Evaluation of a Computerized Complex Instrumental Activities of Daily Living Marker (NMI) (AltoidaML)

• ClinicalTrials.gov Identifier: NCT02843529
• Recruitment Status: Completed
• First Posted: July 26, 2016
• Results First Posted: December 16, 2020
• Last Update Posted: January 26, 2021
• Sponsor: Altoida
• Collaborators: Greek Alzheimer's Association and Related Disorders; University of Roma La Sapienza; IRCCS Centro San Giovanni di Dio Fatebenefratelli; Neuromed IRCCS; Scripps Health; Global Brain Health Institute (GBHI); Takeda Pharmaceuticals International, Inc.; Research Center on Computational Biomarkers (RCCBM); BiHELab - Bioinformatics and Human Electrophysiology Lab; Fundacion Clinic per a la Recerca Biomédica; University of Dublin, Trinity College; University of Barcelona; EIT Health; Klinik Hirslanden, Zurich; Center for BrainHealth - The University of Texas at Dallas
• Information provided by (Responsible Party): Altoida

Tracking Information

• First Submitted Date: May 18, 2016
• First Posted Date: July 26, 2016
• Results First Submitted Date: September 15, 2020
• Results First Posted Date: December 16, 2020
• Last Update Posted Date: January 26, 2021
• Actual Study Start Date: October 17, 2016
• Actual Primary Completion Date: February 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 19, 2020)

Change in Diagnostic Area Under the Receiver Operating Characteristic Curve (ROC-AUC) [ Time Frame: 42 months of follow up ]

The machine learning models capturing voice data, hands micromovements & micro-errors, posture changes, eye tracking, visuospatial navigation micro-errors and spatio-temporal gait parameters developed for the Altoida system will be tested in this prospective cohort. Sensitivity, specificity and accuracy of the model will be tested in differential diagnosis between the study groups as well as the accuracy of prediction cognitive decline as measured by neuropsychological test battery in the MCI group.

Original Primary Outcome Measures (submitted: July 21, 2016)

Change in sensitivity , specificity and accuracy of Altoida models [ Time Frame: baseline, 6 and 12 months of follow up ]

The machine learning models capturing spatio-temporal gait parameters developed for the Altoida system will be tested in this prospective cohort. Sensitivity, specificity and accuracy of the model will be tested in differential diagnosis between the study groups as well as the accuracy of prediction cognitive decline as measured by neuropsychological test battery in the MCI group.

Current Secondary Outcome Measures (submitted: November 19, 2020)

• Change From Baseline in Clinical Measure 1 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
• Change From Baseline in Clinical Measure 2 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Geriatric Depression Scale (GDS)
• Change From Baseline in Clinical Measure 3 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Functional Assessment Questionnaire (FAQ)
• Change From Baseline in Clinical Measure 4 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Mini Mental Status Exam (MMSE)
• Change From Baseline in Clinical Measure 5 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Neuropsychiatric Inventory Questionnaire (NPI-Q)
• Change From Baseline in Clinical Measure 6 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Activities of the daily life (ADL)
• Change From Baseline in Clinical Measure 7 [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Instrumental activities of the daily life (iADL)
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  ADAS Cog
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  -Rey-Osterrieth Complex Figure Test (Copy)
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Trail Making Test
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Digit Span Forward
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Category Fluency (Animals & Vegetables)
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Digit Span Backward
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Rey Osterrieth Complex Figure Test (30 minute delay)
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Wechsler Memory Scale - Revised (WMS-R) Digit Span
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Wechsler Memory Scale Logical Memory
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Wechsler Memory Scale Paragraph Memory (Immediate & Delayed Recall)
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit-Symbol Substitution Test
• Change From Baseline in Cognitive Measure [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Rey Auditory Verbal Learning Test (RAVLT)
• Secondary Resting State EEG Endpoints [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  EEG endpoints (occipital, parietal, and temporal sources of delta and low-frequency alpha rhythms) according to the PharmaCog WP5 European ADNI. These markers are expected to be related to disease status at baseline assessment and disease progression at follow-ups. Exploratory probability level of p < 0.05.
• Secondary Resting State Auditory Oddball ERP Endpoints [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  ERP endpoints (latency of scalp parietal P3b peak and activity of the cingulate and temporal-parietal sources of P3b peak according to PharmaCog WP5 European ADNI). These markers are expected to be related to disease status at baseline assessment and disease progression at follow-ups. Exploratory probability level of p < 0.05.
• Total Abeta 1-42 (Aβ42) Amyloid Deposition [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of beta-amyloid (Abeta) peptide, ultimately leading to formation of Abeta plaques in the brain. Baseline amount of CSF Abeta(42) will be investigated.
• Change of Brain Amyloid Deposition [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Biomarkers of brain beta-amyloidosis are reductions in CSF Abeta(42) and increased amyloid PET tracer retention. The change in amyloid deposition as measured by Abeta 1-42 (Aβ42) and its relation to the genetic, clinical, neuropsychological, EEG and ERP endpoints measurement will be assessed.
• Change of CSF Biomarkers Tau and ptau181 Values [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  The change in CSF biomarkers tau and ptau181 values and its relation to the genetic, clinical, neuropsychological, EEG and ERP endpoints measurement will be assessed.
• MRI (Optional) [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Relationship between MRI measures (brain volume, hippocampus atrophy, vascular lesions) and biomarkers.
• Changes in Driving Breaking Force [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Changes in driving behavior, such as breaking force observed continuesly through in-car sensors or dongles.
• Changes in Driving Acceleration Velocity [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Changes in driving behavior, such as acceleration velocity observed continuesly through in-car sensors or dongles.
• Changes in Driving Direction [ Time Frame: baseline, 6, 12, 24, 36 and 42 months of follow up ]
  Changes in driving behavior, such as sudden changes of direction observed continuesly through in-car sensors or dongles.
• Changes in Driving Violations [ Time Frame: Continuous measurement for 42 months ]
  Changes in driving behavior, such as speed limit violations observed continuesly through in-car sensors or dongles.

