Low LDL cholesterol associated with worse cognitive performance

Posted on January 20, 2012 by Dr. Jonathan

Summary: cholesterol plays critical roles in cell membranes and steroid hormone production. This study associates low LDL cholesterol with worse cognitive performance. As expected, the effect is amplified by inflammation. Care should be taken to apply a balanced approach to cholesterol lowering therapies.

A truly fascinating study was just published in the journal Neurobiology of Aging investigating lipoproteins and loss of cognitive function. The authors state:

“The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation.”

They collected biological and cognitive data on 1003 persons ≥ 65 years of age over 6 years of follow-up, measuring cognition with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). High HDL was associiated with better memory performance, but their data seem to suggest the importance of sufficient LDL cholesterol in brain neuronal membranes:

“We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed.”

Not at all surprisingly they found that inflammation compounds the adverse effects of low LDL:

“Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance.”

And since high triglycerides are commonly provoked by the high insulin levels due to insulin resistance which also have deleterious effects on the brain…

“Also, high triglycerides were associated with lower memory performance in those with high inflammation.”

The authors conclude by suggesting that HDL, LDL and inflammatory indicators can be used as predictors of poor cognitive function:

“Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.”

This compels us to use caution and see the ‘big picture’ when designing strategies to manage lipids—care should be taken to not suppress LDL cholesterol to too low a level.

Diabetes is a significant risk factor for all-cause dementia and Alzheimer’s disease

Posted on October 24, 2011 by Dr. Jonathan

There has been a burst of papers drawing further attention to the damage that glucose and insulin dysregulation does to the brain. A study just published in the journal Neurology investigates specifically…

“…the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia.”

The authors subjected 1,017 community-dwelling dementia-free subjects 60 years and older to an oral glucose tolerance test, then followed them for 15 years. The outcome measure was clinically diagnosed dementia. What did their data show?

The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74; AD: adjusted HR = 2.05; VaD: adjusted HR = 1.82). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L [120.6 mg/dl], the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L [140.4 to 198 mg/dl] or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L [199.8 mg/dl].”

This is striking. The risk of all-cause dementia doubled for those with diabetes, and there was a significant increase in the risk of all-cause dementia and Alzheimer’s disease with a 2 hour post-glucose load level of 140.4 mg/dl or more. Moreover, fasting glucose levels did not reveal the danger that was disclosed only by the functional OGTT. I always risk desensitizing my patients to the damage done to the brain by glucose and insulin dysregulation; better to let the authors’ conclusion do the talking:

“Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.”

Meanwhile, a time study just published in the journal Diabetic Medicine also examines the association of diabetes with Alzheimer’s disease. The authors’ intent was to determine…

“…whether diabetes mellitus influences functional status in patients with Alzheimer’s disease.”

They studied 608 community-dwelling patients with Alzheimer’s disease, assessing diabetes at the beginning. Functional status was examined twice yearly with the Activities of Daily Living scale. Each patient also had a baseline functional disability determined if their Activities of Daily Living score was less than 6. Decreases in these metrics over four years of follow-up exams was used to define worsening of functional disability due to AD. Their data also reveal the ruination of the brain by glucose intolerance:

“At baseline, diabetes was present in 63 participants (10.4%) and, compared with those without diabetes, was associated with functional impairment [age- and sex-adjusted OR = 2.73]. After controlling for confounders, the association remained significant [OR = 2.04]. Follow-up demonstrated a significant interaction between duration of Alzheimer’s disease and diabetes, which was associated with progression of functional impairment in patients who had been diagnosed with Alzheimer’s disease for less than 1 year, but not in those who had been diagnosed with Alzheimer’s disease for more than 1 year. Abnormal one-leg balance, polymedication and obesity seem to be important factors explaining the association between diabetes and functional status.”

