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  1. Dear ALL, The following fascinating article appeared in a University of Rochester publication this morning: https://www.urmc.rochester.edu/news/story/5508/not-all-sleep-is-equal-when-it-comes-to-cleaning-the-brain.aspx It describes the cleansing of the brain of debris by cerebral spinal fluid during slow wave sleep, discovered previously at UR; and notes that, during surgery, especially on older adults, it's important to use the appropriate anaesthetics, ketamine and xylazine, so that the glymphatic system should work as it usually works during deep slow wave sleep, to clear the brain. (The wrong anaesthetics can allow plaques to accumulate. Clinical examples are given. An obvious observation, not mentioned in the article (for obvious reasons): Might it be conceivably eventually a method of helping people having difficulty achieving slow wave sleep, to be take (orally take or inject ?) these two anaesthetics in (who knows what ?) quantity before bed to achieve better quality sleep? (I don't recommend experimenting with this on yourselves; but it would be fascinating if some qualified sleep researcher managed to start a clinical study of this possible method of improving sleep quality on patients at risk of Alzheimers. Probably would be VERY hard to get FDA approval). -- Saul
  2. Does anyone else eat natto, the fermented soybean product which is quite popular in Japan? It is the richest food source of vitamin K2 (menaquinone-7 or MK-7) with 1 mg (1000 mcg) of K2 per 100g natto. That is about 20x higher than the next highest source, certain cheeses like Gouda. Unlike vitamin K1 which is found primarily in leafy greens, there is virtually no vitamin K2 in regular fruits and vegetables. Why should we care about vitamin K2 you ask? First and foremost because it has been shown to be protective against osteoporosis [1-2], a concern for CR practitioners. From [2], a study of 244 postmenopausal women supplemented with 180mcg/day of Vitamin K2 (MK-7) for three years: MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS: MK-7 supplements may help postmenopausal women to prevent bone loss. Another significant benefit of Vitamin K2 is for cardiovascular health. Vitamin K2 seems to prevent artery calcification (aka hardening of the arteries) [3-5], which happens when calcium circulating in the blood is turned into a crust in the arteries. In study [5] the same group of researchers from [2] measured arterial calcification in the same 244 postmenopausal women on 180mcg/day of K2 for three years, and found multiple markers of arterial stiffness improved with K2 supplementation, concluding: Long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness. But those were studies of direct supplementation of vitamin K2 (MK-7), rather than getting it from food. Does eating natto actually raise serum MK-7 levels? Thankfully the answer is yes, according to [6]: erum MK-7 level with the frequency of dietary natto intake were examined in 134 healthy adults (85 men and 39 women) without and with occasional (a few times per month), and frequent (a few times per week) dietary intake of regular natto including MK-7 (775 micrograms/100 g). Serum MK-7 and gamma-carboxylated osteocalcin concentrations in men with the occasional or frequent dietary intake of natto were significantly higher than those without any intake. So where to get natto? I buy my natto in frozen form at my local asian market, for about $2.50 for four styrofoam containers each of which contains about 50g of natto. Here is what the package of four look like: I eat half of a container's worth of natto per day (cost ~ $0.30/day). That 25g of natto per day provides about 250mcg of Vitamin K2 (MK-7), which is about 30% more than the dose shown to improve bone health [2] and reduce arterial stiffness [5] in postmenopausal women. What's natto like you ask? There is no getting around the fact that it looks pretty gross, and has a very slimy texture. As a result, many people can't stomach it, but I actually enjoy the taste, especially when mixed into the serving of other legumes and starches I eat. Below is a photo of natto in the styrofoam container. Pretty appetizing, huh?! The chopsticks in the photo are helpful for scale: For those of you who would be too grossed out by natto to eat it, there are supplements available. In fact I take one of these* to increase my K2 beyond what I get from natto - adding an extra 100mcg MK-7 per day for $0.09. But I'm always in favor of getting nutrients from food sources when practical. This is one of the rare cases where the natural food source is price competitive with supplement sources. So for me natto is a good choice. Does anyone else eat natto? If not, you might consider giving it a try! [Note: This post does not address Natto's brain health benefits. For discussion of that, see this post further down this thread.] --Dean *Note - I've updated my supplement regime to this vegan NOW Foods brand K2 supplement, to make sure I'm getting K2 in MK-7 form, rather than (mostly) MK-4 per my previous supplement. --------- [1] J Bone Miner Metab. 2014 Mar;32(2):142-50. doi: 10.1007/s00774-013-0472-7. Epub 2013 May 24. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. Koitaya N(1), Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishimi Y. Author information: (1)Department of Food Function and Labeling, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjyuku-ku, Tokyo, Japan. Menaquinone-4 (MK-4) administered at a pharmacological dosage of 45 mg/day has been used for the treatment of osteoporosis in Japan. However, it is not known whether a lower dose of MK-4 supplementation is beneficial for bone health in healthy postmenopausal women. The aim of this study was to examine the long-term effects of 1.5-mg daily supplementation of MK-4 on the various markers of bone turnover and bone mineral density (BMD). The study was performed as a randomized, double-blind, placebo-controlled trial. The participants (aged 50-65 years) were randomly assigned to one of two groups according to the MK-4 dose received: the placebo-control group (n = 24) and the 1.5-mg MK-4 group (n = 24). The baseline concentrations of undercarboxylated osteocalcin (ucOC) were high in both groups (>5.1 ng/ml). After 6 and 12 months, the serum ucOC concentrations were significantly lower in the MK-4 group than in the control group. In the control group, there was no significant change in serum pentosidine concentrations. However, in the MK-4 group, the concentration of pentosidine at 6 and 12 months was significantly lower than that at baseline. The forearm BMD was significantly lower after 12 months than at 6 months in the control group. However, there was no significant decrease in BMD in the MK-4 group during the study period. These results suggest that low-dose MK-4 supplementation for 6-12 months improved bone quality in the postmenopausal Japanese women by decreasing the serum ucOC and pentosidine concentrations, without any substantial adverse effects. PMID: 23702931 ------------ [2] Osteoporos Int. 2013 Sep;24(9):2499-507. doi: 10.1007/s00198-013-2325-6. Epub 2013 Mar 23. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Knapen MH(1), Drummen NE, Smit E, Vermeer C, Theuwissen E. Author information: (1)VitaK, Maastricht University, Oxfordlaan 70, 6229 EV, Maastricht, The Netherlands. We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss.INTRODUCTION: Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K's role in maintenance of normal bone. In line with EFSA's opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. METHODS: Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. RESULTS: MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS: MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation. PMID: 23525894 ----------- [3] Acta Physiol Hung. 2010 Sep;97(3):256-66. doi: 10.1556/APhysiol.97.2010.3.2. Vitamin K and vascular calcifications. Fodor D(1), Albu A, Poantă L, Porojan M. Author information: (1)University of Medicine and Pharmacy, 2nd Internal Medicine, Clinic Iuliu Hatieganu, Cluj-Napoca, Romania. dfodor@umfcluj.ro The role of vitamin K in the synthesis of some coagulation factors is well known. The implication of vitamin K in vascular health was demonstrated in many surveys and studies conducted over the past years on the vitamin K-dependent proteins non-involved in coagulation processes. The vitamin K-dependent matrix Gla protein is a potent inhibitor of the arterial calcification, and may become a non-invasive biochemical marker for vascular calcification. Vitamin K(2) is considered to be more important for vascular system, if compared to vitamin K(1). This paper is reviewing the data from recent literature on the involvement of vitamin K and vitamin K-dependent proteins in cardiovascular health. PMID: 20843764 ---------------- [4] Nutrients. 2015 Aug 18;7(8):6991-7011. doi: 10.3390/nu7085318. High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification. Scheiber D(1), Veulemans V(2), Horn P(3), Chatrou ML(4), Potthoff SA(5), Kelm M(6,)(7), Schurgers LJ(8), Westenfeld R(9). Author information: (1)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. daniel.scheiber@med.uni-duesseldorf.de. (2)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. verena.veulemanns@med.uni-duesseldorf.de. (3)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. patrick.horn@med.uni-duesseldorf.de. (4)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. m.chatrou@maastrichtuniversity.nl. (5)Department of Nephrology, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. sebastian.potthoff@med.uni-duesseldorf.de. (6)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. malte.kelm@med.uni-duesseldorf.de. (7)Cardiovascular Research Institute Duesseldorf, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. malte.kelm@med.uni-duesseldorf.de. (8)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. l.schurgers@maastrichtuniversity.nl. (9)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. ralf.westenfeld@med.uni-duesseldorf.de. Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures. PMCID: PMC4555157 PMID: 26295257 ------------- [5] Thromb Haemost. 2015 May;113(5):1135-44. doi: 10.1160/TH14-08-0675. Epub 2015 Feb 19. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C(1). Author information: (1)Cees Vermeer, PhD, VitaK, Maastricht University, Biopartner Center Maastricht, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands, Tel: +31 43 388 5865, Fax: +31 43 388 5889, E-mail: c.vermeer@vitak.com. Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 µg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index βsignificantly decreased in the total group, whereas distension, compliance, distensibility, Young's Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness. PMID: 25694037 ---------- [6] J Bone Miner Metab. 2000;18(4):216-22. Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. Tsukamoto Y(1), Ichise H, Kakuda H, Yamaguchi M. Author information: (1)Central Research Institute, Mitsukan Group Co., Ltd., Aichi, Japan. Changes in circulating vitamin K2 (menaquinone-7, MK-7) and gamma-carboxylated osteocalcin concentrations in normal individuals with the intake of fermented soybeans (natto) were investigated. Eight male volunteers were given sequentially fermented soybeans (natto) containing three different contents of MK-7 at an interval of 7 days as follows: regular natto including 775 micrograms/100 g (MK-7 x 1) or reinforced natto containing 1298 micrograms/100 g (MK-7 x 1.5) or 1765 micrograms/100 g (MK-7 x 2). Subsequently, it was found that serum MK-7 and gamma-carboxylated osteocalcin concentrations were significantly elevated following the start of dietary intake of MK-7 (1298 or 1765 micrograms/100 g). Serum undercarboxylated osteocalcin concentrations were significantly decreased by dietary MK-7 (1765 micrograms/100 g) supplementation. Moreover, the changes in serum MK-7 level with the frequency of dietary natto intake were examined in 134 healthy adults (85 men and 39 women) without and with occasional (a few times per month), and frequent (a few times per week) dietary intake of regular natto including MK-7 (775 micrograms/100 g). Serum MK-7 and gamma-carboxylated osteocalcin concentrations in men with the occasional or frequent dietary intake of natto were significantly higher than those without any intake. The present study suggests that intake of fermented soybean (natto) increases serum levels of MK-7 and gamma-carboxylated osteocalcin in normal individuals. PMID: 10874601
  3. Dean Pomerleau


    I was surprised to find that a search of these forums turned up very little discussion of nootropics, or so-called "smart drugs", at least as far as I could find. Obviously cognitive performance and long-term brain health is an important consideration for everyone, but especially obsessive optimizers like us ☺. So I figured I'd start a thread to inquire if anyone has experimented with nootropics, and if so, which ones (if any) did you find beneficial. To kick off the discussion, I've never experimented with any nootropics myself, except for caffeine, which honestly I don't find has much of an observable effect on me (cognitive or otherwise), but I take it anyway (as coffee/tea, and as a B12-fortified mint) for other health reasons. But today I came across a new multi-nootropic supplement from someone I trust, respect and believe to be quite intelligent - Lincoln Cannon. Lincoln is the co-founder of the Mormon Transhumanism Association, a pretty cool longevity-focused organization to which I and many other non-Mormons belong. Lincoln is also responsible for formulating the New God Argument, which I find pretty compelling (see here for related discussion and here for science/philosophy heavyweights on the topic). But I digress... Thrivous, his new company (to which I have no affiliation), has developed a nootropic supplement called Clarity. Here is the Clarity label: Has anyone any personal experience, or done any research on any of these ingredients? Here is Lincoln's research on them, plus a couple others not included in this version of Clarity. They look reasonably beneficial (and harmless) based on the controlled studies Lincoln has compiled. The price is pretty reasonable - $25 for a month's supply. I'm forever interested in self-experimentation and lifestyle optimization, so I was thinking of conducting a single-blind, crossover trial on myself to see if I notice any difference between taking Clarity vs. a placebo. But if others have had bad experiences with these nootropics, or know of research that says they may be harmful, I'll obviously steer clear. Thanks! --Dean
  4. All, Like we've seen for cardiovascular disease, eating fish can be a mixed blessing. The omega-3 fatty acids (DHA/EPA) are thought to be beneficial, particularly for brain function. But the mercury, PCBs and other contaminants that bioaccumulate in the fat of fish may also have harmful effects. This new study[1] (thanks to Al Pater!) looks at the association between consumption of fish, plant omega-3s, brain mercury levels and Alzheimer's disease and brain mini-strokes. What they found is a bit nuanced, but worth thinking about. They gave 550 quite elderly but initially dementia-free people in several US nursing homes a yearly dietary questionnaire to measure their weekly intake of fish, DHA/EPA and the plant-derived omega-3 Alpha Linolenic Acid (ALA) until they died. Over an average follow-up of 4.5 years, 286 of the participates died (average age 89!). These folks' brains were autopsied to measure mercury levels and to look for physical signs of Alzheimer's disease (plaques and tangles) as well as brain injuries associated with other forms of dementia, in particular macroinfarctions and microinfarctions (i.e. strokes of various sizes). Here are the highlights of what they found: The more fish meals per week a subject consumed, the higher their brain mercury level (P < 0.02). There was no correlation between intake of ALA or DHA/EPA supplements and brain mercury level. For the majority of people (77%) who weren't carriers of the APOE4 allele that increases one's susceptibility to Alzheimer's disease, neither eating fish, dietary DHA/EPA nor consuming ALA had a significant effect (one way or the other) on the risk of Alzheimer's disease. For the minority (23%) of subjects who were APOE4 carriers, eating more fish and more dietary DHA/EPA was associated with a decreased risk of Alzheimer's disease markers (P < 0.04). Neither DHA/EPA supplements nor dietary ALA impacted Alzheimer's risk in these folks. Dietary ALA, but not fish or DHA/EPA, was associated with reduced prevalence of macroinfarctions (P < 0.03) and microinfarctions (P < 0.04) associated with