Original Secondary Outcome Measures (submitted: July 21, 2016)

• Change from Baseline in Clinical Measure 1 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
• Change from Baseline in Clinical Measure 2 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Geriatric Depression Scale (GDS)
• Change from Baseline in Clinical Measure 3 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Functional Assessment Questionnaire (FAQ)
• Change from Baseline in Clinical Measure 4 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Mini Mental Status Exam (MMSE)
• Change from Baseline in Clinical Measure 5 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Neuropsychiatric Inventory Questionnaire (NPI-Q)
• Change from Baseline in Clinical Measure 6 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Activities of the daily life (ADL)
• Change from Baseline in Clinical Measure 7 [ Time Frame: baseline, 6 and 12 months of follow up ]
  Instrumental activities of the daily life (iADL)
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  ADAS Cog
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  -Rey-Osterrieth Complex Figure Test (Copy)
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Trail Making Test
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Digit Span Forward
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Category Fluency (Animals & Vegetables)
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Digit Span Backward
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Rey Osterrieth Complex Figure Test (30 minute delay)
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Wechsler Memory Scale - Revised (WMS-R) Digit Span
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Wechsler Memory Scale Logical Memory
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Wechsler Memory Scale Paragraph Memory (Immediate & Delayed Recall)
• Change from Baseline in Cognitive Measure [ Time Frame: baseline, 6 and 12 months of follow up ]
  Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit-Symbol Substitution Test
• Secondary resting state EEG endpoints [ Time Frame: baseline, 6 and 12 months of follow up ]
  EEG endpoints (occipital, parietal, and temporal sources of delta and low-frequency alpha rhythms) according to the PharmaCog WP5 European ADNI. These markers are expected to be related to disease status at baseline assessment and disease progression at follow-ups. Exploratory probability level of p < 0.05.
• Secondary resting state auditory oddball ERP endpoints [ Time Frame: baseline, 6 and 12 months of follow up ]
  ERP endpoints (latency of scalp parietal P3b peak and activity of the cingulate and temporal-parietal sources of P3b peak according to PharmaCog WP5 European ADNI). These markers are expected to be related to disease status at baseline assessment and disease progression at follow-ups. Exploratory probability level of p < 0.05.
• Total Abeta 1-42 (Aβ42) amyloid deposition [ Time Frame: baseline ]
  Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of beta-amyloid (Abeta) peptide, ultimately leading to formation of Abeta plaques in the brain. Baseline amount of CSF Abeta(42) will be investigated.
• Change of brain amyloid deposition [ Time Frame: baseline, 6 and 12 months of follow up ]
  Biomarkers of brain beta-amyloidosis are reductions in CSF Abeta(42) and increased amyloid PET tracer retention. The change in amyloid deposition as measured by Abeta 1-42 (Aβ42) and its relation to the genetic, clinical, neuropsychological, EEG and ERP endpoints measurement will be assessed.
• Change of CSF biomarkers tau and ptau181 values [ Time Frame: baseline, 6 and 12 months of follow up ]
  The change in CSF biomarkers tau and ptau181 values and its relation to the genetic, clinical, neuropsychological, EEG and ERP endpoints measurement will be assessed.
• MRI (Optional) [ Time Frame: baseline, 6 and 12 months of follow up ]
  Relationship between MRI measures (brain volume, hippocampus atrophy, vascular lesions) and biomarkers.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of a Computerized Complex Instrumental Activities of Daily Living Marker (NMI)
• Official Title: Evaluation of a Computerized Complex Instrumental Activities of Daily Living Marker (NMI) as a Pre-Clinical or Pro-Dromal Alzheimers Diagnosis (Prognosis) for Optimum Outcomes

