AT RISK, SCI, EMCI: THE ALPHABET SOUP OF PRECLINICAL AND PRODROMAL ALZHEIMER DISEASE Mary Ellen Quiceno, MD, FAAN Associate Professor of Neurology Mary Quiceno, MD discloses she has received honoraria from Adamas and Eli Lilly and receives research support from Eli Lilly. This presentation will contain off-label discussion of new clinical trials looking at use of amyloid therapies (monoclonal antibodies and BACE inhibitors). 1
Objectives: Distinguish between the stages of Alzheimer disease (AD) which precede dementia, i.e. preclinical/at risk/stage 1, subjective cognitive impairment or decline (SCI or SCD)/stage 2, and early mild cognitive impairment/prodromal AD/stage 3. Explain the temporal progression and risk factors for progression and treatments for each stage of AD which precedes dementia. Apply recent research findings to be able to identify patients in these stages of AD. Classification of Alzheimer disease and neurodegenerative dementias Global deterioration score Clinical Dementia Rating scale Functional Assessment Staging of Alzheimer s Disease MMSE, neuropsychology Amyloid, tau, neurodegeneration Clinical Function Cognitive Biomarkers 2
The Global Deterioration Scale for Assessment of Primary Degenerative Dementia Developed by Dr. Barry Reisberg Provides caregivers an overview of the stages of cognitive function Broken down into 7 different stages Stages 1-3 are the pre-dementia stages Stages 4-7 are the dementia stages Beginning in stage 5, an individual can no longer survive without assistance. Am J Psychiatry Volume 139, Issue 9, September 1982, pp. 1136-1139 Level 1 No cognitive decline (Preclinical, At risk) 2 Very mild cognitive decline (Subjective Cognitive Impairment or Decline) Clinical Characteristics No subjective complaints of memory deficit & none clinically. Subjective complaints of memory deficit: (a) forgetting where one has placed familiar objects; (b) forgetting names one formerly knew well. No objective evidence of memory deficit on clinical interview. No objective deficits in employment or social situations. Appropriate concern with respect to symptomatology. 3 Mild cognitive decline (Prodromal, Mild Cognitive Impairment) 4 Moderate cognitive decline (Mild Dementia) Earliest clear-cut deficits. Manifestations one or more areas: (a) patient may have gotten lost when traveling to an unfamiliar location; (b) coworkers become aware of patient's relatively poor performance; (c) word and name finding deficit becomes evident to intimates; (d) patient may read a passage or a book and retain relatively little material; (e) patient may demonstrate decreased facility in remembering names upon introduction to new people; (f) patient may have lost or misplaced an object of value; (g) concentration deficit may be evident on clinical testing. Objective evidence of memory deficit obtained only with an intensive interview. Decreased performance in demanding employment and social settings. Denial. 3
ATN C. Jack A/T/N Score Amyloid Tau Neurodegeneration A-/T-/N- None None None A+/T-/N- A+/T+/N- CSF or PET amyloid + CSF or PET amyloid + A+/T-/N+ CSF or PET amyloid + A+/T+/N+ CSF or PET amyloid + None CSF p-tau elevated or PET tau + None CSF p-tau elevated or PET tau + A-/T+/N- None CSF p-tau elevated or PET tau + None CSF t-tau elevated, Abnl FDG PET c/w AD, MRI atrophy c/w AD CSF t-tau/fdg PET/MRI atrophy CSF t-tau/fdg PET/MRI atrophy None A-/T-/N+ None None CSF t-tau/fdg PET/MRI atrophy A-/T+/N+ None CSF p-tau elevated or PET tau + CSF t-tau/fdg PET/MRI atrophy Neurology 2016; 87: 539-47. 4
Preclinical AD-pathophysiological process or AD-P 10 year + period prior to onset of clinical manifestations of AD or ADclinical (AD-C) 30% of 65yo and older have amyloid accumulation 18,000+ Ft Worth 31,000+ Dallas 5
RECENT LITERATURE ON PRECLINICAL AD What comes first? De Leon MJ et al. PLoS One 2018 Current thinking: reductions in the CSF levels of Aβ 42, which are associated with brain amyloid deposition, precede elevations in CSF tau levels, a marker of neurodegeneration and lower CSF Aβ 42 levels predict cognitive decline Transgenic animal models show CSF Aβ 42 elevations occur prior to Aβ 42 reductions and brain deposition, a trend also seen in early onset AD Utilizing cross-sectional (n = 766) and longitudinal data (n = 651) from three normal elderly cohorts with similar clinical and CSF protocols, we tested and confirm two major hypotheses: 1) CSF Aβ 42 levels have a non-linear relationship with both age and CSF biomarkers for tau pathology. We observed during mid to late-adult life, a quadratic or U- function uniquely and significantly described the CSF Aβ42 relationships to age and to CSF tau levels. For CSF Aβ38 or Aβ40, only linear relationships were found with age and tau levels; and 2) the cross-sectional and longitudinal results confirm the hypothesis that elevated Aβ42 levels contribute to the prediction of future cognitive decline. These data suggest that tau pathology precedes Aβ 42 pathology CSF biomarker studies that rely on decreased CSF Aβ 42 levels to identify brain amyloid sequestration and mark the onset of preclinical AD will have missed an earlier stage of elevated Aβ 42 also accompanied by elevated tau levels 6
