Type 2 Diabetes and Brain Disease in Older Adults. Erin L. Abner, PhD, MPH Asst. Professor University Of Kentucky

Type 2 Diabetes and Brain Disease in Older Adults Erin L. Abner, PhD, MPH Asst. Professor University Of Kentucky

Disclosures to Participants Requirements for Successful Completion: For successful completion, participants are required to be in attendance in the full activity, complete and submit the program evaluation at the conclusion of the educational event. Conflicts Of Interest and Financial Relationships Disclosures None Disclosure of Relevant Financial Relationships and Mechanism to Identify and Resolved Conflicts of Interest: No conflicts of Interest Non-Endorsement Of Products: Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity. Off-Label Use: Participants will be notified by speakers to any product used for a purpose other than that for which it was approved by the Food and Drug Administration. Activity-Type : Knowledge-based

SAMPLE-This continuing nursing education activity was approved by the American Association of Diabetes Educators, an accredited approver by the American Nurses Credentialing Center s Commission on Accreditation. SAMPLE-The American Association of Diabetes Educators is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.5 contact hours (.15 CEU s) of continuing education credit. ACPE Universal Activity Number: 0069-9999-xx-xxx-L01-P Effective Date: November xx, 2015 to November xx, 2016

Learning Goals 1. Describe the risk of cognitive dysfunction and dementia associated with diabetes 2. Describe specific brain pathologies observed among older adults with diabetes 3. List knowledge gaps related to diabetes and less common brain diseases

Cognitive Dysfunction vs. Dementia Cognitive Dysfunction/Impairment Self-reported Deficits on neurocognitive testing Diagnosis of Mild Cognitive Impairment Dementia Clinically significant impairment in at least two domains, including memory Impaired activities of daily living due to cognitive impairment Decline from earlier levels of functioning

How do we measure cognition? Cognitive function is measured by tasks that assess global cognitive function or specific domains Scoring usually takes into account age and educational level Assessments can be done in person, over the phone, or computer-based

Z scores & Standard Deviations Z = -1.5 means score is lower than 93% of scores

Diabetes is associated with slightly worse cognition Koekkoek PS, et al. Lancet Neurol

Van den berg, et al. Biochimica et Biophysica Acta 2009;470-481 Multiple cognitive domains are affected Domain Decrement Range (SDs) Number of Studies General intelligence -0.1 to -2.3 7 Memory 0 to -1.2 14 Processing speed 0 to -1.4 11 Attention -0.1 to -1.9 6 Cognitive flexibility -0.1 to -0.9 13 Construction -0.1 to -0.7 5 Language -0.4 1

Multiple cognitive domains are affected Reijmer et al., Diabetes Metab Res Rev DM No DM

Cognitive decline in diabetes may be accelerated in younger adults Whitehall II cohort study (N=5,653), ages 35-55 at baseline, followed for 10 years Compared to normoglycemic participants, participants with known diabetes had 45% faster decline in memory 29% faster decline in reasoning 24% faster decline in global cognition Tuligenga RH, et al. Lancet Diab Endocrinol

Cognitive decline in diabetes may not be accelerated in older adults Van den Berg, et al. Black circles = Control group (n=56) White circles = Diabetes group (n=122)

Not all studies show an association between diabetes and cognition New Mexico Elder Health Survey (N=883) Lindeman et al. Diabetes Care

Results of randomized intervention studies have not yet provided promising therapies to improve cognition ACCORD MIND Study: Intensive glucose lowering no difference at 40 months (Launer et al., Lancet Neurol 2011;10:969-77.) Intensive blood pressure control and lipid lowering no difference (Williamson et al., JAMA Internal Med 2014;174:324-33.) Low-carb diet no difference at 52 weeks (Tay et al., Brit J Nutrition 2016;116:1745-53.) Several studies on diet and exercise currently underway

Summary of evidence for cognitive dysfunction in diabetes Most studies show an association between diabetes and subtle cognitive dysfunction in adults, between 0.1 and 0.4 standard deviations below peers without diabetes Multiple cognitive domains show similar associations Level of dysfunction and rate of decline may depend on age and duration of diabetes Conflicting results may be due to differences in methods of analysis and study design, including the sensitivity of the cognitive tests and the populations studied

