Metabolic Disturbances and

Cognitive Impairment

DR. RAVI SONIDM SR III

DEPT. OF GERIATRIC MENTAL HEALTHKGMU, LKO

Highlights

Metabolic syndrome Epidemiology Relation between MetS and Cognitive

impairment Explanatory models Prevention of MetS Treatment of MetS Metabolic causes of dementia Symptoms Work up Treatment

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Metabolic Syndrome Called a global epidemic by WHO Major Health problem >34 % of the Americans over the age of 20 years

estimated to be affected 9.4% of adolescents are affected and prevalence

increases to 44% among those who are obese

Metabolic syndrome (MetS) is a cluster of risk factors including abdominal obesity, hypertension, lipid abnormalities, and impaired metabolism of glucose and insulin that is associated with cardiovascular disease, diabetes, and dementia.

Metabolic syndrome

Indian scenario: About one-third of the urban population in large cities in India

have MetS. Reported from South India: 31.4% abdominal obesity, 45.6%

hypertriglyceridemia, 65.5% low HDL, 55.4% hypertension, and 26.7% raised fasting plasma glucose.

Community-based study from eastern India: prevalence of MetS of 31.4%, with females-(48.2%), males-(16.3%)

Rural prevalence of MetS: reasonably low compared to the urban prevalence MetS was seen in 9.3% (8.2% in males and 10.7% in females)

Recent population survey conducted in a semi-urban area in South India showed that the prevalence of MetS is 29.7% (26.5% in men and 31.2% in women)

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Definition of Metabolic Syndrome Presence of three or more of the following criteria: 1. Abdominal obesity: waist >102 cm (>40 in) for men or >88

cm (>35 in) for women; 2. Triglycerides ≥150 mg/dL; 3. High-density lipoprotein <40 mg/dL for men or <50 mg/dL for

women; 4. Blood pressure ≥130/≥85 mmHg or current use of anti-

hypertensive medications; and 5. Fasting glucose level ≥110 mg/dL.

The International Diabetes Federation uses a slightly modified definition where one of the three criteria must be abdominal obesity in addition to two of the other four criteria, and the abnormal threshold for fasting glucose is set at ≥ 100 mg/dL

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MetS and Cognitive Impairment

MetS affects cognition and raises the risk of dementia

Studies have shown mixed results Poorer cognitive performance No association with dementia and cognitive

performance Even reduced risk of AD and decelerated cognitive

decline in individuals over age 75 Findings may vary by sex

Men being more affected in some reports Women in others Some reporting no sex differences

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Studies on MetS and Cognitive Impairment

Reference FindingsBokura et al. 2010 MetS is associated with Impaired

executive function independent of silent brain lesions

Cavalieri et al. 2010 MetS is related to memory and executive function in men but not in women

Gatto et al. 2008 Correlation between hypertension and lower cognition; Significant cognitive impairment with increasing MetS factors

Haley et al. 2010 No significant cognitive differencesHassenstab et al. 2010 Significant reductions in recall, lower

overall IQ; increasing MetS factors associated with lower performance

Studies on MetS and Cognitive Impairment

Reference Findings Komulainen et al. 2007 MetS at baseline = greater risk of

memory impairment at follow-up; memory declines with increasing MetS factors

Muller et al. 2009 MetS is related to memory and visuospatial dysfunction but not to executive dysfunction

Schuur et al. 2010 MetS associated with executive dysfunction in women but not men

Segura et al. 2010 No significant cognitive differences between groups

Tournoy et al. 2010 MetS not associated with cognitive impairment; Diabetes linked to poorer memory, executive functions and processing speed

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MetS and affected Cognitivedomains

Multiple cognitive domains are affected MetS has been linked to deficits in

Memory Visuospatial abilities Executive functioning Processing speed Overall intellectual functioning

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Impact of MetS on Brain

MetS is a known risk factor for ischemic stroke Subclinical ischemic brain damage in adults with MetS Increased silent brain infarction has been observed in

both elderly and middle-aged individuals with MetS Increased prevalence of intracranial arteriosclerosis,53

periventricular white matter hyperintensities (PWMH), and subcortical white matter (WM) lesions

Segura et al. (2009) characterized reductions of WM micro-structural integrity involving primarily the frontal and temporal lobes

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Impact of MetS on Brain

Haley et al. (2010) demonstrated changes in brain metabolism characterized by increased myoinositol/creatine and glutamate/creatine ratios in occipito-parietal gray matter in cognitively intact middle-aged adults with MetS (suggestive of increased microglia or neuroinflammation)

Using functional MRI, Hoth et al. (2011) observed blunted brain activation in the absence of cognitive compromise.

