administration is suggested

South Med J. 1989 Dec;82(12):1581-2.

Reglan (Metoclopramide)-induced parkinsonism.

Sethi KD1, Patel B, Meador KJ.

Author information

1Department of Neurology, Medical College of Georgia, Augusta 30912-2366.

Abstract

Metoclopramide hydrochloride (Reglan) is a widely prescribed drug for treatment of upper gastrointestinal symptoms. Although the drug is relatively safe, a growing body of literature has noted movement disorders after its administration. We have reported six cases of metoclopramide-induced parkinsonism seen in consultation over a two-year period. Five of these six patients had renal failure. Their parkinsonism improved on discontinuation of metoclopramide therapy. Metoclopramide-induced parkinsonism is not rare, and appropriate dose reduction in patients with renal failure will help reduce the incidence of this morbidity.

J Emerg Med. 2006 May;30(4):411-3.

Abdominal pain with rigidity secondary to the anti-emetic drug Reglan (metoclopramide).

Khan NU1, Razzak JA.

Author information

1Section of Emergency Medicine, Department of Medicine, The Aga Khan University, Karachi, Pakistan.

Abstract

We report a case of abdominal pain with rigidity, mimicking an acute abdomen, caused by metoclopramide, a common anti-emetic drug. Extrapyramidal symptoms are commonly reported side-effects of this medication. They generally include involuntary movements of limbs, torticollis, oculogyric crisis, rhythmic protrusion of tongue, trismus, or dystonic reactions resembling tetanus, etc. Abdominal rigidity due to this medication, resembling an acute abdomen, has not been reported previously. This case report illustrates the importance of considering medication side-effects when evaluating a patient with abdominal pain and rigidity.

Synapse. 2011 Feb;65(2):119-24. doi: 10.1002/syn.20825.

Antipsychotic drug binding in the substantia nigra: an examination of high Reglan (metoclopramide) binding in the brains of normal, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis patients, and its relation to tardive dyskinesia.

Chen S1, Seeman P, Liu F.

Author information

1Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada M5T 1R8.

Abstract

This project was done in order to determine why the annual incidence of metoclopramide-associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics to the dissected melaninized regions of postmortem human substantia nigra was measured. The nonspecific binding at 1 nM [³H]ligand was 7.3, 4.2, 2.6, 0.91 and 0.66 fmoles/mg for [³H]haloperidol, [³H]clozapine, [³H]raclopride, [³H]metoclopramide, and [³H]olanzapine, respectively. After adjusting these values for the known free concentrations of these drugs in plasma or spinal fluid, the amounts that would be bound under clinical conditions would be 231, 113, 15, 11, and 3.4 fmoles/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively. Using rat striatum as baseline to define antipsychotic binding to nonnigral tissue, the excess amount of binding to the Alzheimer nigral tissue under clinical conditions would be 209, 19, 0, 3.4 and 0.8 fmole/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively, with a similar pattern for nigral tissues from Huntington and Multiple Sclerosis patients. The high accumulation of metoclopramide is sufficiently high to cause nigral nerve cell membrane damage by metoclopramide’s detergent-like action, possibly explaining metoclopramide’s toxic ability to elicit early tardive dyskinesia. In addition, the nonspecific binding of metoclopramide was much higher in Alzheimer-diseased substantia nigra, consistent with the fact that older individuals are relatively more vulnerable to metoclopramide tardive dyskinesia.

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EPIGENETICS Preconception cold–induced epigenetic inheritance

News & Views | Published:

EPIGENETICS

Preconception cold–induced epigenetic inheritance

Nature Medicinevolume 24pages1308–1309 (2018) | Download Citation

Preconception cold–induced alterations of sperm DNA methylation result in offspring with altered brown adipose tissue and improved adaptation to overnutrition and hypothermia.

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Carbs, Good for You? Fat Chance!

https://www.wsj.com/articles/carbs-good-for-you-fat-chance-1536705397

 

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