Clinical implications regarding cognitive dysfunction No need to routinely screen patients with diabetes for cognitive dysfunction, especially below ages 60-70 Intensive glucose control, blood pressure control, and lipid lowering are not recommended Clinicians should follow up on cognitive complaints Diagnosis of MCI or dementia may indicate need for tailoring diabetes treatment to reduce risk of medication errors

Diabetes is associated with increased risk for dementia Among patients with dementia, patients with diabetes are overrepresented Meta-analyses suggest a two-fold increase in risk of dementia (Biessels et al., Lancet Neurol 2006;5:64-74) Several factors modify dementia risk among patients with diabetes

Dementia risk is modified by APOE Ahtiluoto et al. Neurology 2010;75:1195-

Age and education modify risk of dementia Exalto et al., Lancet Neurol

Diabetes complications may increase risk of dementia Gangrene, lower limb ulcer, lower extremity amputation Peripheral artery disease, myocardial infarction, CABG, angioplasty, CHF Diabetic retinal or end-stage renal disease Stroke, precerebral arterial disease, carotid endarterectomy Severe hypoglycemic or hyperglycemic events Exalto et al., Lancet Neurol

Dementia in old age results from pathological changes in the brain Alzheimer s disease Cerebrovascular disease Lewy Body disease Hippocampal sclerosis TDP-43 proteinopathy Frontotemporal lobar degeneration

http://www.uky.edu/coa/adc

Alzheimer s disease Identified in 1910 Progressive disorder marked by amyloid plaque and neurofibrillary tangle pathology Estimated prevalence in US is currently about 5 million Fatal, #5 leading cause of death Only 5 drugs approved for treatment since 1993, last one in 2002

Montine et al. Acta Neuropathol 2012;123 CERAD Neuritic Plaque Staging NONE SPARSE MODERATE FREQUENT

Braak & Braak Neurofibrillary Tangle Stages http://www.nyas.org/publications/ebriefings/detail.aspx?cid=3cea036e-6b33-4cd1-

Epidemiology of Alzheimer s disease Alzheimer s Disease Facts & Figures,

Alzheimer s Disease Facts & Figures,

Hypothesized model of Alzheimer s disease biomarkers 10-20 years Jack et al. Lancet Neurol

Risk factors for Alzheimer s disease dementia Age APOE-ε4 Sex Education Lifestyle (diet, physical activity, smoking, alcohol) Comorbidities (diabetes, hypertension, depression, head injury)

Modifiable risk factors for AD dementia Norton et al. Lancet Neurol

Diabetes increases risk of AD dementia diagnosis Lu FP et al. PLoS One 2009;4(1):e4

How might we explain the observed association between diabetes and AD dementia? Diabetes and AD share common causes? Diabetes causes AD neuropathological changes? Diabetes causes neuropathological changes distinct from AD but that cause AD-like symptoms? Diabetes doesn t cause AD but lowers the threshold of AD pathology required to produce symptoms?

If diabetes is a cause of Alzheimer s disease, we would expect to see Higher incidence of AD Increased levels of AD biomarkers Higher prevalence of AD pathology among autopsied persons

Diabetes is associated with structural changes on MRI Lower volumes of white matter, gray matter, and hippocampus (Moran et al. Diab Care 2013;36:4036-42; Van Harten et al. Diab Care 2006;29:2539-48.) Less severe than that seen in AD (comparable to 3-5 years of normal aging) Increased mean diffusivity in white matter, indicating blood-brain barrier dysfunction Decreased functional connectivity

Biessels & Reijmer, Diabetes

Diabetes is not associated with brain amyloid on PET Gottesman et al. JAMA

Moran et al. Neurology

Diabetes is associated with neurodegeneration Increased atrophy on MRI Increased p-tau and total tau in CSF

Diabetes is not associated with Alzheimer pathology Abner et al. Alz & Dement 2016;12:88

