Roy Yaari

The Alzheimer's Questionnaire: A Proof of Concept Study for a New Informant-Based Dementia Assessment

The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimers disease (AD) that can be administered in a primary care setting. The Alzheimers Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.

Validation and diagnostic accuracy of the Alzheimer's questionnaire

BACKGROUND accurately identifying individuals with cognitive impairment is difficult. Given the time constraints that many clinicians face, assessment of cognitive status is often not undertaken. The intent of this study is to determine the diagnostic accuracy of the Alzheimers questionnaire (AQ) in identifying individuals with mild cognitive impairment (MCI) and AD. METHODS utilising a case-control design, 300 [100 AD, 100 MCI, 100 cognitively normal (CN)] older adults between the ages of 53 and 93 from a neurology practice and a brain donation programme had the AQ administered to an informant. Diagnostic accuracy was assessed through receiver-operating characteristic analysis, which yielded sensitivity, specificity and area under the curve (AUC). RESULTS the AQ demonstrated high sensitivity and specificity for detecting MCI [89.00 (81.20-94.40)]; [91.00 (83.60-65.80)] and AD [99.00 (94.60-100.00)]; [96.00 (90.10-98.90)]. AUC values also indicated high diagnostic accuracy for both MCI [0.95 (0.91-0.97)] and AD [0.99 (0.96-1.00)]. Internal consistency of the AQ was also high (Cronbachs alpha = 0.89). CONCLUSION the AQ is a valid informant-based instrument for identifying cognitive impairment, which could be easily implemented in a clinicians practice. It has high sensitivity and specificity in detecting both MCI and AD and allows clinicians to quickly and accurately assess individuals with reported cognitive problems.

Utility of the telephone interview for cognitive status for enrollment in clinical trials.

The modified Telephone Interview for Cognitive Status (TICS‐m) assesses cognitive status via the telephone and has been used to recruit for clinical trials by screening for amnestic mild cognitive impairment (aMCI). The utility of screening for aMCI has not been validated, and it is unknown which questions best predict aMCI.

Non-cholinergic drug development for Alzheimer's disease

Background: Recent advances in the understanding of the pathobiology of Alzheimers disease have led to a large number of non-cholinergic targets for the development of therapeutic agents. These include, for example, neurotransmitter-based, anti-amyloid, antitangle, antioxidant, anti-excitotoxic, and growth factor strategies. There are several hundred agents in, or approaching, clinical trials. Some hold promise for treatment of those affected, some may have potential for prevention, some for both. Objectives: Key examples of each of these development approaches will be summarized. Conclusions: It is too soon to predict which, if any, of these approaches will bear fruit. At the moment, it appears that the amyloid-based therapies are the farthest along in development, and have shown in some cases that the amyloid dysregulation cascade can be interrupted. It is unknown, however, whether altering this aspect of the pathobiology of Alzheimers will actually yield clinical benefit. Efforts to affect tangle development would appear to be a fruitful approach, although these efforts lag behind the anti-amyloid efforts. The same is essentially true for the other approaches reviewed as well. Given the fact that many new interventions target specific pathways that can be measured biologically in go–no go proof of concept studies, the opportunity exists to capitalize on biomarkers in earlier stages of development. The same can be said for evolving imaging techniques. Given the number of agents in development, we offer the provocative suggestion that the biggest threat to identifying effective therapies may prove to be the implementation of enough treatment trials, and applying out-of-the-box prevention methodologies, rather than the discovery of promising candidates. This prediction may or may not hold true.

Managing Patients with Alzheimer’s Disease and Related Dementias

Management is one of the most common reasons why families seek medical attention for people with dementia. Families often know that the person has Alzheimer’s disease (AD), but need information on how to manage dementia and its symptoms after the diagnosis is established.

Predicting driving safety in people with dementia

longitudinal study of community-dwelling PwAD was performed between April 2009 and March 2012 encompassing a baseline and a 2.5-year follow-up. We focused on new GL events and the associated factors from their demographic data, cognitive functions by CASI and MMSE, and daily navigational abilities by the Questionnaire of Everyday Navigational Ability (QuENA). The study population consisted of 185 PwAD and their co-habitant collaterals. At the baseline, 95 had experienced GL (Group B), while and the remaining 90 (Group A) had not. Results: After a 2.5-year period, 33.3% inGroupA developedGL (incidence) and 40% inGroupB developed GL (recurrence). Multiple logistic regression analysis revealed that inattention on the QuENA and orientation on the CASI had independent effects on the incidence, while younger age and the absence of a safety range spelled danger for recurrence. The nature of incidence and recurrence of GL in these AD patients was quite different. During the 2.5 years, PwAD with GL incidence deterioratedmore inmentalmanipulation onCASI than thosewithout. Conclusions: CASI and the QuENA can indicate risk of GL incidence. We suggest that once GL occurs, the collaterals of PwAD must take the responsibility to prevent it from recurring, especially for younger patients. In addition, GL may be a behavioral manifestation for subtypes of AD.

Combination Therapies for Treating Alzheimer’s Disease

The pathobiology of Alzheimer’s disease (AD) is extremely complex and not yet fully understood. AD is characterized by the clinical syndrome of a slowly progressive dementia and the classic neuropathological findings of amyloid plaques, neurofibrillary tangles, and neuronal death. These histological features develop in heterogeneous patterns and in people with varying genetic predisposition, nutritional histories, and exposure to either potentially harmful or helpful environmental agents.