Clinicians (non-neurologists), how often do you check one-leg balance? The authors’ data suggests that a year after a clear-cut Alzheimer’s diagnosis the damage is too extensive to discriminate the effect of diabetes, thus they conclude:

“At baseline, the presence of diabetes significantly increases the risk of functional disability in patients with Alzheimer’s disease; our longitudinal data confirm that in patients with a recent diagnosis of Alzheimer’s disease (but not in those who have had Alzheimer’s disease for longer than 1 year), diabetes continues to worsen functional status.”

Regarding mechanisms, an interesting paper just published in Current Diabetes Reviews examines recent findings illuminating the link between IGF-1 signaling and diabetes-associated dementia. The authors state:

“Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer’s disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF-1) might represent a molecular link between T2DM and AD, characterizing AD as “brain-type diabetes”.”

They describe recent research findings that suggest decreased IGF-1 signaling (IIS) in the brain is a compensatory attempt to reduce the accumulation of toxic β-amyloid (Aβ):

“According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins…suggesting that decreased IIS [insulin/IGF-1 signaling] might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less β-amyloid (Aβ) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases Aβ toxicity. This effect is accomplished via two transcription factors…suggesting that Insulin/IGF-1 transmitted signals influence Aβ proteotoxicity.”

This important point should not go unnoticed by those who are contemplating therapies that increase IGF-1—they may increase risk factors for Alzheimer’s disease and dementia.

And another paper recently published in Neurology highlights the damage done to the brain by advanced glycation end products due to poor glucose tolerance. The authors observe:

“Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging.”

They studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose, and examined baseline AGE concentration by urine pentosidine in association with performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. What did the data show?

“On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level [more AGEs] compared to those in the lowest tertile. Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile.”

We are probably just beginning to understand the ways that glucose and insulin regulation, whose profound leverage on the physiology is evolutionarily preserved from relatively primitive organisms to humans, has on the brain. Regarding damage done by excessive glucose interaction with tissues, it is not necessary for glucose dysregulation to have progressed to diabetes as the authors conclude:

“High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.”

The advantages of intermittent versus continuous calorie restriction for long term weight loss

Posted on October 14, 2011 by Dr. Jonathan

There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”

Moreover…

“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

“IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”

Moreover…

“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

“Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).“

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

“Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

“Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

“Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.

Sleep-disordered breathing is a risk factor for dementia in women

Posted on August 29, 2011 by Dr. Jonathan

Adding to the damage list associated with sleep-disordered breathing, a study just published in JAMA (The Journal of the American Medical Association) offers evidence that sleep apneas and hypopneas can contribute to serious cognitive impairment. This is not surprising considering the importance of oxygen for brain health. The authors state:

“Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) is common among older adults. Cross-sectional studies have linked sleep-disordered breathing to poor cognition…”

So they designed their study to…

“…determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association.”

Defining sleep-disordered breathing as an apnea-hypopnea index of 15 or more events per hour of sleep, they examined polysomnography (‘sleep study’) data for 298 women without dementia collected between January 2002 and April 2004. They then used data collected between November 2006 and September 2008 to correlate hypoxia, sleep fragmentation, and sleep duration with cognitive status (normal, dementia, or mild cognitive impairment). What did the data reveal?

“Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% vs 44.8%). Elevated oxygen desaturation index (≥15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 and AOR, 2.04, respectively).”

In other words, the higher strata of sleep-disordered breathing doubled the risk for dementia. Interestingly…

“Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment.”

Clinicians need to bear in mind the serious metabolic, cardiovascular and cognitive penalties of sleep-disordered breathing and question patients about tell-tale signs such has heavy snoring and daytime somnolence. The authors conclude:

“Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment.”

This study cohort was all female subjects, but I can think of no reason why the same consideration does not apply to male patients.

Insulin resistance marks Alzheimer’s disease risk at the earliest stage

Posted on November 21, 2010 by Dr. Jonathan

An important paper recently published in the Archives of Neurology offers evidence that insulin resistance is a causal factor for Alzheimer’s disease at its earliest stages. The authors observe:

“Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fludeoxyglucose F 18–positron emission tomography (FDG-PET) in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.“

With this in mind they set out to…

“…examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task.”

