Mild Cognitive Impairment or Mild Neurocognitive Disorder: Implications for Clinical Practice. Hypothesized Key Players in the Pathogenesis of AD

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1 AD is a Neurodegenerative Disease as Seen in the PET Scan and is Characterized by Amyloid Plaques and Neurofibrillary Tangles Mild Cognitive Impairment or Mild Neurocognitive Disorder: Implications for Clinical Practice George T. Grossberg, MD Samuel W. Fordyce Professor Director, Geriatric Psychiatry Program Department of Psychiatry St. Louis University School of Medicine St. Louis, Missouri Neuritic Plaques Neurofibrillary Tangles PET scans from UCLA Center on Aging. AD = Alzheimer s disease; PET = positron emission tomography. Accessed July 1, Nelson PT, et al. J Neuropathol Exp Neurol. 2009;68(1):1-14. Hypothesized Key Players in the Pathogenesis of AD Aβ = amyloid beta; ApoE4 = apolipoprotein E-ε4. Mucke L. Nature. 2009;461(7266): Established Risk Factors Older age Family history of AD APOE-ε4 gene (especially amnestic subtype) CV disease and associated CV risk factors (eg, smoking, diabetes, hyperlipidemia, hypertension, obesity) Less education Traumatic brain injury Elevated plasma homocysteine levels Risk Factors Emerging Risk Factors Inflammation Chronic kidney disease Thyroid dysfunction Dietary factors and activity level Social isolation Depression CV = cardiovascular; = mild cognitive impairment. Alzheimer s Association Alzheimer s Disease Facts and Figures. Accessed July 1, de Bruijn RF, et al. BMC Med. 2014;12:130. Subjective Cognitive Impairment Diagnosis of Mild Cognitive Impairment and Alzheimer s Disease SCI, also referred to as Senior Moments, is not in the SCI may represent a prodrome to Mild Neurocognitive Disorder (formerly called ) SCI = subjective cognitive impairment.

2 Terminology: An Update Delirium Delirium Mild Neurocognitive Disorder Major Neurocognitive Disorder Replaces DSM-IV Delirium, Mild Cognitive Impairment, and Dementia Preclinical AD due to AD All-cause dementia AD dementia Probable AD dementia Possible AD dementia Dementia unlikely to be due to AD Disturbance in attention and awareness Develops over short period of time, and tends to fluctuate in severity during the day An additional cognitive domain disturbance Physiologic consequence of a medical condition, substance intoxication or withdrawal, toxin exposure, or multiple etiologies The Confusion Assessment Method (CAM) is considered the best screening tool for delirium AA = Alzheimer s Association; NIA = National Institute on Aging. Edition. Arlington, VA: American Psychiatric Association; Sperling RA, et al. Alzheimers Dement. 2011;7(3): Albert MS, et al. Alzheimers Dement. 2011;7(3): McKhann GM, et al. Alzheimers Dement. 2011;7(3): Edition. Arlington, VA: American Psychiatric Association; Inouye SK, et al. Ann Intern Med. 1990;113(12): The Continuum of AD Defining a Preclinical Stage of AD () Cognitive Function Preclinical Aging Stage 1 Asymptomatic amyloidosis High PET amyloid tracer retention Low CSF A 1-42 Stage 2 Amyloidosis + Neurodegeneration Neuronal dysfunction on FDG-PET/fMRI High CSF tau/p-tau Cortical thinning/hippocampal atrophy on smri Biomarker evidence of AD without clinical symptoms of cognitive decline Years Dementia Stage 3 Amyloidosis + Neurodegeneration + Subtle Cognitive Decline Evidence of subtle change from baseline level of cognition Poor performance on more challenging cognitive tests Does not yet meet criteria for AD Dementia Sperling RA, et al. Alzheimers Dement. 2011;7(3): CSF = cerebrospinal fluid; FDG = fluorodeoxyglucose; fmri = functional magnetic resonance imaging; smri = structural MRI. Sperling RA, et al. Alzheimers Dement. 2011;7(3): Cognitive and Behavioral Domains That May Be Affected in or Dementia Attention * Sustained and divided attention, processing speed Executive function/ability * Planning/decision making/judgment Reasoning and handling of complex tasks Learning and memory * Immediate and recent recall, free recall, cued recall and recognition Ability to acquire and remember new information Language * Expressive and receptive Speaking, reading, writing Visuoconstructionalperceptual activity/visuospatial abilities * Social cognition Emotions and behavioral regulation Changes in personality, behavior, or comportment *;. Edition. Arlington, VA: American Psychiatric Association; Albert MS, et al. Alzheimers Dement. 2011;7(3): McKhann GM, et al. Alzheimers Dement. 2011;7(3): Mild Neurocognitive Disorder/ Cognitive deficits do not occur exclusively in context of delirium Self- or informantreported cognitive complaint Objective cognitive impairment Preserved functioning No dementia due to AD Exclusion of vascular, traumatic, medical causes of cognitive decline (when possible) Evidence of longitudinal decline in cognition (when feasible) History consistent with AD genetic factors (when relevant) Edition. Arlington, VA: American Psychiatric Association; Albert MS, et al. Alzheimers Dement. 2011;7(3):

