Relationship of Metabolic syndrome and cognitive impairment has been discussed. Metabolic causes of Dementia and their reversibility has been discussed.

1. Metabolic
Disturbances and
Cognitive Impairment
DR. RAVI SONI
DM SR III
DEPT. OF GERIATRIC MENTAL HEALTH
KGMU, LKO

2. 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
2

3. 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.

4. 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)
4

6. 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
6

7. 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
7

8. Studies on MetS and Cognitive
Impairment
Reference Findings
Bokura 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 differences
Hassenstab et al. 2010 Significant reductions in recall, lower
overall IQ; increasing MetS factors
associated with lower performance

9. 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
9

10. MetS and affected Cognitive
domains
 Multiple cognitive domains are affected
 MetS has been linked to deficits in
 Memory
 Visuospatial abilities
 Executive functioning
 Processing speed
 Overall intellectual functioning
10

11. 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
11

12. 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.

13. 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.
13

14. 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
14

15. 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
15

16. 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.
16

17. Explanatory model for association
between MetS and Brain deficits
 Proposed explanatory models:
Neuro-inflammation
Oxidative stress
Abnormal brain lipid metabolism
Impaired vascular reactivity
Deposition of amyloid
Accelerated production of neurofibrillary
tangles
17

18. 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.
18

19. 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:
19

20. 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.
20

21. 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
21

22. 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.
22

23. 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
23

24. 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
24

25. 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.
25

26. 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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27. 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
27

28. 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
28

29. Treatment of MetS
Insulin Resistance
29

30. 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
30

31. 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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32. 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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33. 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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34. 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
34

35. 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
35

36. 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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37. King George’s Medical University UP, LucknowKing George’s Medical University UP, Lucknow
INDIAINDIA