non-Alzheimer's cognitive impairment, independent of APOE4 status. Those were the major, statistically significant findings. There is one more thing I noticed looking at the table below that appears interesting/suggestive for the majority of us who are lucky enough not have the APOE4 gene. The cells I've highlighted below represent the level of various markers of Alzheimer's disease for APOE4-negative folks. The red cells represent the level of Alzheimer's markers for people who ate the most fish (top red row), or the most dietary DHA/EPA (bottom red row). From the confidence intervals, you can see that none of them are individually significant. But also notice that all of them are positive, meaning there was a trend towards increased markers of Alzheimer's disease in APOE4-negative people who ate the most fish, especially fatty fish. In contrast, now look at the green cells, representing markers for Alzheimer's disease in APOE4-negative people who consumed the most plant-derived ALA. Notice these too are not individually significant, but all of them are negative, pointing towards a reduced risk of Alzheimer's disease with increasing ALA intake. From all this, my summary takeaway message from this study would be the following: For people with the APOE4 gene and therefore increased risk of Alzheimer's disease, eating fish is likely to reduce one's risk of Alzheimer's disease, despite increasing brain mercury levels For people without the APOE4 gene, fish consumption doesn't seem to reduce, and may even increase, one's risk of Alzheimer's disease For people without the APOE4 gene, plant-derived omega-3 ALA (e.g. from walnuts, olive oil, flax, chia) consumption may reduce one's risk of Alzheimer's disease For everyone, dietary ALA appears to reduce one's risk of brain markers for non-Alzheimer's cognitive impairment. Or more succinctly, ALA is likely to be good for everyone's brain health, and fish is likely to be good for the brain health of only the minority of people who carry the APOE4 allele. This seems like an illustration of a benefit of getting one's DNA sequenced with a company like 23andMe to determine whether one is a carrier of the APOE4 allele. --Dean ------------ [1] JAMA. 2016 Feb 2;315(5):489-97. doi: 10.1001/jama.2015.19451. Association of Seafood Consumption, Brain Mercury Level, and APOE e4 Status With Brain Neuropathology in Older Adults. Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O. Full text: http://jama.jamanetwork.com.sci-hub.io/article.aspx?articleID=2484683 Abstract IMPORTANCE: Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE: To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES: Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES: Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS: Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (??=?0.16; P?=?.02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (=?1 meal/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (ß?=?-0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (ß?=?-0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (ß?=?-0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE e4) carriers. Higher intake levels of a-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology. PMID: 26836731
  5. AlPater

    Dementia Test

    Dementia Test (only 4 questions) download?mid=2_0_0_1_277144_AEwNiWIAADxh Yep, it's that time of year again for us to take our annual senior citizen test. Exercise of the brain is as important as exercise of the muscles. As we grow older, it's important to keep mentally alert. If you don't use it, you lose it! Here is a very private way to gauge how your memory compares to your last test. Some may think it is too easy, but the ones with memory problems may have difficulty. Take this test to determine if you're losing it or not. The spaces below are so you don't see the answers until you've made your answer. OK, relax, clear your mind and begin. #1. What do you put in a toaster? Answer: 'bread.' If you said 'toast', just give up now and go do something else. And, try not to hurt yourself. If you said, bread, go to Question #2. # 2. Say 'silk' five times. Now spell 'silk.' What do cows drink? Answer: Cows drink water. If you said 'milk,' don't attempt the next question. Your brain is already over-stressed and may even overheat. Content yourself with reading more appropriate literature such as Women's Weekly or Auto World. However, if you did say 'water', proceed to Question #3. If a red house is made from red bricks, and a blue house is made from blue bricks, and a pink house is made from pink bricks, and a black house is made from black bricks, what is a green house made from? Answer: Greenhouses are made from glass. If you said 'green bricks', why are you still reading this??? PLEASE, go lie down!!! But, if you said 'glass,' go on to Question #4. # 4. Do not use a calculator for this: You are driving a bus from New York City to Philadelphia. In Staten Island, 17 people got on the bus. In New Brunswick, 6 people get off the bus and 9people get on. In Windsor, 2 people get off and 4 get on. In Trenton, 11 people get off and 16 people get on. In Bristol, 3 people get off and 5 people get on. And, in Camden, 6 people get off and 3 get on. You then arrive at Philadelphia Station. Without going back to review, how old is the bus driver? Answer: Oh, for crying out loud!!! Don't you remember your own age?!?! It was YOU driving the bus!!! download?mid=2_0_0_1_277144_AEwNiWIAADxh If you pass this along to your friends, pray they do better than you. PS: 95% of people fail most of the questions!!!