3 Major Neurocognitive Disorder (A Syndrome) / Dementia (Major Neurocognitive Disorder) Evidence of significant cognitive decline in 1 cognitive domains Significant cognitive decline noted by patient, informant, or clinician Objective evidence of substantial impaired cognition, preferably by standard neuropsychological testing Symptoms interfere with ability to function at work or at everyday activities Not explained by delirium or () major psychiatric disorder (Dementia) Evidence of cognitive or behavioral impairment involving 2 domains Noted in history-taking from patient and knowledgeable informant Objective cognitive assessment ( bedside mental status examination or neuropsychological testing) Represent a decline from previous levels of functioning and performing Edition. Arlington, VA: American Psychiatric Association; McKhannGM, et al. Alzheimers Dement. 2011;7(3): Major Neurocognitive Disorder Due to AD / Probable AD Dementia Criteria met for probable AD Either: Evidence of a causative AD genetic mutation (< 1% of all AD) OR All 3 of the following Decline in memory and learning plus at least 1 other cognitive domain Steady, gradual decline without extended plateaus No evidence of mixed etiology Not better explained by CV disease, another neurodegenerative disorder, or another mental, neurologic, or systemic disorder Initial/most prominent cognitive deficits evident on history and examination in 1 of the following Amnestic presentation* Nonamnestic presentations Criteria met for major Diagnosis should not be applied neurocognitive disorder/dementia Insidious onset and gradual progression when there is evidence of Substantial concomitant cerebrovascular disease A specified neurodegenerative disorder OR Another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could substantially affect cognition *Deficits include impairment in learning and recall of recently learned information as well as evidence of cognitive dysfunction in at least 1 other cognitive domain; Most prominent deficits in word-finding (language presentation), spatial cognition (visuospatial presentation), and impaired reasoning, judgment, and problem solving (executive dysfunction); Core features of Dementia with Lewy bodies other than dementia itself, prominent features of behavioral variant fronterotemporal dementia, or prominent features of semantic variant primary progressive aphasia. Edition. Arlington, VA: American Psychiatric Association; McKhann GM, et al. Alzheimers Dement. 2011;7(3): The Office-Based Assessment of Neurocognitive Disorder A careful history from a family member/reliable informant Quantify cognitive function, eg, Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MOCA), St. Louis University Mental Status Evaluation (SLUMS) ADL screening (Barthel Inventory or Katz Index of ADL) Screening neurological exam Laboratory: CMP, CBC, TSH, B12/folate; UA; RPR, HIV testing, if indicated; some also recommend: Vitamin D level; CRP; homocysteine level MRI or CT (old stroke, tumor, NPH, frontotemporal atrophy) Complete neuropsychological testing (if available) Repeat cognitive assessment in 6 to 12 months to confirm/clarify diagnosis, measure disease trajectory Importance of early recognition Benefits of Early Diagnosis in AD Allows patient and family to learn about AD Allows time for future planning while patient still capable, eg, update will; health care proxy; POA Allows clinician to begin AD medications early and to educate patient and family about lifestyle interventions, which may slow disease progression or delay onset in family members Allows participation in clinical trials ADL = activities of daily living; CBC = complete blood count; CMP = complete metabolic profile; CRP = C- reactive protein; NPH = normal pressure hydrocephalus; RPR = rapid plasma reagin; TSH = thyroid stimulating hormone; UA = urinalysis. Weiner MF, et al (Eds). Clinical Manual of Alzheimer Disease and Other Dementias. Arlington, VA: American Psychiatric Publishing; POA = power of attorney. Natural History: Symptom Progression in and AD Amyloid and Tau Biomarkers in SCI MMSE Score 30 Mild, Mild AD 25 subjective Forgetfulness Objective Short-term Moderate AD Memory loss memory loss 20 Progression of cognitive Normal ADL Repetitive deficits function questions Aphasia 15 Hobbies, Severe AD Dysexecutive syndrome interest loss Agitation Impaired basic ADLs Impaired 10 Altered sleep instrumental Transitions in care patterns functions Total 5 Anomia dependence: dressing, feeding, bathing Years Amyloid and Tau biomarker profiles become increasingly abnormal from SCI to to AD Amyloid and Tau biomarkers are unable to differentiate between SCI and healthy controls but may be able to differentiate between SCI patients who cognitively decline over time vs those who do not Estimates of duration of survival following diagnosis of AD range from 3 to 12 years. Feldman H, et al. Accessed July 5, Feldman HH, et al. Neurology. 2005;65(6 Suppl 3):S10-S17. Kua EH, et al. Psychogeriatrics. 2014;14(3): Colijn MA, et al. J Alzheimers Dis. 2015;47(1):1-8.

