delaying dementia – a case of nutritional inadequacies?
TRANSCRIPT
Delaying dementia – a case of nutritional inadequacies?
Nina BaileyBSc MSc PhD ANutr
Defining dementia
• Dementia is an umbrella term, used to describe a syndrome that can have many different causes and that is characterised by gradual decline in cognitive abilities and neuropsychiatric symptoms
• The causes are most commonly brain disease including Alzheimer’s disease, vascular dementia, frontotemporal dementia, Lewy body dementia, Korsakoff's syndrome, Huntingdon’s chorea, Parkinson's disease
• These diseases begin to damage the brain many years before symptoms become apparent and cause a progressive decline in functioning as more of the brain is damaged
Treat, prevent or delay?
• In the last few decades, huge advances have been made in understanding the neurobiology of dementia, leading to an increase in trials assessing various treatments
• Drugs used to treat dementia are of limited clinical benefit and so do not treat the underlying cause
• Preventing or postponing the onset of dementia and delaying or slowing its progression appear to be required options, leading to a consequent improvement of health status and quality of life in older age
Risk factors for cognitive decline and dementia
Brain functionHigher mental stimulation through education, occupation or leisure is associated with lower riskHigher social interaction in later life is associated with lower risk
Lifestyle factorsRegular physical exercise at all ages is associated with lower riskCurrent smoking increases riskExcessive alcohol use increases riskDiabetes increases riskDepression increases riskElevated homocysteine levels increases riskHigh blood pressure increases riskElevated cholesterol increases risk
The apolipoprotein E (APOE) gene, on chromosome 19, is the major genetic source of the common forms of late-onset Alzheimer’s disease
APOE carries and delivers cholesterol to the nerve cells which use it for the repair and establishment of new connections
There are three common variants of the APOE gene:
APOE 3 variant is the most common (neutral)
APOE 2 variant appears to have a protective influence
APOE 4 variant is thought to increase the risk of Alzheimer’s disease
People who inherit one copy of APOE4 are three times more likely to develop Alzheimer's and people who inherit two copies are 12 times more likely to develop the disease
Mutations in the Amyloid Precursor Protein (APP), Presenilin 1 and Presenilin 2 and inherited Alzheimer's disease
• The APP gene makes a protein that is present on the surface of nerve cells and may help them grow and move
• The presenilin 1 and 2 genes make proteins that are required for the correct functioning of the APP protein
• Mutations in any one of these genes can cause the APP protein to be cut off from the surface of nerve cells, leading to an accumulation in amyloid plaques which are a hallmark of Alzheimer’s disease
Cardiovascular health
Hypertension can cause problems by damaging and narrowing the blood vessels in the brain, raising the risk of a blood vessel becoming blocked or bursting, leading to an increased risk of stroke, cognitive impairment and vascular-related dementia
Hypertension is associated with higher levels of neurofibrillary tangles and amyloid plaques (poor clearance) and greater hippocampal and cortical atrophy (loss of neurones)
High blood pressure in mid life rather than late life appears to be associated with an increased risk of developing dementia (Power et al., 2011)
Cardiovascular health
Cholesterol plays an essential role in healthy brain function
High cholesterol in mid life rather than late life appears to be associated with an increased risk of developing dementia (Anstey et al., 2008)
High cholesterol levels may accelerate the production of beta amyloid,with autopsy data showing lower midlife cholesterol to be associated with lower numbers of plaques and tangles (Kivipelto et al., 2006)
Higher HDL is associated with larger hippocampal volume and reduced risk of cognitive impairment and Alzheimer's disease
Elevated homocysteine
Elevated homocysteine
Elevated homocysteine levels damage cells directly by promoting oxidative stress
Reduced glutathione production results in compromised detoxification
Reduced methyl donor productionThe methylation cycle supplies methyl groups for a large number of methylation-dependent reactions, including those involved in the synthesis of substances including creatine, choline, carnitine, coenzyme Q10, melatonin and myelin proteins Low SAMe levels also result in a reduction in neurotransmitter production
Methylation is a fundamental process required for normal cell division and DNA repair
Compromised methylation is also implicated in accelerated ageing!!