  6. Perspective HISTORY OF MEDICINE Is Dementia in Decline? Historical Trends and Future Trajectories David S. Jones, M.D., Ph.D., and Jeremy A. Greene, M.D., Ph.D. N Engl J Med 2016; 374:507-509February 11, 2016DOI: 10.1056/NEJMp1514434 In 2005, researchers from the Duke Center for Demographic Studies reported a “surprising trend”: data from the National Long-Term Care Surveys showed that the prevalence of severe cognitive impairment in the Medicare population had decreased significantly between 1982 and 1999.1 At a time when baby-boomer demographics led to predictions of a looming dementia crisis, this finding offered hope. Since that time, other reports have similarly shown that the incidence or prevalence of dementia is decreasing in various populations. Researchers have offered many possible explanations, including increased wealth, better education, control of vascular risk factors, and use of statins, antihypertensive agents, and nonsteroidal antiinflammatory drugs.1,2 However, even as researchers describe their “cautious optimism” about specific populations, they still project a quadrupling of global prevalence over the coming decades.3 In this issue of the Journal, Satizabal and colleagues report more “robust evidence” of dementia’s decline (pages 523–32). Using surveillance data collected from the Framingham Heart Study from 1975 to the present, they found a 20% decrease in dementia incidence each decade, even as average body-mass index, diabetes prevalence, and population age have increased. Can we now conclude that the tide has turned in the dementia epidemic? The potential decline of dementia, seen in light of the rise and fall of other major diseases, raises an even more tantalizing prospect: Can we control our burden of disease? This is not the first time that the medical profession and the public health community have struggled to interpret reports of an unexpected reversal of a chronic-disease epidemic.4 In 1964, California health officials reported that rates of coronary artery disease (CAD) had begun to decrease. This finding, which defied the widespread belief that the CAD epidemic would only worsen as life expectancy grew, garnered scant attention. Even a decade later, most health officials assumed that CAD was still on the rise. It was only in 1974 that researchers began taking the prospect of decline seriously. By 1978, they had accepted that CAD’s national decline had begun in the mid-1960s. Similar decreases were soon reported in many other high-income countries, from Australia to Finland. This recognition triggered debate over the contribution of medical and public health interventions, in hopes that knowledge of the causes of decline would guide policies and resource allocation and ensure continuation of these health benefits. The history of the debate on CAD decline carries important lessons for emerging reports of dementia’s decline. First, it can be extremely difficult to produce timely and convincing data about the trajectories of chronic diseases.4 When physicians began to debate CAD trends in 1974, they had to rely on government data that were 5 years out of date. It took 4 years of concerted effort to reach consensus about an inflection that had occurred more than a decade earlier. Even though better and timelier data are now available, dementia researchers must still be resourceful in seeking convincing data. As Satizabal et al. indicate, each existing report has limitations. Their new data, which overcome many of these limitations, demonstrate the value of investments in long-term, longitudinal epidemiologic research such as the Framingham Heart Study. But the data still reflect only one population sample. Whether they are accepted as conclusive evidence of a broad-based reduction in dementia incidence will become clear only over time. Second, since trajectories of chronic-disease incidence reflect complex interactions of many causal factors, it will almost always be uncertain whether decreases will continue or reverse. Even as consensus about international CAD reduction consolidated between the 1970s and the 1990s, worrisome evidence about countervailing trends also appeared.4 Enthusiasm for anti-CAD public health campaigns has been fragile, even in countries like Finland that demonstrated their promise so well. The widespread increases in obesity and diabetes could fuel CAD resurgences. Many researchers have warned that CAD’s decline could stall or even reverse — something that has happened among young adults and other subpopulations in Europe, Australia, and the United States. Other countries, such as China, continue to see increases in CAD with no evidence of plateau or reversal. All these countervailing trends could affect dementia as well. Rocca and colleagues have warned that increases in obesity, diabetes, and hypertension could undermine the gains achieved through improved education, wealth, and control of vascular risk factors. Even if a dementia decline has begun, it might not last: the outcome depends on the balance of diverging trends.2,3 Third, these ambiguities open up a battleground for conflicting interpretations by interested parties. Policymakers can use the same data to