4 FDG-PET and Neuropsychological Testing in SCI 24 women with SCI followed for 24 months Changes in cognitive domain scores and regional cerebral metabolic rate of glucose measured Significant reduction in executive functions found without changes in other cognitive domains Declines in regional glucose metabolism found Change in executive function was positively correlated with decreased glucose metabolism in the right posterior cingulate gyrus Risk Factors for SCI APOE-ε4 genotype Especially in those 70 years of age Positive amyloid PET and/or Tau PET findings Presence of anxiety or depression (may mimic SCI vs risk factor) Jeong HS, et al. Acta Neurol Scand. 2016;[Epub ahead of print]. Krell-Roesch J, et al. J Neuropsychiatry Clin Neurosci. 2015;27(4): Colijn MA, et al. J Alzheimers Dis. 2015;47(1):1-8. Yates JA, et al. Aging Ment Health. 2015;[Epub ahead of print]. Predictors of Clinical Progression from SCI to CREDOS study from South Korea enrolled 129 participants with SCI Follow-up duration of 0.5 to 4.7 years Median time to event was 3.64 years Predictors of conversion from SCI to Older age Lower MMSE score APOE-ε4 carrier Lower verbal delayed recall score Predictors of Clinical Progression from SCI to (continued) Presence of white matter hyperintensities Worried complainers Low general life satisfaction CREDOS = Clinical Research Centers for Dementia of South Korea. Hong YJ, et al. Dement Geriatr Cogn Disord. 2015;40(3): Benedictus MR, et al. Stroke. 2015;46(9): Mendonca MD, et al. Am J Alzheimers Dis Other Demen. 2015;31(2): Peitsch L, et al. Int Psychogeriatr. 2016;28(7): Conversion from to AD Not all patients convert to AD Usually 50% of patients convert to AD over 5 years Stress reduction (meditation, yoga), spiritual fitness, dietary modification, physical exercise, mental stimulation, and socialization may delay progression from to AD The 12 Years Preceding Due to AD: The Temporal Emergence of Cognitive Decline Investigated the prodromal phase of over a 12-year period in 27 initially healthy participants with subsequent preceding AD (NC-) vs 60 matched healthy individuals (NC-NC) Sequence of cognitive decline Began with verbal memory and savings: 8 years preceding Verbal episodic learning, visual memory, semantic memory (animal fluency): 4 years preceding Executive functioning, psychomotor speed, and informant-based reports: 2 years preceding Khalsa DS. J Alzheimers Dis. 2015;48(1):1-12. Mistridis P, et al. J Alzheimers Dis. 2015;48(4):

5 Treatment of SCI/ Conclusion No FDA approved therapies exist Recent SCI study using fish oil (EPA+DHA: 2.4 g/dl, n = 11) vs placebo (corn oil, n = 10) for 24 weeks Results: Increased RBC Omega-3 content Improved working memory Improved cortical blood oxygen level-dependent (BOLD) activity during working memory challenge SCI is a prodrome to, which is a prodrome to AD SCI is not listed in the ; however, a variety of biomarkers, as well as clinical features enable us to diagnose SCI There is growing evidence that anxiety and depression may mimic SCI There is growing evidence that lifestyle modification may slow progression from SCI to to AD EPA = eicosapentaenoicacid; DHA = docosahexaenoic acid. Boespflug EL, et al. J Nutr Health Aging. 2016;20(2): Practical Take-Aways There is growing evidence that Mild Neurocognitive Disorder (), especially of the amnestic type, is a risk factor/prodrome to AD Clinicians need to advise their at-risk patients to: 1) Control any and all cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, obesity, smoking, lack of exercise 2) Keep mentally, physically, socially and spiritually active 3) Treat/avoid stress/anxiety/depression, eg, mindfulness/relaxation therapy 4) Avoid head trauma (protect the brain) 5) Adopt a Mediterranean Diet By following these guidelines, patients have a better chance of delaying/decreasing their risk of AD