Elevated homocysteine
Infertility
Osteoporosis
Inflammatory bowel disease
Chronic fatigue syndrome
Pregnancy complications
Atherosclerosis/heart attack/stroke
Compromised cell cycle control
Diabetes
Neurodegenerative disease
Depression/mood disorders
Homocysteine and dementia
• High values of plasma homocysteine and low levels of vitamin B12 and folate are frequently present in Alzheimer’s patients (Coppede 2010)
• Deficiencies of B vitamins (folate, vitamin B6 and vitamin B12) and elevated homocysteine levels have been associated with increased risk of cognitive impairment, Alzheimer’s disease and vascular dementia (Herrman & Obeid 2011)
• Elevated homocysteine may also increase oxidative stress and the production of beta-amyloid plaques in the brain (Herrman & Obeid 2011
Homocysteine and dementia risk factors
• Elevated homocysteine is also associated with cardiovascular disease, diabetes and major depression
• As levels of homocysteine in the blood are directly influenced by levels of the B-complex vitamins (folic acid, vitamin B6 and vitamin B12), supplementation with these key nutrients offers preventive strategies for a number of conditions related to high homocysteine
• Studies have shown that supplementing with B6, B12 and folic acid successfully lowers homocysteine (VITAL 2003; Schnyder et al., 2002; Lonn et al., 2006; Stanger et al., 2009)
Using B vitamins to lower homocysteine as a method to reduce dementia risk
• Clinical trials in older adults have not shown that increasing B vitamin intake or using supplements reduces the risk of cognitive decline or dementia; however, some trials demonstrated slowing of brain atrophy and improvement in some domains of cognitive function
• It is possible that if such supplementation were begun in midlife, when chronic elevations in homocysteine could be prevented, they would be more beneficial, although further research is required to determine this
Diabetes, especially type 2, and metabolic syndrome appear to be risk factors for cognitive impairment and dementia
• Meta-analysis finding suggests that diabetes may be associated with a 47% increased risk of any dementia, a 39% increased risk of Alzheimer’s disease, and a 138% increased risk of vascular dementia (Lu et al., 2009)
• APOE4 genotype combined with diabetes doubles the relative risk of dementia compared with diabetes alone (Peila et al., 2002; Xu et al., 2004)
Depression is a common comorbidity in dementia
• A history of depression has been associated with an increased risk of Alzheimer's disease
• A review of epidemiological studies reported that a history of depression was associated with around double the risk of Alzheimer's (Ownby et al., 2006)
• Depression is associated with increased inflammation and high cortisol, both of which have a detrimental impact on brain structure and function
ComorbidityDementia
Diabetes
CardioDepression
• Dementia is NOT a normal part of ageing, although the risk of developing dementia increases with age
• Many nutrients, micronutrients and metabolic enzymes known to be essential for substrate metabolism, substrate utilisation and energy transfer are known to reduce with age
• Deficiencies in a number of nutrients and micronutrients have been observed in dementia patients, including omega-3 fatty acids, vitamin A, vitamin B12, vitamin D, folate, iron, vitamin E and vitamin C (Lopes da Silva et al., 2013)
Oxidative damage and mitochondrial decay in ageing
• Oxidative stress-induced damage in the brain is thought to contribute to cognitive impairments in ageing humans
• Oxidative stress and lipid peroxidation are believed to be contributing factors leading to neuronal loss and mitochondrial dysfunction in Parkinson's disease and may play an early role in the pathogenesis of Alzheimer's disease
• Several studies show that there is an emerging link between individual stress and intracellular oxidative stress as measured by inflammatory cytokine (TNF-α), glycosylated haemoglobin (HbA1C) and malondialdehyde (MDA) and low levels of enzyme antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPX) (Padurariu et al, 2009)
• Cognitive decline is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources
• As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors to make the phospholipids required to build neuronal membranes may have beneficial effects
• Oxidative damage, inflammation, demyelination, impaired processing and metabolic deficits are all associated with the ageing brain
• Could a cocktail of multiple antioxidants with anti-inflammatory agents be beneficial in the prevention of neurodegenerative disease?