tell vastly different stories about public health. Forecasts of CAD’s future continue to swing between narratives of triumph and catastrophe.4 The good news is that more and more countries are reporting evidence of decline. The bad news is the evidence of the fragility of these gains. Narratives of dementia remain similarly malleable. In the early 1980s, even after CAD’s decline had been accepted and despite knowledge that dementia shares many risk factors with CAD, physicians began to warn about an exploding dementia epidemic.5 The decrease in prevalence that surprised Manton and colleagues in 2005 could have been predicted decades earlier. But dementia will remain a problem despite these decreases. The prevalence of dementia can increase, even if the incidence falls, if global populations live longer. The absolute number of people with dementia can increase, even if both incidence and prevalence fall, if the size of the elderly population grows. That explains why, 10 years into the era of reports of decreasing dementia in selected populations, Satizabal and colleagues still write that the “prevalence of dementia is expected to soar as our societies age.” Even researchers rigorously examining the evidence of decreases continue to worry about what the future will bring. History offers reasons for hope. Evidence of dementia’s decline shows once again that our burden of disease is malleable. This lesson has been hard won. Mid-19th-century physicians saw cholera and tuberculosis as inevitable scourges of urban environments. But those epidemics yielded to sanitary reform, improved standards of living, and eventually medical care. As control of infectious disease led to dramatic gains in life expectancy, physicians in the early 20th century came to see CAD and cancer as the inevitable scourges of long lives. Over recent decades, that pessimism has largely given way as well: CAD and many forms of cancer are increasingly preventable and curable. The burden of disease of the 20th century, like that of the 19th, was not an inevitable fact of life, but a product of lives lived amid specific — and malleable — conditions. What should we expect as cancer and heart disease come under control? Many people think that we can live even longer lives — but lives compromised by dementia, vision loss, and hearing loss. Whether that fate is inevitable or whether these, too, are malleable scourges remains to be seen. Such questions are better left to futurists and geriatricians than to historians. Yet Satizabal et al. believe there’s cause for “cautious hope.” Primary and secondary prevention might diminish the magnitude of the long-feared dementia epidemic. Something else might save our vision and hearing. Faced with choices between equally defensible epidemiologic projections, physicians and researchers must think carefully about what stories they emphasize to patients and policymakers. The implications, especially for investment in long-term care facilities, are enormous. Our explanations of decline are equally important, since they guide investments in behavior change, medications, and other treatments. With this latest contribution, optimism about dementia is more justified than ever before. Even if death and taxes remain inevitable, cancer, CAD, and dementia may not. But cautious optimism should not become complacency. If we can elucidate the changes that have contributed to these improvements, perhaps we can extend them. Today, the dramatic reductions in CAD-related mortality are under threat. The incipient improvements in dementia are presumably even more fragile. The burden of disease, ever malleable, can easily relapse. Incidence of Dementia over Three Decades in the Framingham Heart Study Claudia L. Satizabal, Ph.D., Alexa S. Beiser, Ph.D., Vincent Chouraki, M.D., Ph.D., Geneviève Chêne, M.D., Ph.D., Carole Dufouil, Ph.D., and Sudha Seshadri, M.D. N Engl J Med 2016; 374:523-532February 11, 2016DOI: 10.1056/NEJMoa1504327 Journal pre-amble: In the Framingham Heart Study, the incidence of dementia among participants 60 years of age or older has declined over three decades; the 5-year cumulative hazard rate declined from 3.6 per 100 persons in the 1970s and 1980s to 2.0 per 100 persons in the 2000s and 2010s. Abstract Dementia is the leading cause of dependence and disability in the elderly population worldwide.1-3 As the average life expectancy increases, the prevalence of dementia4 and associated monetary costs are expected to increase exponentially.5 A few studies have suggested that the age-specific incidence of dementia (i.e., the risk of dementia at any specific age) might be decreasing, but these studies either have shown a trend that failed to reach significance6,7 or have relied on comparisons of prevalence data that were ascertained at multiple time points.8-10 One study showed no decline in incidence.11 Temporal trends are best derived through continuous monitoring for new cases in a representative community-based sample over an extended observation period, with the use of consistent diagnostic criteria; however, such data from published studies are limited. We estimated temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study.