How to identify Preclinical AD neuropsychologically: Accelerated long-term forgetting Present in autosomal dominant Alzheimer s disease mutation carriers, who were on average 7 years from predicted symptom onset Learning and recall of a 15-item word list, a short story, and a complex visual figure from the Adult Memory and Information Processing Battery At the 7-day telephone call, participants' free recall of the test materials was reassessed. For the figure, they were asked to draw the figure on a blank piece of paper included in the envelope, and for the verbal tests recall was done orally. Forced-choice recognition memory was then assessed Might be a very early feature of Alzheimer s disease-related cognitive decline Subtle increased subjective cognitive concerns also appear to be a presymptomatic feature of autosomal dominant Alzheimer s disease, which could be underpinned by accelerated long-term forgetting. Amyloid imaging is costly and CSF is invasive: Other imaging identification Eur J Nucl Med Mol Imaging. 2018 Feb 2 The use of cognition as the primary outcome of clinical trials in individuals with preclinical AD difficult slow rate of change high sample sizes and long follow-up times Combined Aβ and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of diseasemodifying therapies on [ 18 F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD. 7
JAGS 2018 The presence of an abnormally high level of Aβ42 was unrelated to screen-positive depression Age was the only independent predictor of screen positive depression with the risk increasing 1.06 times for every additional year of age Oncotarget 2017 Oct 31;8(62):104706-104716 J Affect Disord 2018 Preclinical AD Studies FINGER study A4 DIAN/API Colombian Kindred EARLY GENERATIONS US POINTER 8
A Multidomain Two-Year Randomized Controlled Trial to Prevent Cognitive Impairment- the FINGER study The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) Investigated the effects of a 2-year intervention targeting several lifestyle and vascular risk factors simultaneously 1) Dietary guidance: Finnish Nutrition Recommendations 2) Physical activity: the Dose Responses to Exercise Training (DR s EXTRA) protocol 3) Cognitive training and social activities: 10 group sessions lead by a psychologist (approximately 60-90 minutes/session) plus computer program and group discussions on memory-related themes (age-related changes in cognition, memory strategies, and every-day memory training). 4) Intensive monitoring and management of metabolic and vascular risk factors: Meet study nurse Q3mo during the first year, then Q6mo during the second year for anthropometric measurements (weight, blood pressure, hip and waist) The control group received regular health advice. 1260 participants aged 60-77 years Results: We found a significant beneficial intervention effect on overall cognitive performance. The beneficial effect was seen on each cognitive domain: memory; executive function, and psychomotor speed. Improvement in the neuropsychological test battery total score after 24 months was 25% higher in the intervention group than in the control group We also noted a significant intervention effect for the secondary cognitive outcomes of executive functioning (p=0 039) and processing speed (p=0 029) Improvement in executive functioning was 83% higher, and in processing speed 150% higher, in the intervention group than in the control group. The intervention was not associated with significant change in the prespecified memory domain. Conclusions: This is the first large RCT showing that it is possible to prevent cognitive decline using a multidomain intervention among older at-risk individuals. These results highlight the value of the feasible and novel multidomain approach that is effective for several cognitive domains. http://www.alzheimersprevention.org/downloadables/finger-study-report-by-arpf.pdf 9
Passive Immunization Against Amyloid The Dominantly Inherited Alzheimer Network (DIAN) Observational Study Enables researchers around the world to monitor and identify changes in individuals who carry one of the gene mutations (Presenilin1, Presenilin2 or APP) known to cause dominantly inherited Alzheimer s disease (DIAD). There is currently no treatment that can prevent or delay the progression of AD, and no new treatments have been approved in over ten years. DIAN aims to define the natural history of AD and establish reliable biomarkers that track with disease. 10