Taken together, these subclinical alterations in cerebral metabolism and cerebrovascular reactivity may represent early brain compromise associated with peripheral metabolic disturbances.

MetS and Early Alzheimer’s disease

Watts et al. has studied Metabolic Syndrome and Cognitive Decline in Early Alzheimer’s Disease and Healthy Older Adults in 2013

Findings: MetS may not have the same association with cognitive

decline in healthy older adults and those with early AD. In healthy older adult controls, MetS did not predict

cognitive decline, while in those with early AD a higher MetS score predicted better cognitive performance and less cognitive decline.

In mid-life, elevated levels of biomarkers may be causal indicators of the onset of a disease process, whereas, in old age, biomarkers are more likely signs of disease rather than causal indicators.

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Continued…… Insulin was found to be most consistent predictor of

cognitive performance and decline in both groups In healthy controls, higher insulin predicted more rapid

declines in attention and verbal memory over two years In those with early AD, higher insulin predicted better

cognitive performance AD patients with type 2 diabetes may have slower rates

of cognitive decline than non-diabetic AD patients Insulin signaling may affect brain health in a disease

specific manner or insulin signaling may be affected by changes in the AD brain

It remains unclear whether altered insulin signaling contributes to the development and progression of AD or whether insulin regulation changes are the result of AD brain changes

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Continued….. Authors suggested that MetS components should not be

evaluated in isolation

The relationship between insulin and cognitive outcomes was dependent on APOE carrier status, suggesting that insulin is not acting alone but interacts with other components.

Other indicators independently associated with cognitive performance includes cholesterol, blood pressure, glucose, and body mass index and not always in a linear direction

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Continued….. Declines in verbal memory and attention are some of the

earliest cognitive changes in AD Review of studies suggests that attention and verbal

memory were among the domains most frequently assessed and the most frequently associated with MetS.

Study Found that Insulin and glucose were the two individual MetS components

most strongly associated with verbal memory and attention Poor verbal memory is the cognitive domain most

consistently associated with diabetes in large epidemiological studies

In non-diabetics, verbal memory and attention have been shown to be impaired during an oral glucose challenge with a magnitude similar to impairment seen in diabetics

In early AD, higher insulin predicted better verbal memory at the two year follow up, while higher glucose predicted more rapid declines in attention over two years.

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Explanatory model for association between MetS and

Brain deficits Proposed explanatory models:

Neuro-inflammationOxidative stressAbnormal brain lipid metabolismImpaired vascular reactivityDeposition of amyloidAccelerated production of

neurofibrillary tangles

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Continued…..

Vascular pathway: Impaired cerebrovascular reactivity, increased carotid

stiffness, and intima-media thickness (IMT) have been reported in adults with MetS.

Carotid artery is the main blood supply to the central nervous system and that carotid atherosclerosis has been linked to cognitive impairment68 and increased brain atrophy

Above findings suggest that the WM damage seen in adults with MetS are likely vascular in nature.

Endothelial dysfunction, carotid stiffness, and intima-media thickness also have been reported with MetS, obesity, hypertension and type 2 DM.

Those with uncontrolled DM have more severe carotid alterations.

Vascular involvement likely plays a role in cognitive and brain impairment in Adults.

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Continued…..

Damages brain integrity through vascular reactivity abnormalities

Vascular reactivity is key to maintaining energy-dependent processes such as regional brain activation by clearing the metabolic “waste” produced by neuronal activity.

Conceptual model:

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Insulin Resistance and MetS

Among individuals with insulin resistance and MetS, Vascular reactivity is dysfunctional

Dysfunction of vascular reactivity is due to the direct or indirect deleterious effects of insulin resistance and/or obesity-associated inflammation on the micro-vasculature

The impaired vascular reactivity may, in turn, lead to an inability to maintain energy-dependent processes and clear metabolic “waste” under conditions of increased demand

Endothelial dysfunction, when coupled with other potentially damaging influences such as inflammation, HPA axis dysregulation, or increased oxidative stress, may damage the brain, particularly those regions more vulnerable to damage.

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Risk factors for MetS

Increasing age: affecting 40 percent of people over the age of 60.

Race: Hispanics and Asians Low birth weight Menopause, gestational DM Lack of exercise and midlife obesity Diabetes, hypertension Stress Dietary habits (sugar sweetened beverage

consumption) Sedentary behavior TG > 250 and/or HDL < 40mg/dl

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Prevention of MetS Multipronged approach is essential, which should include

behavior modification, dietary modifications, increase in physical activities, prevention of smoking and alcohol excess

Behavioral modification: It is essential to identify maladaptive behavior related to

eating habits and rewards, especially in children and younger adults.