DIAN-TU ADAPTIVE PREVENTION TRIAL LAUNCH AND BASELINE DATA

Age – Mean y Education M Sex F Racial Catego American In Asian Native Haw Black/Afric White Unknown/N Ethnicity Hispanic or Not Hispani Unknown Marital Statu Married Divorced Widowed Never marri Unknown Participant R Family Histor APOE Genot ε2/ε2 ε2/ε3 ε2/ε4 ε3/ε3 ε3/ε4 ε4/ε4 PET SUVr M x Fisher’s E 1 Compariso value to accou LAUNCH AND BASELINE DATA Randall J. Bateman, Susan Mills, Anna Santacruz, Martin R. Farlow, Stephen Salloway, John C. Morris, Tammie L. S. Benzinger, Anne M. Fagan, Alison Goate, Jason Hassenstab, Guoqiao Wang, Chengjie Xiong, Clifford R. Jack, Jr,, Bob Koeppe, Ferenc Martenyi, Alison Searle, Roy Yaari, Eric Siemers, Eric McDade,

TAU PET IN A4: PRELIMINARY REPORT

ASHS volume measurements (mm), standard deviation in parentheses Number of subjects 178 90 139 103 116 Anterior hippocampus 1722.0 (223.6) 1707.4 (205.3) 1662.7 (236.9) 1517.2 (260.0) 1414.7 (207.7) % Diff 0.8 3.4 11.9 17.8 t value <2 2.3 6.9 11.8 p value >0.1 0.023 2.4e-11 1.1e-26 Posterior hippocampus 1652.3 (159.8) 1664.3 (163.1) 1575.6 (180.3) 1400.4 (205.9) 1336.1 (179.3) % Diff -0.7 4.6 15.2 19.1 t value <2 4.0 10.7 15.8 p value >0.1 7.6e-5 8.1e-21 4.6e-41 Whole hippocampus 3374.4 (300.2) 3371.6 (302.9) 3238.3 (353.6) 2917.6 (414.1) 2750.8 (337.4) % Diff 0.1 4.0 13.5 18.5 t value <2 3.6 9.8 16.6 p value >0.1 3.4e-4 3.7e-18 6.4e-44 Entorhinal cortex 593.9 (76.2) 585.4 (69.5) 575.4 (82.1) 518.4 (93.0) 462.1 (84.1) % Diff 1.4 3.1 12.7 22.2 t value <2 2.1 7.0 13.9 p value >0.1 0.039 5.2e-11 4.2e-34 Brodmann area 35 617.8 (82.6) 608.9 (82.8) 586.4 (94.9) 542.0 (98.4) 483.3 (89.1) % Diff 1.4 5.1 12.3 21.8 t value <2 3.1 6.9 13.2 p value >0.1 1.8e-3 3.5e-11 1.2e-31 Brodmann area 36 1824.9 (254.2) 1844.1 (245.7) 1789.4 (219.8) 1683.0 (257.3) 1551.5 (234.9) % Diff -1.1 1.9 7.8 15.0 t value <2 <2 4.5 9.3 p value >0.1 >0.1 l.le-5 3.8e-18 Parahippocampal cortex 869.6 (120.9) 893.3 (125.0) 885.4 (145.9) 831.5 (129.4) 773.3 (121.9) % Diff -2.7 -1.8 4.4 11.1 t value <2 <2 2.5 6.7 p value >0.1 >0.1 0.014 1.4e-10

BRAIN AMYLOID BURDEN, SLEEP, AND CIRCADIAN REST/ACTIVITY RHYTHMS: SCREENING FINDINGS FROM A4 AND LEARN

3-8 year period were measured via multiple reaction monitoring (MRM) mass spectrometry. CSF Ab1-42, total-Tau (tTau) and phosphorylated-Tau (pTau-181) were measured using Luminex xMAP platform, and brain hippocampal volume was obtained from magnetic resonance imaging (MRI). From these candidate markers, optimal diagnostic signatures with decision thresholds on a few markers that separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms (Huang et al, 2017). The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict their future progression to AD. This procedure was first carried out on only four well-known markers (CSF Ab1-42, tTau and pTau, and MRI hippocampal volume), then using 320 MRM peptides, and finally using all the markers. Results:This multivariate analysis yielded a simple diagnostic signature comprising CSF tTau to Ab1-42 ratio, MRI hippocampal volume and a novel VGF peptide, with a decision threshold on each marker. When tested in an independent MCI group, signature positive subjects progress 4-fold faster to AD with 81% positive predictive value (PPV). However, with only the well-known markers (i.e., without the VGF peptide), this drops to 2-fold faster progression to AD with 65% PPV. VGF is a neurosecretory protein that may be a marker for neuronal dysfunction. Conclusions:This 4-marker signature is a major advance over the current diagnostics based on widely used markers (Shaw et al., 2009), and is much easier to use in practice than recently published complex signatures (Llano et al., 2017, Spellman et al., 2015). In addition, this signature reinforces the ATN construct from the 2018 NIA-AA research framework.