  7. Michael R

    Tofu, Soy Products, and Dementia

    All: Following up on a question from Vincent in another thread ... The long-running tofu-dementia connection remains a strong concern. To date, to the best of my knowledge, the ONLY prospective data on the long-term effects of soy products in the human diet are the White et al report (1), which is very rigorous prospective epidemiology in a very well-characterized long-term cohort study, and did indeed find that even what we might think of as pretty moderate increases in tofu consumption were associated with greater brain brain atrophy and poorer late-life cognitive scores. More recently, there are two reports from Hogervorst et al. (2,3) a weaker (cross-sectional) study which confirmed the finding of brain atrophy and cognitive decline: "weekly tofu intake had a negative association with memory in analyses controlled for age, sex, education and site. ... The analyses were not much altered when entering other foods. ... Analyses using median splits of soy product intake per week gave similar results to those concerning continuous consumption per week, showing a better memory performance in those who did not consume tofu daily or more than once daily." The effect was not seen in younger subjects ((3): indeed, oddly, such subjects seemed to have better cognitive function on a higher-tofu diet), but our proper concern is with longer-term effects, not what may be a short-term boost ((by analogy, not equivalence, cf. the effects of amphetamines). I have also come across (4), a prospective study in a cohort of Japanese Americans in King County, Washington. The results were all over the map (tho' perhaps suggestive, with the bidirectional relationships with HRT use), and it was an early report from only 2 y of followup in the cohort and after only 1 dietary assessment (dietary reporting instruments really need to be repeated, both because people are highly imperfect at reporting and because people's diets do actually change over time). I wrote to the authors to inquire about further followup: unfortunately, they won't be doing "a longer follow-up because of approximately 1200 women in the cohort, only 274 were in this sub-cohort. We likely do not have sufficient statistical power to conduct these newer analyses" (personal communication, Dr. Amy R. Borenstein). And, finally, there is (5), another cross-sectional study (this one in Hong Kong). It found that in women, and not men, higher consumption of an a posteriori-identified "vegetables-fruits" dietary pattern "rich in vegetables, fruits, soy products and legumes" was associated with reduced risk of cognitive impairment — but so was a "'snacks-drinks-milk products' pattern which was a mixture of healthy and unhealthy food groups including fast food, sweets and desserts, nuts, milk products and whole grains". Obviously, aside from being cross-sectional, there's no way to determine in that mix if soy products were playing a protective, deleterious, or neutral role in the overall protective association of the "vegetables-fruits" dietary pattern, even if we don't laugh the whole exercise out of the court of scientific opinion. Tofu, or Soy Generally? As Rodney says, so far this has only been found for tofu — but that's because very few soy foods have even been looked at. (1) found that miso was not associated with brain atrophy, but the serving size is very small and it is a complicatedly-processed food. Hogervorst et al actually found a protective effect of tempeh (2): this could be due to something about its processing neutralizing a toxic factor (formaldehyde was not found in market samples of tempeh, but again its presence in Indonesian tofu has only been intermittent, so that might be a sampling error), or enhancing a protective factor (eg., its higher levels of folate), or it could be a fluke (this is, again, a smaller and weaker study than White et al). We just don't know, and won't until we get (a) more studies confirming (or refuting) the link to tofu and a non-link to other soy foods. Isoflavones? White et al fingered isoflavones (soy phytoestrogens) as the most likely culprit for the tofu association, based on some animal data (and, presumably, the sheer fact that their presence is teh main thing to distinguish them from other similar foods). Phytoestrogens are found to improve cognitive function in some short-term studies in (usually menopausal or perimenopausal) women, but that doesn't mean that there isn't a long-term deleterious effect, or one specific to their hormonal status (cf. the HRT bidirectionality in (4) and maybe the inverse association of the "vegetables-fruits" dietary pattern of cognitive impairment in women but not men in (5)). Most soy foods, including most processed soy foods (soy burgers and hot dogs) and soy protein powders, have lots of isoflavones in them, and some are even "fortified" with extra isoflavones. So if those are the culprits, individual foods could be risky or harmless depending on how much isoflavone they contain. However, it could be something else entirely, in which case it would depend on whether the food contains "Contaminant X." Again, we just don't know, and won't until we get (a) more studies confirming (or refuting) the link to tofu, and (b) a non-link to other soy foods, and © a strong mechanistic explanation for any discrepancy. Thus, we shouldn't (yet) rule in or out any particular soy product on the basis of the presence or absence of phytoestrogens or any other factor. Again, more studies needed! Formaldehyde? Following up on a throwaway comment by an unreliable previous poster, Dean diligently found an interview by the lead author of (2) indicating the possible involvement of formaldehyde contamination as a factor in Indonesian tofu — which is, in fact, mentioned in the MS of (2). There is plenty of evidence that formaldehyde exposure is negatively associated with cognitive function, and in experimental studies it can hyperphosphorylate tau (leading to intraneuronal lesions that drive neuronal death and cognitive decline). So that's a plausible driver -- in the Indonesian study. It would not, however, explain the original finding in a cohort of Japanese men living in Hawai'i, which (again) was a stronger study design to begin with.