In other words, the authors correlated glucose and insulin measurements, brain scans of glucose metabolism and a radioactive emission brain scan (fludeoxyglucose F 18–positron emission tomography) during a memory encoding task. What did the data show?

“Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D…During the memory encoding task, healthy adults showed activation in right anterior and inferior prefrontal cortices, right inferior temporal cortex, and medial and posterior cingulate regions. Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.“

The authors’ conclusion adds to the weight of evidence indicating that blood sugar dysregulation and insulin resistance are fundamental causal factors and early risk indicators for Alzheimer’s disease:

“Insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment.“

Mild memory loss is neuropathology, not ‘normal aging’

Posted on September 24, 2010 by Dr. Jonathan

There is an erroneous popular notion that mild memory lapses, so-called ‘senior moments’, are a normal consequence of aging. A study just published in the journal Neurology introduces more evidence that age-related memory decline does not occur in the absence of the same kind of neuropathologic brain lesions associated with full-blown dementia. The authors’ intention was…

“To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function.”

They examined 354 subjects for up to 13 years with annual clinical evaluations including detailed tests of cognitive function. At death their brains underwent autopsy and were examined for neuropathologies including neurofibrillary tangles, Lewy bodies and cerebral infarct (evidence of stroke)—the same pathologies known to be associated with dementia. Their data offers strong encouragement to learn how to take care of your brain:

“During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions.”

In other words, not everyone experiences memory decline with age. When it does occur, it is due to the same damage to brain tissue that can evolve into dementia. As the authors state in their conclusion:

“Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia.“

See earlier and forthcoming posts in the Brain Health category for more science on how to take care of your brain.

Alzheimer’s disease and insulin resistance

Posted on September 23, 2010 by Dr. Jonathan

Evidence continues to accumulate for the role of insulin resistance and type 2 diabetes in Alzheimer’s disease. Research just published in Archives of Neurology add more certainty to the association. The authors observe:

“Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu)…in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.”

They structured their investigation by setting out to…

“…examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task.”

They correlated data on adults with glycemic criteria for pre-diabetes or T2DM (and normal controls) with PET imaging of brain glucose metabolism and memory tests. They also examined the cerebral metabolic glucose rate (CMRglu) during the memory task. What did the data show?

“Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-hour OGTT glucose concentration, or apolipoprotein E {varepsilon}4 allele carriage…Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.”

Their conclusion suggests both the role of insulin resistance in the development of AD as well as its use as an early indicator of risk:

“Insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment.“

Interestingly, these findings were published along with another study in the same journal that reports on the accuracy of a constellation of blood test indicators for early diagnosis of AD. The authors set out…

“To develop an algorithm that separates patients with Alzheimer disease (AD) from controls.”

They analyzed serum protein–based biomarker data from 197 patients diagnosed with AD and compared it them 203 normal controls. The statistical analyses they used to create a biomarker risk score included a number of analytes that can be linked to insulin resistance and inflammation, including fibrinogen, interleukin-10, and C-reactive protein. When the numbers were crunched their biomarker risk score was highly accurate:

“The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively, and an area under the curve of 0.91 in detecting AD [identified 80% with AD, excluded 91% without]. When age, sex, education, and APOE status were added to the algorithm, the sensitivity, specificity, and area under the curve were 0.94 [94%}, 0.84 [84%], and 0.95, respectively.”

This is very valuable because other proposed tests involve lumbar puncture for cerebrospinal fluid or expensive neuorimaging, both with obvious drawbacks. The authors’ conclusion also highlights the importance of inflammation (vascular and otherwise, associated with insulin resistance) in the development of AD:

“These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. A disproportionate number of inflammatory and vascular markers were weighted most heavily in the analyses…suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.”