Inflammation and dementia
• Inflammation factors are known to be associated with a higher risk for Alzheimer's disease and cognitive decline (Halliday et al., 2000)
• Two large-scale prospective studies showed baseline blood levels of inflammatory markers are associated with higher risk of incident Alzheimer's disease (Schmidt et al., 2002; Engelhart et al., 2004)
Steps to reducing dementia risk:
Reduce oxidative damageIncrease antioxidant enzymesDecrease homocysteine and cholesterol levelsManage blood pressure
Modulate inflammationIncrease cellular energy Optimise neuroprotectionEnhance neurogenesisSupport cell membrane integrityOptimise neurotransmitter levels
Steps to reducing dementia risk:
Reduce oxidative damageAlpha lipoic acidVitamin EVitamin CCarnosineCoenzyme Q10
Regulators of antioxidant systemsSuperoxide dismutase (SOD) (copper, zinc, manganese & selenium)Glutathione (Vitamin B6, cysteine)
Alpha lipoic acid is an endogenous antioxidant and essential cofactor for many enzyme complexes that interrupt cellular oxidative processes
Increases acetylcholine production by activation of choline acetyl-transferase
Increases glucose uptake Acts as a metal chelator Down-regulates the expression of redox-sensitive pro-inflammatory
proteins including TNF-a and inducible nitric oxide synthase Scavenges lipid peroxidation products such as 4-hydroxynonenal and
acrolein
(lui, 2007; Moreira et al., 2007; Maczurek et al., 2008; Salinthone et al., 2008)
Carnosine is a naturally occurring antioxidant and metal chelator
• Inhibits lipid peroxidation and the formation of advanced glycation end products (AGEs) which have been implicated in the progression of diseases including dementia, cardiovascular disease and stroke
• Inhibits protein glycation and DNA/protein cross-linking which protects against a beta-amyloid accumulation (Alzheimer’s disease), and alpha-synuclein accumulation (Parkinson’s disease)
• Carnosine also plays a vital role in carrying fatty acids from the cytosol into the mitochondria where they are oxidised for energy
Coenzyme Q10 has a dual function as it is essential for generating energy in mitochondria whilst also being a powerful anti-oxidant and anti-oxidant recycler including vitamin E, vitamin C and lipoic acid
• Its ability to quench free radicals helps to maintain the structural integrity and stability of mitochondrial and cell membranes
• Supplementation with CoQ10 may have benefits for Huntington's and neurodegenerative diseases such as Parkinson's and Alzheimer's
• Coenzyme Q10 has been shown to be neuroprotective and dose-dependently inhibits the formation α-synuclein and β-amyloid fibrils (Spindler et al., 2009)
• Coenzyme Q10 also has major implications for cardiovascular health
Optimising the diet
• At present, for older subjects, healthy diets, antioxidant supplements, the prevention of nutritional deficiencies, and moderate physical activity could be considered the first line of defence against the development and progression of predementia and dementia syndromes
• The Mediterranean-style diet was first described in the Seven-Country study in the 1950s to 1960s in the south of Europe, where adult life expectancy was among the highest in the world and rates of coronary heart disease, certain cancers and other nutrition-related chronic diseases were among the lowest (Keys et al., 1986)
Mediterranean diet
• Dietary patterns characterised by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats, high fat dairy and sweets/sugars seem to be associated with lower risk of cognitive impairment and dementia (Gu et al., 2011)
Several studies have found a lower risk of dementia is associated with higher intake of fruit and vegetables and higher adherence to the Mediterranean diet (Solfrizzi et al., 2011)
Mediterranean diet
• A study of 1433 older people showed 6.5% of cases of mild cognitive impairment or dementia to be attributable to low fruit and vegetable consumption Ritchie et al., 2010)
• Increasing fruit and vegetable consumption and eliminating depression and diabetes are likely to have the biggest impact on reducing the incidence of dementia (Ritchie et al., 2010)
• Another study showed an 88% lower risk of any dementia and 92% lower risk of Alzheimer’s disease in those with an overall healthy diet at midlife, compared to those with an unhealthy diet (Eskelinen et al., 2011)
Mediterranean diet
• A 2011 systematic review found that a Mediterranean diet appeared to be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors, such as lowering cholesterol level and blood pressure (Nordman et al., 2011)
• Adherence to the Mediterranean diet may affect not only risk for Alzheimer’s disease but also subsequent disease course (Scarmeas et al., 2007)
What is the Mediterranean diet?