(1) The one further complication is that the problem of formaldehyde contamination in Indonesia is not specific to tofu: aside from only being intermittently found in tofu, it's also been found in chicken and noodles, in use by restaurants and food stalls, and "scores of snacks and beverages containing formalin and rhodium-B were sold at a number of schools."! That might to some extent make its presence in tofu a bit of a wash relative to other foods, effectively taking it off the table as an explanation for the tofu-dementia link: we just don't know. Update: Aluminum? After I wrote this post, I realized that I hadn't addressed the question of aluminum contamination from processing with Al-based pots, or increased Al accessibility from the tofu-making process, which had both been invoked as potential causes of the association — a link that seems to have first been made in this post by Honolulu vegan advocate Dr. William Harris. I was inclined to dismiss this, as the last time I reviewed the evidence on this it seemed as if it had largely collapsed under the weight of negative studies. However, re-reviewing it now (see eg. these studies), the evident confusion about the bioavailability and body distribution of aluminum from different sources, and looking at cautious and responsible sources like the CDC's Agency for Toxic Substances and Disease Registry and the skeptical Steven Novella's blog on Alzheimer's and aluminum, my overall impression is that while there is no slam-dunk, there clearly seems to be a rational basis for concern. In light of this, people should not be making definitive statements either way about aluminum's link to AD specifically — and more importantly, to dementia more broadly. In the real world, no one gets pure AD, or vascular dementia, or dementia with Lewy bodies, or hippocampal sclerosis: one gets brain aging featuring elements of all of these, with (in most cases) features of one dominating neuropathologically and corresponding to a clinical dementia phenotype that is more or less characteristic of that neuropathological pattern. Age-related cognitive decline, dementia, and specific dementia phenotypes emerge from the aggregate loss of functional reserve. Aluminum could be neurotoxic in a way that is not specific to AD, and still increase the number of people who emerge with clinical dementia characterized as AD (or not). In turn, they should not be making definitive statements attributing the tofu-dementia association to aluminum toxicity. We only have the most tentative suggestion (via Dr. Williams) that tofu in one geographic location (Honolulu — which was the site of (1), but not of (2,3)), at one particular point in time (some years after the patients in (1) were eating the tofu that is somehow linked to their brain atrophy) had variable but potentially worrisome levels of aluminum. And, again, an uncertain if worrisome link between oral aluminum exposure and dementia or AD. A mixture of uncertain epidemiology, mixed animal data, and weak circumstantial evidence is not a basis for definitive statements. I'm not aware, unfortunately, of anyone marketing tofu or other products using methods that specifically minimize aluminum content, or that test and certify to the low levels in their product. And, as indicated, if such products exist, it's not clear whether that would be sufficient grounds to start liberally consuming soy again with no fear of dementia Bottom Line With the best available study (1) finding an association with brain atrophy and cognitive impairment; with supportive evidence from a weaker study (2,3); and absent even ONE equally-strong report of a lack of effect or of a protective one, it seems quite prudent to minimize or eliminate consumption of tofu per se (I see you rolling your eyes, Mary!), and likely soy products generally, especially in men. Reference 1. White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. Brain aging and midlife tofu consumption. J Am Coll Nutr. 2000 Apr;19(2):242-55. PMID: 10763906 Free Full Text [www.jacn.org] 2. High tofu intake is associated with worse memory in elderly Indonesian men and women. Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. Department of Human Sciences, Loughborough University, Loughborough, UK. Dement Geriatr Cogn Disord. 2008;26(1):50-7. Epub 2008 Jun 27. PMID 18583909 3: Hogervorst E, Mursjid F, Priandini D, Setyawan H, Ismael RI, Bandelow S, Rahardjo TB. Borobudur revisited: soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res. 2011 Mar 16;1379:206-12. doi: 10.1016/j.brainres.2010.10.083. Epub 2010 Oct 28. PubMed PMID: 21035431. 4: Rice MM, Graves AN, McCurry SM, Gibbons L, Bowen J, McCormick W, Larson EB. Tofu consumption and cognition in older Japanese American men and women. J Nutr. 2000 Mar 1;130(3 Suppl):676S. http://jn.nutrition.org/content/130/3/666S.full 5: Chan R, Chan D, Woo J. A cross sectional study to examine the association between dietary patterns and cognitive impairment in older Chinese people in Hong Kong. J Nutr Health Aging. 2013 Sep;17(9):757-65. doi: 10.1007/s12603-013-0348-5. PubMed PMID: 24154648.
  8. All: This is the first clinical trial to show that a comprehensive prevention intervention can slow the rate of cognitive decline in the normal elderly. The guidance here is consistent with the epidemiology and generally-accepted health advice, of course, but that's exactly why the trial was structured this way: (a) because you want to try what you think is grounded in evidence, but also ( B) the very fact that everyone is assuming that this is the way to go and that it's being widely recommended makes it all the more important to actually test it.