Brief Summary

The proposed study is designed to evaluate the performance of the ALTOIDA™ System as a tool to assist physicians in diagnosing Alzheimer's Disease (AD) in real-world clinical settings. The design of this study is guided by two overriding factors: 1) to optimize the performance of the ALTOIDA™ Neuro Motor Index (NMI) prognosis classifiers, the subjects making up the training sets must be well characterized as to their clinical diagnosis, and 2) all ALTOIDA™ tests must be performed and reproduced in real-world clinical settings.

Although there is already a large body of peer-reviewed scientific literature demonstrating that certain digital biomarker patterns are associated with certain neurologic conditions, the utilization of such tools for the evaluation of neurologic disorders is still considered an emerging science and therefore in the investigational stage. Although this protocol will report on brain patterns of certain neurologic conditions such as cognitive impairment and Alzheimer's disease, based on patterns published in peer-reviewed journals, such findings are not considered stand alone or diagnostic per se and should always be considered by the primary physician in conjunction with the patient's clinical condition. These data should only be used as additional information to add to the primary physician's diagnostic impression.

Detailed Description

The goal of the study is to determine relationships among the clinical, cognitive, imaging, genetic, and biochemical biomarker characteristics of the stage of the AD spectrum that precedes MCI, the mildest symptomatic phase of AD, referred to here as MCI. The ADNI-GO model posits that AD begins with amyloid β (Aβ) deposition in the cortex, which leads to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline.

It may be possible to determine the future development of ALZ in a preclinical state in a cognitively normal but high risk individual at least 18-24 months before any symptoms develop of cognitive impairment. In addition a newly proposed research framework proposes to use biomarkers for amyloid, tau, and neurodegeneration (ATN) to classify MCI patients.

Some of the leading-edge technologies under study are brain-imaging techniques, such as positron emission tomography (PET), including FDG-PET (which measures glucose metabolism in the brain); PET using a radioactive compound (F-AV-45) that measures brain beta-amyloid; and structural MRI. Brain scans are showing scientists how the brain's structure and function change as AD starts and progresses. Biomarkers in cerebrospinal fluid are revealing other changes that could identify which patients with MCI will develop Alzheimer's. Scientists are looking at levels of beta-amyloid and tau in cerebrospinal fluid. (Abnormal amounts of the amyloid and tau proteins in the brain are hallmarks of Alzheimer's disease.)

The aim of the study is to evaluate the performance of the ALTOIDA™ System as as a tool to assist physicians in diagnosing Alzheimer's Disease (AD) in real-world clinical settings.

The study will be :

A. Multi-Center Study:

primary goal of this study will be to evaluate the ALTOIDA™ Platform across multiple study locations. This will demonstrate an ability to perform tests, collect data, and generate classifications irrespective of variations in testing locations and personnel.

12 international study sites will be selected with the US based sites being a recognized NIH Center of Excellence for Alzheimer's disease or other nationally recognized Alzheimer's disease research center. Each site will evaluate up to 60 community dwellers evenly divided between MCI patients and age-matched controls (while the prevalence of AD is approximately 12% in the general population, the ratio of AD to normal among those who visit a clinic for memory or cognitive related issues is between 50-60%).

Each site will follow the same testing protocols. Participants will be asked if they would like to participate in a protocol that monitors their prospective risk for developing ALZ short term, and whether certain of their prescribed medications may have a protective effect. Those who are accepting to be participants are then enrolled in the study.