Brain health is linked to heart health, implications for blood pressure medication

Posted on August 26, 2010 by Dr. Jonathan

An interesting study just published in the journal Circulation provides evidence of the link between brain health and the capacity of the heart to send blood to the brain. The authors first note the importance of cerebral perfusion (getting blood into the brain):

“Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury.“

They set out to test whether the cardiac index (the amount of blood the heart pumps in proportion to body size) as a metric for cardiac function would correlate with loss of brain tissue as shown by brain MRI and neuropsychological markers of ischemia (reduction of oxygen due reduced blood flow) and Alzheimer’s disease. What did the data show?

“…cardiac index was positively related to total brain volume and information processing speed and inversely related to lateral ventricular volume…participants in the bottom cardiac index tertile and middle cardiac index tertile had significantly lower brain volumes than participants in the top cardiac index tertile.”

Even the people with the middle cardiac group (low normal) had showed signs of serious neurodegeneration with brain atrophy (lower brain volume). How important is it to get better than a low normal amount of blood to the brain?

“Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.“

Consider this in light of earlier research that aggressive treatment of blood pressure is harmful. Clinicians must respect the need to balance cardiovascular protection from excessive pressure dynamics with the profound need to ensure adequate cerebral perfusion. Are you concerned that your blood pressure therapy may be stronger than it should? Read the earlier research posts and discuss the matter with your doctor.

Adolescence, a dangerous time for alcohol excess—but so is anytime

Posted on July 17, 2010 by Dr. Jonathan

Adding more concern to the reported increase in heavy alcohol consumption among adolescents is the emerging science regarding alcohol’s effect on the brain. This research just published in the Proceedings of the National Academy of Sciences elucidates the mechanism by which binge drinking damages the developing brain.

“Binge alcohol consumption in adolescents is increasing, and studies in animal models show that adolescence is a period of high vulnerability to brain insults. The purpose of the present study was to determine the deleterious effects of binge alcohol on hippocampal neurogenesis…”

The authors made a number of startling observations regarding the effect of alcohol on the brain’s center for short-term memory and adrenal regulation, the hippocampus:

“Heavy binge alcohol consumption over 11 mo dramatically and persistently decreased hippocampal proliferation and neurogenesis…Alcohol significantly decreased the number of actively dividing type 1, 2a, and 2b cell types…suggesting that alcohol interferes with the division and migration of hippocampal preneuronal progenitors. Furthermore, the lasting alcohol-induced reduction in hippocampal neurogenesis paralleled an increase in neural degeneration mediated by nonapoptotic pathways.”

Yikes. The authors sum up their findings with these memorable comments:

“Altogether, these results demonstrate that the hippocampal neurogenic niche during adolescence is highly vulnerable to alcohol… This lasting effect, observed 2 mo after alcohol discontinuation, may underlie the deficits in hippocampus-associated cognitive tasks that are observed in alcoholics.”

A fascinating paper published last month in the Journal of Neuroscience now reveals how alcohol feeds an immune inflammatory attack on the brain:

“Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation.”

This is an extremely persuasive argument for moderation for anyone interesting in preserving brain health.

The authors go on to report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells by demonstrating that ‘turning off’ TLR4 prevents the neuroinflammatory brain damage:

“Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates…cytokine levels [interleukin (IL)-1β, tumor necrosis factor-{alpha}, IL-6] in the cerebral cortex,…TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.”

Science Translational Medicine 0710 For us the main message is that excessive alcohol consumption fires up the brain’s glial cells (immune cells) and the resultant neuroinflammation does serious damage to the brain. This important research was highlighted in an editorial published last week in Science Translational Medicine which contains some notable comments:

“Ethanol is the most widely used psychotropic substance in the world, and chronic ethanol abuse leads to harmful changes in virtually every organ system in the body. Notably, this includes the brain, where consumption of alcohol can lead to irreversible changes in cognition, mood, and behavior. Although it has been known that this often involves degenerative, inflammatory-mediated processes, their precise nature has not been characterized. In a recent article, Alfonso-Loeches and colleagues report that much of the ethanol-induced inflammation in the brain depends on signaling through Toll-like receptors (TLRs). These receptors participate in innate immunity responses to infection but are also implicated in reactions to injury and degeneration in the brain.”