BACE1 inhibitor drugs in clinical trials for AD β-site amyloid precursor protein cleaving enzyme 1 (BACE1) β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide Drug target for reducing the levels of Aβ in the brain Generation Two therapies given separately, both targeting amyloid, one IM and the other PO In participants at risk for the onset of clinical symptoms of Alzheimer's disease Cognitively unimpaired individuals with two APOE4 genes and age 60 to 75 years Randomized, double-blind, placebo-controlled, twocohort, parallel group design in which participants receive one of the investigational treatments or their matching placebo for at least 60 months up to a maximum of 96 months An unbalanced randomization (active: placebo) of 5:3 ratio in Cohort I (430 CAD106 :260 Placebo) and 3:2 ratio in Cohort II (390 CNP520 : 260 Placebo) will be applied Required to undergo at least two PET scans during the course of the study. Additional PET scans, blood and CSF collection will be voluntary 11
The Alzheimer's Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Intervention Methods will Include: Physical Exercise Nutritional Counseling & Modification Cognitive & Social Stimulation Improved Self-Management of Health Status 2-year clinical trial To test whether lifestyle intervention focused on combining physical activity, healthy nutrition, social and intellectual challenge and improved self-management of medical conditions can protect cognitive function in older adults who are at increased risk for cognitive decline SUBJECTIVE COGNITIVE DECLINE 12
SCD Preprodromal or pre-mci stage of AD Biomarker evidence for AD plus subtle cognitive decline, which does not reach the level of objective impairment required for the MCI diagnosis Research Diagnostic Criteria: Self-experienced persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event. Normal age-, gender-, and educationadjusted performance on standardized cognitive tests, which are used to classify mild cognitive impairment (MCI) or prodromal AD. Neuron 84, Nov 5, 2014 Stage 0 no biomarker abnormalities; not thought to be on the AD trajectory Stage 1 cerebral amyloidosis Stage 2 amyloidosis + markers of neurodegeneration Stage 3 amyloidosis + neurodegeneration + subtle cognitive and behavioral decline that is not yet sufficient to meet criteria for mild cognitive impairment or dementia due to AD. 13
What about tau? 133 subjects HBAS, CDR 0 SMC questions Subjective cognitive decline in clinically healthy older adults manifests in the context of increasing entorhinal cortical tauopathy SCD marking one of the earliest behavioral changes among increasing pathologic change in clinically healthy older adults Entorhinal tauopathy in the presence of minimal Aβ load is argued to be the earliest component of the AD pathologic continuum, and as such, endorsement of SCD symptoms may represent the earliest signs of preclinical AD in some cases Have you recently experienced any change in your ability to remember things? [CHANGE IN MEMORY] Do you have more trouble than usual remembering a short list of items, such as a shopping list? [SHORT LIST] Do you have trouble remembering things from one second to the next? [ONE SECOND TO THE NEXT] Do you have much more trouble than usual remembering recent events? [RECENT EVENTS] Do you have any difficulty in understanding or following spoken instructions? [UNDERSTANDING INSTRUCTIONS] Do you have more trouble than usual following a group conversation or plot in a TV program due to your memory? [FOLLOWING A CONVERSATION] Do you have trouble finding your way around familiar streets? [GETTING LOST] JAMA Neurol. 2017 Dec 1;74(12):1455-63 Is it just normal aging? About 20% of older adults have subjective memory complaints A recent meta-analysis has revealed that about 25% of cognitively healthy older adults who report SCD will develop MCI due to AD in the next 4 years. In addition, these individuals have two-fold risk of progression to dementia during a 5-year follow-up period. Do you have memory complaints Our results suggest that SMC should not merely be considered as a benign agerelated phenomenon as our meta-analysis demonstrates that those with SMC are at significantly increased risk of future cognitive decline 99 ADNI participants with SCD: Being female, ApoE4, h/o tobacco smoking assoc with amyloid + Acta Psychiatrica Scandinavica 2014 & Compr Psychiatry 2018 14
Vitamin D and Subjective Memory Complaint in Community-Dwelling Older Adults Subjective memory complaints memory lapses, problems learning new information, problems finding words, problems calculating problems concentrating Participants with 25OHD 68nmol/L had less often problems learning new information (P=0.027) There were no between-group differences for the other memory complaints Curr Alzheimer Research 2018 MCI 15