Habits are difficult to change in older individuals. It is essential that corrective measures continue even after

the achievement of a healthy lifestyle.

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Prevention of MetS Dietary modifications:

Dietary modifications, including a reduction in intake of saturated fat and refined carbohydrates and sweetened beverages, help in modifying childhood obesity

Dietary strategies should highlight the need to stick to traditional diets and restriction of sweetened beverages, high saturated and trans fat containing food stuffs.

Avoidance of salted and processed food is essential to prevent hypertension

Increased dietary fiber and including green leafy vegetables and fruits need to be encouraged to help prevent obesity

Snacking between major meals should be discouraged Low-fat dairy food should be encouraged

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Prevention of MetS Physical Activity:

Regular exercise should be promoted to increase energy expenditure and achieve weight loss and increase insulin sensitivity.

Exercise is also known to reduce blood pressure, increase HDL-C and lower TG levels.

Institution of physical activity needs to be gradual and graded.

Community based interventions: Several programs have been launched to prevent obesity

and MetS at a community level These include CHETNA and MARG The objectives of the programs are to make children aware

of obesity and diabetes and educate them regarding the beneficial effects of a healthy diet and increased physical activity

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Prevention of MetS

Community based intervention: A school-based program has been launched which aims to

impart health education on the prevention of obesity, diabetes, and heart disease in school children, code named CHETNA (Childrens’ Health Education Through Nutrition and Health Awareness).

A large prospective, school-based behavioral intervention study, code named MARG (Medical education for children/Adolescents for Realistic prevention of obesity and diabetes and for healthy aGing) is being carried out in 14 cities in North India.

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Prevention of MetS

Pharmacological interventions: According to the current international guidelines, none of

the pharmacological agents are approved for use for prevention of obesity or MetS in children.

Metformin is found to be beneficial in obese children and has effects on body composition and insulin sensitivity.

Pharmacological therapy of dyslipidemia is not recommended in children less than 10 years of age.

Community intervention programs amongst Asian Indians in South India demonstrated a relative risk reduction of 28.5% in cumulative incidence of diabetes through interventional lifestyle modification, which was higher than that achieved by metformin alone (24%).

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Treatment of MetS

The metabolic syndrome cannot be treated with a single agent, since it is a multifaceted health problem

Healthy lifestyle Management of obesity through exercise and

dietary modification Pharmacological agents which deal with obesity,

hypertension, dyslipidemia, diabetes can be used alone or in combination. Anti-obesity drugs, thiazolidinediones, metformin, statins,

fibrates, renin-angiotensin system blockers, glucagon like peptide-1 agonists, sodium glucose transporter-2 inhibitors, and some antiplatelet agents such as cilostazol

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Treatment of MetS

Obesity: Sibutramine, orlistat, metformin, rimonabant

Glucose intolerance, insulin resistance, and type 2 diabetes mellitus: Metformin, glitazones

Dyslipidemia: Statins, fibrates, niacin, omega 3 oil

Hypertension: modern drugs are more beneficial than older drugs (beta blockers and diuretics) ‘modern’ antihypertensive drugs: calcium antagonists, ACE

inhibitors and AT1 receptor blockers

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Treatment of MetSInsulin Resistance

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Metabolic causes for Dementia Endocrine disorders: Addison’s disease, cushing’s

disease, hypothyroidism, thyrotoxicosis, hyperparathyroidism, hashimotos encephalitis

Repeat episodes of low blood sugar (hypoglycemia), most often seen in people with diabetes who use insulin

Chronic hepatic encephalopathy Chronic uremic encephalopathy Nutritional disorders: vit B1, folate, B12 deficiencies,

pellagra Porphyria Severe alcohol use Wilson’s disease Chronic electrolyte disturbances Anemia

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Symptoms Fluctuating arousal, impaired attention, and disturbances

in memory. May cause confusion, changes in thinking and reasoning Severe disturbances of language and the other higher

cortical functions such as apraxia and agnosia are uncommon.

Motor system abnormalities including tremor, asterixis, and myoclonus often accompany the observed confusional state.

Acute changes are associated with delirious symptoms and not with dementia Causes like hypoxemia, acute electrolyte disturbances, acute

renal failure Chronic changes in blood biochemistry, endocrinal

disturbances, alcohol use, chronic renal failure, chronic metal poisoning, chronic hypo/hyperglycemia, nutritional disorders are associated with symptoms of dementia

Chronic causes of dementia as mentioned above are also called as reversible causes of dementia

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Nutritional deficiency Cyanocobalamin and folic acid are biochemically

interrelated vitamins that exert both a separate and concomitant influence on cognition and mood

Vitamin B12 deficiency leads to impaired memory, psychosis, and depression

Additional neuropsychological impairment is an infrequent finding.