The editorial concludes with the compelling comparison of the brain damage done by activation by alcohol of neuroinflammation through Toll-like receptors with other common neurodegenerative conditions:

“These results suggest that TLRs play a critical role in alcohol-related brain changes, just as they have been previously implicated in Alzheimer’s disease, ischemic brain injury, and HIV infection.”

Besides curtailing excess and enjoying alcohol only in moderation we may be able to use coffee as protective therapy. There is abundant evidence of the benefit of coffee for the liver, including this recent study published in the journal Inflammation Research. The authors present data that:

“Treatment with caffeine significantly attenuated the elevated serum aminotransferase enzymes and reduced the severe extent of hepatic cell damage, steatosis and the immigration of inflammatory cells… Furthermore, caffeine decreased serum and tissue inflammatory cytokines levels, tissue lipid peroxidation and inhibited the necrosis of hepatocytes. Kupffer cells isolated from ethanol-fed mice produced high amounts of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α), whereas Kupffer cells from caffeine treatment mice produced less ROS and TNF-α.”

The authors conclude:

“These findings suggest that caffeine may represent a novel, protective strategy against alcoholic liver injury by attenuating oxidative stress and inflammatory response.”

Could this protective effect extend to the brain? There’s a lot of emerging evidence that suggests the answer is ‘yes’. Fascinating research published last month in the journal Experimental Neurology demonstrates that caffeine protects the brain from the kind of damage involved in Parkinson’s disease caused by pesticides:

“Environmental exposures suspected of contributing to the pathophysiology of Parkinson’s disease (PD) include potentially neurotoxic pesticides, which have been linked to an increased risk of PD. Conversely, possible protective factors such as…caffeine have been linked to a reduced risk of the disease. Here we assessed whether caffeine alters dopaminergic neuron loss induced by exposure to environmentally relevant pesticides (paraquat and maneb) over 8 weeks.”

The data led to a conclusion that increases my enthusiasm for exercising the French press:

“Caffeine at 20 mg/kg significantly reduced TH+ neuron loss (to 85% of the respective control). The results demonstrate the neuroprotective potential of caffeine in a chronic pesticide exposure model of model of PD.”

Journal of Alzheimer's Disease As for Alzheimer’s disease, a supplemental issue of the Journal of Alzheimer’s Disease has no less than 22 papers on the benefits of caffeine for AD and other neurodegenerative disorders. I suggest you have a look, drink alcohol in moderation (or not at all if you prefer), and enjoy your coffee and tea if there are no contraindications.

With alcohol, as with so many other substances and stimuli, we can appreciate the principle of hormesis: a small amount may have benefit while a larger amount is harmful.

Neuroinflammation plays a crucial role in neurodegenerative diseases

Posted on May 26, 2010 by Dr. Jonathan

This excellent review published recently in the journal Molecular Neurodegeneration elucidates the epidemiologic, pharmacologic and genetic evidence that explains why inflammation in the brain and the rest of the central nervous system is a key factor in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis.

“While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults.”

Inflammatory stimuli include allergens (gluten, etc.), infections, trauma, neurogenic activation of the inflammatory response, and others. Microglia (the immune cells in the brain) are activated and release inflammatory mediators, the cytokines and chemokines that we measure with lab tests.

“…chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult.”

Once chronic neuroinflammation has been established, these inflammatory mediators perpetuate a cascading inflammatory cycle.

Neuroinflammation, neuronal dysfunction and degeneration

“Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines.”

In other words, microglial activation and the chronic inflammation it perpetuates is the convergence point for all the kinds of stimuli associated with these neurodegenerative disorders as well as many other conditions affected by compromised brain function. This is partly why it is of such great practical importance to profile immune dysregulation in the central nervous system with the appropriate lab tests as a basis for rational therapy.