The concepts of early MCI (EMCI) and late MCI (LMCI) made on the basis of modest or advanced impairment of delayed recall of logical memory The concept of EMCI will bridge the gap between normal elderly memory function approximately 1.0 SD below expected education adjusted norms LMCI subjects are more amnestic than EMCI subjects approximately 1.5 SD below expectation. EMCI developed dementia at a rate of 2.3% and LMCI participants went on to dementia at a rate of 17.5% per year Wu L et al. PLoS ONE 7(10):e47905 ADNI MCI 1. Subject must have a subjective memory concern as reported by subject, study partner, or clinician. 2. Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale Revised (the maximum score is 25): a. 9 11 for 16 or more years of education. b. 5 9 for 8 15 years of education. c. 3 6 for 0 7 years of education. 3. Mini-Mental State Exam score between 24 and 30 (inclusive) (Exceptions may be made for subjects with less than 8 years of education at the discretion of the project director). 4. Clinical Dementia Rating = 0.5; Memory Box score must be at least 0.5. 5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit. 16
EMCI can be differentiated from HC and LMCI Functional connectivity in the precuneus, bilateral medial frontal, parahippocampal, middle temporal, right superior temporal, and left angular gyri was decreased in EMCI subjects compared with CN subjects LMCI subjects exhibited decreased functional connectivity in the precuneus, bilateral medial frontal gyri, and left angular gyrus, as compared to EMCI EMCI have more hippocampal atrophy than HC, more amyloid deposition ad higher total tau levels in CSF Alz Dis Assoc Disord. 2016:30(4);289-96 & Front. Aging Neurosci., 01 April 2013 & Alz Dement. 2015 Jul;11(7):734-9 Brief clinical index to predict whether older adults diagnosed with amnestic MCI will progress to probable AD within 3 years Low risk (<20%) 0-2 points Moderate risk (21-89%) 3-8 points High risk (>90%) 9-16 points Lee SJ et al. PLoS ONE 2014 17
Amyloid plaque reduction with aducanumab & Aducanumab effect (change from baseline) on CDR-SB and MMSE J Sevigny et al. Nature 537, 50 56 (2016) doi:10.1038/nature19323 dtcs Age 50-80 Interventions: reasoning training following transcranial direct current stimulation (tdcs) for 20 minutes using 2mA or less targeting the inferior frontal gyrus reasoning training following sham transcranial direct current stimulation (tdcs) on frontal- lobe mediated cognitive measures of executive control TDCS is thought to produce cognitive effects by modulating membrane potentials and the synaptic strength between stimulated neurons 18
Nicotinic acetylcholine receptor loss in AD & nicotine can improve cognitive performance Subjects with MCI that convert to AD have loss of nicotinic receptors Non-smoking adults, ages 55+, who either notice changes in their memory or whose family members notice memory changes may be eligible to participate. The purpose of this study is to determine whether nicotine (in patch form) improves memory and functioning in adults diagnosed with MCI. Connors Continuous Performance Test showed significant improvement with improvements in attention, memory, psychomotor speed, & overall subjective cognitive function The purpose of the SNIFF study is to find out whether a type of insulin, when administered as a nasal spray, improves memory in adults with a mild memory impairment or Alzheimer s disease (AD). We are looking for 250 adults age 55-85 diagnosed with amnestic mild cognitive impairment (amci) or early AD improving central nervous insulin signaling via intranasal insulin or insulin sensitizers, which cross the blood-brain barrier, could represent an effective way to prevent or treat AD In AD, there is reduced brain insulin receptor sensitivity & insulin receptors are altered by amyloid oligomers Improved delayed memory, improved metabolic function in brain 19
The Alzheimer s Disease Neuroimaging Initiative (ADNI) unites researchers with study data as they work to define the progression of Alzheimer s disease. ADNI researchers collect, validate and utilize data such as MRI and PET images, genetics, cognitive tests, CSF and blood biomarkers as predictors for the disease. Data from the North American ADNI s study participants, including Alzheimer s disease patients, mild cognitive impairment subjects and elderly controls, are available. 1,070-2000 total participants will be enrolled across 3 cohorts: cognitively normal (CN), mild cognitive impairment (MCI), and mild AD dementia. Approximately, 700-800 will be Rollover participants from ADNI2, and 370-1200 will be newly enrolled. 55-90 (inclusive) years of age neuroimaging and lumbar punctures to be carried out Neuropsychological testing 20