Enrollees will be tested for risk factors for having pre-clinical ALZ. Individuals identified as being at risk at baseline are followed at 6 month intervals for a 48 month period using psychometric testing and functional neuroimaging. Their maintenance of cognitive stability or cognitive decline is monitored while under the care of their PMD and while taking medications of interest.

All test data will be uploaded to the online ALTOIDA™ database server.

B. The overall impact of this study will be increased knowledge concerning the sequence and timing of events leading to MCI and from MCI to AD, development of better clinical and Neuro Motor Index prognosis methods for early detection and for monitoring the progression of these conditions, and facilitation of clinical trials of treatments to slow disease progression, ultimately contributing to the prevention of AD.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Adults at high risk of developing ALZ within 18-40 months (MCI) or cognitively normal for their age sex matching group. Risk factors include parents with a history of ALZ, and/or positive APOE4 alleles.

Masking: Double (Participant, Investigator)
Primary Purpose: Diagnostic

Condition

• Alzheimer Disease
• Mild Cognitive Impairment
• Memory Disorders
• Cognitive Impairment
• Dementia
• Presymptomatic Disease

Intervention

Other: Altoida: neuropsychological, MRI, EEG and CSF biomarkers

Data collection at baseline: clinical (neurological, activity of the daily life, instrumental activity of the daily life, depression scale), standard neuropsychological exam, ALTOIDA and neurophysiology (EEG/ERPs) in both Prodromal and Preclinical AD subjects. In both Prodromal and Preclinical AD subjects, APOE genotyping. The local clinical Unit should document the positivity at the baseline session of at least one of the biomarkers of AD mentioned above.

Data collection at 6, 12, 24 and 36 months of follow up: clinical (neurological, activity of the daily life, instrumental activity of the daily life, depression scale), standard neuropsychological exam, ALTOIDA and neurophysiology (EEG/ERPs) in both Prodromal and Preclinical AD subjects.

Study Arms

• Experimental: Prodromal AD (MCI)

  Altoida: neuropsychological, MRI, EEG and CSF biomarkers

  MCI participants will undergo at baseline and every 6 months a neurological examination and a neuropsychological assessment. Alzheimer disease biomarkers' measurements will be performed at inclusion and at the end of the study (or the conversion).

  Intervention: Other: Altoida: neuropsychological, MRI, EEG and CSF biomarkers
• Experimental: Preclinical AD (cognitively normal)

  Altoida: neuropsychological, MRI, EEG and CSF biomarkers

  Cognitively normal participants at risk will undergo at baseline and every 6 months a neurological examination and a neuropsychological assessment. Alzheimer disease biomarkers' measurements will be performed at inclusion and at the end of the study (or the conversion).