The principal aspects of this diet include:
• High consumption of olive oil, legumes, unrefined cereals, fruits and vegetables
• Moderate to high consumption of fish, moderate consumption of dairy products (mostly as cheese and yoghurt), moderate wine consumption
• Low consumption of meat and meat products
Mediterranean diet nutrients
• Low in saturated fat• High in polyunsaturated and monounsaturated fat• Rich source of quality protein• Rich in essential vitamins and minerals • High in omega-3 fatty acids• Low in omega-6 fatty acids• High in dietary fibre • High in antioxidants• High in polyphenols and flavonoids
Fish consumption and dementia
• High fish consumption tends to be inversely associated with cognitive impairment and decline (Kalmijn 2000)
• Elderly people who eat fish or seafood at least once a week are at lower risk of developing dementia, including Alzheimer's disease (Barberger-Gateau et al., 2002)
• Fish is a unique nutritional package
• Fish is a predominant source of long-chain omega-3 fatty acids
Omega-3 and dementia
• Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFA), which are a main component of cell membranes
• The physiological roles of omega-3 PUFA in the brain include regulation of cell membrane fluidity, dopaminergic and serotonergic transmission, regulation of cellular signal transduction, brain glucose metabolism, eicosanoid synthesis, gene expression and cell cycle control
• Deficiencies in omega-3 fatty acids are observed in dementia patients (Lopes da Silva et al., 2013)
• A higher plasma EPA concentration is associated with a lower incidence of dementia (Samieri et al, 2008)
• 2012 meta-analysis of 10 studies (including 2,280 subjects) - EPA and total n-3 PUFAs were decreased in patients with dementia- levels of EPA, but not DHA or other PUFAs, were significantly lower in
patients with pre-dementia syndrome- EPA may act as a disease-state marker AND a risk factor for cognitive
impairment (Lin et al, 2012)
• A higher plasma EPA concentration is associated with a lower incidence of dementia (Samieri et al, 2008)
• High AA:DHA and omega-6:omega-3 is associated with an increased risk of dementia (Samieri et al., 2008)
• EPA intake is more advantageous than DHA in reducing "brain effort" relative to cognitive performance (in young adults) (Bauer et al., 2014)
35
EPA and brain conditions• The HPA-axis is the body’s mechanism for dealing with stress
• EPA helps reduce its dysregulation, which plays a role in the onset of several conditions, including: ⁻ depression ⁻ chronic pain and fatigue syndromes ⁻ neurodegenerative disease such as Huntington’s and Alzheimer's
disease ⁻ reduction in brain grey matter
(Caetano et al, 2007,Burgmer et al, 2009, van Duijn et al, 2010, Puri et al, 2008)
• EPA and not DHA has been shown to reduce the symptoms of these conditions and support the brain’s natural protective processes (Salvati et al, 2004; Salvati et al, 2008)
36
EPA has several neuroprotective roles in the brain
EPA up-regulates gene expression concerned with neurogenesis neurotransmission and connectivity, improves endothelial nitric oxide generation and decreases inflammatory cytokine levels ((Salvati et al, 2004; Salvati et al, 2008; Calder 1997)
EPA enhances brain acetylcholine levels, and suppresses the production of pro-inflammatory cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) (McCarty 1999)
The neuroprotective effect of EPA is also in part, thought to be through its ability to inhibit neuronal apoptosis (Martin et al, 2002; Lonergan et al, 2004)
GLA in conjunction with EPA, is known to decrease inflammatory leukotriene B4, IL-1 and IL-6 consequently offers cerebral anti-inflammatory effects (McCarty 1999).
Reducing the risk of developing dementia
Keep an active mindKeep fit and active
Eat a Mediterranean-style dietLook after cardiovascular health
Reduce the risk of developing diabetes
ComorbidityDementia
Diabetes
CardioDepression
Steps to reducing dementia risk:
Reduce oxidative damage Increase antioxidant enzymes
Decrease homocysteine and cholesterol levels Manage blood pressure
Modulate inflammation Increase cellular energy
Optimise neuroprotection Enhance neurogenesis
Support cell membrane integrity Optimise neurotransmitter levels