Clouding of consciousness appears to be a consistent feature of the alteration in mental status associated with this nutritional cause of dementia.

Replacement therapy of vitamin B12 deficiency rarely leads to complete restoration of intellectual function.

It is less clear to what extent isolated folic acid deficiency may cause dementia.

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Toxic Causes for dementia The neuropsychological impairment of chronic alcoholism

has been historically considered to be a severe amnestic disorder related to a nutritional deficiency of thiamine (korsakoff’s psychosis).

Along with anterograde and retrograde memory impairment, alcoholism is associated with visuoperceptual and problem-solving disability.

Impaired performance of verbal fluency tasks and poor abstract concept formation have also been noted.

Improvement of dementia may occur with abstinence, but complete restoration of intellectual function is rare.

Alcohol-associated dementia is more common in the elderly population than in younger alcoholic populations.

The dementia associated with alcoholism may be in part a product of thiamine deficiency but is likely also to reflect a direct toxic effect of alcohol.

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Management of Metabolic causes of Dementia

Blood and urine investigations: Blood chemistry, electrolytes Blood glucose level BUN, creatinine to check kidney function Liver function tests Lumbar puncture Nutritional assessment Thyroid function tests Urinalysis Vitamin B12 level Ammonia level in the blood

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Management of Metabolic causes of Dementia

Important steps: Metabolic causes are responsible for non-degenerative

types of dementia It presents with similar cognitive and behavioral

symptoms as compared to degenerative dementia, based on the severity

Identification of underlying cause is crucial for management

Presence of metabolic cause specific signs an symptoms are very crucial for identification of cause

Investigation should include clinical details (history and examination), laboratory work up and imaging if indicated

Delirium due to metabolic disturbances improve as soon as the underlying cause is corrected

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References: Yaffe K, Weston AL, Blackwell T, Krueger KA. The metabolic syndrome and development of cognitive impairment

among older women. Arch Neurol [Internet]. 2009 Mar [cited 2016 Feb 2];66(3):324–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2685462&tool=pmcentrez&rendertype=abstract

Yaffe K, Haan M, Blackwell T, Cherkasova E, Whitmer RA, West N. Metabolic syndrome and cognitive decline in elderly latinos: Findings from the Sacramento Area Latino Study of Aging Study. J Am Geriatr Soc. 2007;55(5):758–62.

Yates KF, Sweat V, Yau PL, Turchiano MM, Convit A. Impact of Metabolic Syndrome on Cognition and Brain: A Selected Review of the Literature. Arterioscler Thromb Vasc Biol. 2013;32(9):2060–7.

Watts AS, Loskutova N, Burns JM, Johnson DK. Metabolic syndrome and cognitive decline in early Alzheimer’s disease and healthy older adults. J Alzheimers Dis [Internet]. 2013 Jan [cited 2016 Mar 5];35(2):253–65. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3665401&tool=pmcentrez&rendertype=abstract

Pandit K, Goswami S, Ghosh S, Mukhopadhyay P, Chowdhury S. Metabolic syndrome in South Asians. Indian J Endocrinol Metab [Internet]. 2012;16(1):44–55. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3263197&tool=pmcentrez&rendertype=abstract

Sawant A, Mankeshwar R, Shah S, Raghavan R, Dhongde G, Raje H, et al. Prevalence of metabolic syndrome in Urban India. Cholesterol. 2011;2011.

Binesh Marvasti T, Adeli K. Pharmacological management of metabolic syndrome and its lipid complications. Daru [Internet]. 2010 Jan [cited 2016 Mar 6];18(3):146–54. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3304358&tool=pmcentrez&rendertype=abstract

Lim S, Eckel RH. Pharmacological treatment and therapeutic perspectives of metabolic syndrome. Rev Endocr Metab Disord [Internet]. 2014 Dec [cited 2016 Mar 6];15(4):329–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25342235

The Primary Care Guide To Understanding The Role Of The Metabolic Syndrome In Cognitive Decline Of Older Persons. 2005;(7):1–6.

Panza F, Frisardi V, Capurso C, Imbimbo BP, Vendemiale G, Santamato A, et al. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimers Dis [Internet]. 2010 Jan [cited 2016 Mar 2];21(3):691–724. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20571214 

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King George’s Medical University UP, Lucknow King George’s Medical University UP, Lucknow INDIA INDIA