Nelson et al. Acta Neuropathol

Diabetes increases risk of Vascular Dementia diagnosis Lu FP et al. PLoS One

Diabetes increases risk of AD diagnosis Lu FP et al. PLoS One 2009;4(1):e4

Cerebrovascular pathology is associated with cognitive impairment Lacunar Infarct White Matter Lesion Ischemic Infarct CAA Arteriolosclerosis Korczyn et al. J Neurol Sciences 2012;322

Viswanathan et al. Neurology

Cerebrovascular lesions are more common in higher Braak stages Jellinger, Neuro- Degenerative Diseases

Infarct pathology increases odds of AD diagnosis Schneider et al., Ann Neurol 2009;66:20

How might we explain the observed association between diabetes and AD dementia? Diabetes and AD share common causes? Possible; mid-life obesity Diabetes causes AD neuropathological changes? Unlikely Diabetes causes neuropathological changes distinct from AD but that cause AD-like symptoms? Yes; CVD & cerebral atrophy Diabetes doesn t cause AD but causes neuropathological changes that lower the threshold of AD pathology required to produce symptoms? Likely

Diabetes may be linked to neurodegeneration through: Insulin resistance Glucose toxicity (chronic hyperglycemia) Amylin amyloidosis

Insulin and brain function Insulin and insulin receptors are abundant in the brain Hippocampus Substantia nigra Frontal cortex Insulin is involved in many mechanisms related to neuronal activity Modulates neurotransmitters Modulates glucose uptake

Insulin resistance in the brain promotes oxidative stress de la Monte et al. Curr Opin Investig Drugs

Insulin promotes Aβ clearance Craft & Watson. Lancet Neurol 2004;3:169-78.

Craft & Watson. Lancet Neurol 2004;3:169-78.

The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF) Phase II/III clinical trial to evaluate efficacy of intranasal insulin to improve cognition in older adults (55-85 y) with MCI or early AD Excludes persons with diabetes Concludes 2018 https://clinicaltrials.gov/ct2/show/nct01767909

Glycemic variability is associated with worse cognition in persons without dementia Geijselaers et al. Lancet Diab Endocrinol 2015;3:75-89.

Glycemic variability is associated with brain atrophy Cui et al. PLoS One 2013;

Glycemic variability is associated with mild brain atrophy Cui et al. PLoS One

Amylin accumulates in the brain Jackson et al. Ann Neurol

Lutz & Meyer. Frontiers in Neurosci 2015;9.

Tauopathies, amyloidopathies, and synucleinopathies Jellinger. ScientificWorldJournal 2011;11:189

Synucleinopathies Lewy Body disease Parkinson s disease (200 cases per 100,000 persons > 80 y) Dementia with Lewy Bodies (100 cases per 100,000 persons > 70 y) McKeith et al. Neurology

PDD vs. DLB Different clinical course PDD: movement disorder precedes cognitive impairment by years DLB: cognitive disorder, with or without movement disorder; visual hallucinations, REM sleep disorder Different anatomical distribution PDD: brainstem, motor cortex DLB: cerebral cortex Similar risk factors Onset between age 50-85 More men than women affected Genetics/Family history?

Diabetes may increase risk of Parkinson s disease Yang et al. Medicine

Why would diabetes increase risk of PD? Share common causes? Mixed evidence regarding overweight & obesity Insulin resistance? Diabetes causes an intermediate condition that causes PD? CVD Diabetes causes PD? Unclear

Non-AD tauopathies Frontotemporal lobar degeneration (15 per 100,000) Progressive supranuclear palsy (1 per 100,000) Corticobasal degeneration (5 per 100,000) TDP-43 (???)

Summary Diabetes is associated with: Cognitive dysfunction & dementia Brain atrophy (neurodegeneration) Aggressive clinical interventions to manage diabetes and improve cognition have not shown promise Insulin dysregulation, independent of diabetes, may promote neurodegeneration; mechanism is not well understood

Summary Diabetes has not been shown to be associated with AD pathology Diabetes has been shown to be associated with CVD pathology Diabetes may be associated with Parkinson s disease Other brain diseases not well studied

Implications for clinical practice Cognitive impairment and dementia are complications of diabetes; risk increases with age Prevention of other diabetes-related complications may reduce dementia risk Decreasing glucose variability may reduce risk Maximizing cardiovascular health may reduce risk