  Intervention: Other: Altoida: neuropsychological, MRI, EEG and CSF biomarkers

Publications *

• Tarnanas I, Tsolaki M, Nef T, M Müri R, Mosimann UP. Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer's disease? Alzheimers Dement. 2014 Nov;10(6):790-8. doi: 10.1016/j.jalz.2014.01.002. Epub 2014 Mar 18.
• Vallejo V, Mitache AV, Tarnanas I, Muri R, Mosimann UP, Nef T. Combining qualitative and quantitative methods to analyze serious games outcomes: A pilot study for a new cognitive screening tool. Annu Int Conf IEEE Eng Med Biol Soc. 2015 Aug;2015:1327-30. doi: 10.1109/EMBC.2015.7318613.
• Nef T, Urwyler P, Büchler M, Tarnanas I, Stucki R, Cazzoli D, Müri R, Mosimann U. Evaluation of Three State-of-the-Art Classifiers for Recognition of Activities of Daily Living from Smart Home Ambient Data. Sensors (Basel). 2015 May 21;15(5):11725-40. doi: 10.3390/s150511725.
• Tarnanas I, Laskaris N, Tsolaki M, Muri R, Nef T, Mosimann UP. On the comparison of a novel serious game and electroencephalography biomarkers for early dementia screening. Adv Exp Med Biol. 2015;821:63-77. doi: 10.1007/978-3-319-08939-3_11.
• Tarnanas I, Papagiannopoulos S, Kazis D, Wiederhold M, Widerhold B, Tsolaki M. Reliability of a novel serious game using dual-task gait profiles to early characterize aMCI. Front Aging Neurosci. 2015 Apr 22;7:50. doi: 10.3389/fnagi.2015.00050. eCollection 2015.
• Dimitriadis SI, Laskaris NA, Bitzidou MP, Tarnanas I, Tsolaki MN. A novel biomarker of amnestic MCI based on dynamic cross-frequency coupling patterns during cognitive brain responses. Front Neurosci. 2015 Oct 20;9:350. doi: 10.3389/fnins.2015.00350. eCollection 2015.
• Tarnanas I, Schlee W, Tsolaki M, Müri R, Mosimann U, Nef T. Ecological validity of virtual reality daily living activities screening for early dementia: longitudinal study. JMIR Serious Games. 2013 Aug 6;1(1):e1. doi: 10.2196/games.2778.
• Xekardaki A, Rodriguez C, Montandon ML, Toma S, Tombeur E, Herrmann FR, Zekry D, Lovblad KO, Barkhof F, Giannakopoulos P, Haller S. Arterial spin labeling may contribute to the prediction of cognitive deterioration in healthy elderly individuals. Radiology. 2015 Feb;274(2):490-9. doi: 10.1148/radiol.14140680. Epub 2014 Oct 7.
• Woodard JL, Seidenberg M, Nielson KA, Smith JC, Antuono P, Durgerian S, Guidotti L, Zhang Q, Butts A, Hantke N, Lancaster M, Rao SM. Prediction of cognitive decline in healthy older adults using fMRI. J Alzheimers Dis. 2010;21(3):871-85. doi: 10.3233/JAD-2010-091693.
• Rizk-Jackson A, Insel P, Petersen R, Aisen P, Jack C, Weiner M. Early indications of future cognitive decline: stable versus declining controls. PLoS One. 2013 Sep 9;8(9):e74062. doi: 10.1371/journal.pone.0074062. eCollection 2013.
• Lazarczyk MJ, Hof PR, Bouras C, Giannakopoulos P. Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals. BMC Med. 2012 Oct 25;10:127. doi: 10.1186/1741-7015-10-127. Review.
• Haller S, Nguyen D, Rodriguez C, Emch J, Gold G, Bartsch A, Lovblad KO, Giannakopoulos P. Individual prediction of cognitive decline in mild cognitive impairment using support vector machine-based analysis of diffusion tensor imaging data. J Alzheimers Dis. 2010;22(1):315-27. doi: 10.3233/JAD-2010-100840.
• Green RC, Christensen KD, Cupples LA, Relkin NR, Whitehouse PJ, Royal CD, Obisesan TO, Cook-Deegan R, Linnenbringer E, Butson MB, Fasaye GA, Levinson E, Roberts JS; REVEAL Study Group. A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease. Alzheimers Dement. 2015 Oct;11(10):1222-30. doi: 10.1016/j.jalz.2014.10.014. Epub 2014 Dec 9.
• Christensen KD, Roberts JS, Whitehouse PJ, Royal CD, Obisesan TO, Cupples LA, Vernarelli JA, Bhatt DL, Linnenbringer E, Butson MB, Fasaye GA, Uhlmann WR, Hiraki S, Wang N, Cook-Deegan R, Green RC; REVEAL Study Group*. Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial. Ann Intern Med. 2016 Feb 2;164(3):155-63. doi: 10.7326/M15-0187. Epub 2016 Jan 26.
• Galluzzi S, Marizzoni M, Babiloni C, Albani D, Antelmi L, Bagnoli C, Bartres-Faz D, Cordone S, Didic M, Farotti L, Fiedler U, Forloni G, Girtler N, Hensch T, Jovicich J, Leeuwis A, Marra C, Molinuevo JL, Nobili F, Pariente J, Parnetti L, Payoux P, Del Percio C, Ranjeva JP, Rolandi E, Rossini PM, Schönknecht P, Soricelli A, Tsolaki M, Visser PJ, Wiltfang J, Richardson JC, Bordet R, Blin O, Frisoni GB; PharmaCog Consortium. Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'. J Intern Med. 2016 Jun;279(6):576-91. doi: 10.1111/joim.12482. Epub 2016 Mar 4.
• Cavedo E, Lista S, Khachaturian Z, Aisen P, Amouyel P, Herholz K, Jack CR Jr, Sperling R, Cummings J, Blennow K, O'Bryant S, Frisoni GB, Khachaturian A, Kivipelto M, Klunk W, Broich K, Andrieu S, de Schotten MT, Mangin JF, Lammertsma AA, Johnson K, Teipel S, Drzezga A, Bokde A, Colliot O, Bakardjian H, Zetterberg H, Dubois B, Vellas B, Schneider LS, Hampel H. The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations. J Prev Alzheimers Dis. 2014 Dec;1(3):181-202.
• Tarnanas I, Tsolaki A, Wiederhold M, Wiederhold B, Tsolaki M. Five-year biomarker progression variability for Alzheimer's disease dementia prediction: Can a complex instrumental activities of daily living marker fill in the gaps? Alzheimers Dement (Amst). 2015 Nov 14;1(4):521-32. doi: 10.1016/j.dadm.2015.10.005. eCollection 2015 Dec.
• Buegler M, Harms R, Balasa M, Meier IB, Exarchos T, Rai L, Boyle R, Tort A, Kozori M, Lazarou E, Rampini M, Cavaliere C, Vlamos P, Tsolaki M, Babiloni C, Soricelli A, Frisoni G, Sanchez-Valle R, Whelan R, Merlo-Pich E, Tarnanas I. Digital biomarker-based individualized prognosis for people at risk of dementia. Alzheimers Dement (Amst). 2020 Aug 19;12(1):e12073. doi: 10.1002/dad2.12073. eCollection 2020.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 22, 2019): 548
• Original Estimated Enrollment (submitted: July 21, 2016): 500
• Actual Study Completion Date: February 21, 2020
• Actual Primary Completion Date: February 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Between 55 and 90 years of age
• Study partner to accompany patient to all clinic visits for the duration of the protocol
• Memory complaint by patient and/or study partner
• Abnormal memory function score on Wechsler Memory Scale (adjusted for education)
• Mini-Mental State Exam score between 24 and 30 (inclusive)
• Clinical Dementia Rating = 0.5; Memory Box score at least 0.5
• 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
• Stability of the following permitted medications for 4 weeks (unless stated otherwise):
• Antidepressants lacking significant anticholinergic side effects
• Estrogen replacement therapy
• Gingko biloba is permissible, but discouraged
• Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening
• Cholinesterase inhibitors and memantine if stable for 12 weeks prior to screening
• Geriatric Depression Scale less than 6
• Visual and auditory acuity adequate for neuropsychological testing
• Good general health with no diseases expected to interfere with the study
• Not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile)
• Hachinski less than or equal to 4
• Six grade education or has a good work history (sufficient to exclude mental retardation)
• Fluent in English or Spanish
• Agrees to at least one lumbar puncture for the collection of CSF
• Willing and able to complete all baseline assessments
• Willing to undergo repeated MRIs and at least two PET scans and willing to provide DNA and plasma samples as specified
• Willing and able to participate in a longitudinal imaging study

Exclusion Criteria:

• Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities
• Screening/baseline MRI scans with evidence of infection, infarction, or other focal lesions; multiple lacunes or lacunes in a critical memory structure
• Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body
• Major depression, bipolar disorder as described in DSM-IV within the past 1 year
• Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol
• History of schizophrenia
• History of alcohol or substance abuse or dependence within the past 2 years
• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol
• Clinically significant abnormalities in B12, or TFTs that might interfere with the study
• Residence in skilled nursing facility
• Current use of specific psychoactive medications (e.g.,certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.); current use of warfarin (exclusionary for lumbar puncture)
• Use of investigational agents one month prior to entry and for the duration of the trial
• Exclusion for amyloid imaging with 18F -AV-45: Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the participant in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1
• Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the protocol director

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT02843529
• Other Study ID Numbers: altoidaML01
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: neuromotor data sharing

• Current Responsible Party: Altoida
• Original Responsible Party: Same as current
• Current Study Sponsor: Altoida
• Original Study Sponsor: Same as current

Collaborators

• Greek Alzheimer's Association and Related Disorders
• University of Roma La Sapienza
• IRCCS Centro San Giovanni di Dio Fatebenefratelli
• Neuromed IRCCS
• Scripps Health
• Global Brain Health Institute (GBHI)
• Takeda Pharmaceuticals International, Inc.
• Research Center on Computational Biomarkers (RCCBM)
• BiHELab - Bioinformatics and Human Electrophysiology Lab
• Fundacion Clinic per a la Recerca Biomédica
• University of Dublin, Trinity College
• University of Barcelona
• EIT Health
• Klinik Hirslanden, Zurich
• Center for BrainHealth - The University of Texas at Dallas

Investigators

• Study Chair: Mark Wiederhold, PhD; Scripps Clinic La Jolla Poole Building

• PRS Account: Altoida
• Verification Date: January 2021