Search

Background Arousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. Methods Resting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left–right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. Results Functional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left–right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. Conclusions Functional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. Clinical trial registration NCT02275026.

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story ‘Twin Towers’. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these ‘WTC-affected’ individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals. Here, the authors summarize the evidence concerning the neurological health of individuals affected by the 11 September 2001 terrorist attacks and present the outcome of a meeting convened by the US National Institute for Occupational Safety and Health that aimed to generate recommendations for future research in this population.

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer’s disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of ageing and Alzheimer’s disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer’s disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer’s disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, 50 participants who met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer’s disease biomarker and predictor of disease progression, declined significantly less in several prespecified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated participants in comparison to the placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group × visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer’s disease.

Introduction World Trade Center (WTC) responders have a high risk of early-onset cognitive impairment (CI), but little is known about the etiology including the extent to which CI in WTC responders is accompanied by cortical atrophy as is common in progressive diseases causing age-related CI such as Alzheimer’s disease and related dementias. In the current study, we entrained an artificial neural network (ANN) to determine the accuracy of cortical thickness (CTX) on magnetic resonance imaging to identify World Trade Center responders at midlife (aged 44–65 years) with possible dementia. Methods A total of 119 WTC responders (57 with CI and 62 with intact cognition) underwent a structural MRI scanning protocol including T1-weighted MPRAGE as part of two imaging studies. The discovery study was divided into training and validation samples, while a second replication sample was used. An ANN was trained using regional CTX measured across 34 unilateral regions of interest (ROIs) using Freesurfer software and ‘Desikan-Killiany’ brain atlas. The discovery sample was used for model development, and the replication sample was used to evaluate predictive accuracy. Results In the WTC responder cohort, the ANN algorithm showed high discrimination performance for CI. The ANN model using regional CTX data from both hemispheres achieved an area under the receiver operating characteristic curve (AUC) of 0.96 95% C.I. ​= ​[0.91–1.00] (Accuracy ​= ​96.0%, Precision ​= ​97.8%, Recall ​= ​95.8%, Sensitivity ​= ​95.8%, Specificity ​= ​98.0%, F1 ​= ​96.8%) for the discovery sample and AUC ​= ​0.90 [0.70–1.00] (Accuracy ​= ​90.0%, Precision ​= ​90.0%, Sensitivity ​= ​90.0%, Specificity ​= ​90.0%, F1 ​= ​90.0%) in the replication sample. Conclusion Analysis of bilateral regional CTX data derived from T1-weighted MPRAGE images by ANN analysis demonstrated excellent accuracy in distinguishing WTC responders with early-onset CI.

Background: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife. Objective: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders. Methods: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen’s Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas. Results: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning. Conclusions: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer’s disease.

In March 2020, the novel coronavirus (COVID-19) became a global pandemic that would cause most in-person visits for clinical studies to be put on pause. Coupled with protective stay at home guidelines, clinical research at the Icahn School of Medicine at Mount Sinai Alzheimer's Disease Research Center (ISMMS ADRC) needed to quickly adapt to remain operational and maintain our cohort of research participants. Data collected by the ISMMS ADRC as well as from other National Institute on Aging (NIA) Alzheimer Disease centers, follows the guidance of the National Alzheimer Coordinating Center (NACC). However, at the start of this pandemic, NACC had no alternative data collection mechanisms that could accommodate these safety guidelines. To stay in touch with our cohort and to ensure continued data collection under different stages of quarantine, the ISMMS ADRC redeployed their work force to continue their observational study via telehealth assessment. On the basis of this experience and that of other centers, NACC was able to create a data collection process to accommodate remote assessment in mid-August. Here we review our experience in filling the gap during this period of isolation and describe the adaptations for clinical research, which informed the national dialog for conducting dementia research in the age of COVID-19 and beyond.

Background A growing body of literature addresses the possible long-term cognitive effects of anaesthetics, but no study has delineated the normal trajectory of neural recovery attributable to anaesthesia alone in adults. We obtained resting-state functional MRI scans on 72 healthy human volunteers between ages 40 and 80 (median: 59) yr before, during, and after general anaesthesia with sevoflurane, in the absence of surgery, as part of a larger study on cognitive function postanaesthesia. Methods Region-of-interest analysis, independent component analysis, and seed-to-voxel analysis were used to characterise resting-state functional connectivity and to differentiate between correlated and anticorrelated connectivity before, during, and after general anaesthesia. Results Whilst positively correlated functional connectivity remained essentially unchanged across these perianaesthetic states, anticorrelated functional connectivity decreased globally by 35% 1 h after emergence from general anaesthesia compared with baseline, as seen by the region-of-interest analysis. This decrease corresponded to a consistent reduction in expression of canonical resting-state networks, as seen by independent component analysis. All measures returned to baseline 1 day later. Conclusions The normal perianaesthesia trajectory of resting-state connectivity in healthy adults is characterised by a transient global reduction in anticorrelated activity shortly after emergence from anaesthesia that returns to baseline by the following day. Clinical trial registration NCT02275026.

Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP2) homeostasis to the susceptibility of developing Alzheimer’s Disease (AD). In the present study, we have identified miR-195 as a top micro-RNA candidate involved in the ApoE/PIP2 pathway using miRNA profiles in human ROSMAP datasets and mouse microarray studies. Further validation studies have demonstrated that levels of miR-195 are significantly lower in human brain tissue of ApoE4+/− patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared to ApoE4−/− subjects. In addition, brain miR-195 levels are reduced along with disease progression from normal aging to early AD, and cerebrospinal fluid (CSF) miR-195 levels of MCI subjects are positively correlated with cognitive performances as measured by mini-mental status examination (MMSE) and negatively correlated with CSF tau levels, suggesting the involvement of miR-195 in early development of AD with a potential impact on cognition. Similar differences in miR-195 levels are seen in ApoE4+/+ mouse hippocampal brain tissue and cultured neurons when compared to ApoE3+/+ counterparts. Over-expressing miR-195 reduces expression levels of its top predicted target synaptojanin 1 (synj1), a brain PIP2-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4+/+ mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4+/+ AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted at ApoE4-associated brain PIP2 dyshomeostasis, cognitive deficits, and AD pathology.

Introduction World Trade Center (WTC) responders who aided in the search and rescue efforts are now at midlife, and evidence has demonstrated that many are experiencing early-onset cognitive impairment and are at risk of developing dementia, such as Alzheimer’s disease (AD). According to the recent NIA-AA framework, AD is characterized by a neuropathological cascade commencing with β-amyloid deposition (A), followed by tauopathy (T) and neurodegeneration (N). However, the ATN model has not been replicated utilizing recently validated plasma-based biomarkers, and the role of the Aβ40 subtype in A is not well understood. This study examined plasma-based neuropathological markers of Aβ42 and Aβ40 for A, total tau for T, and NfL for N in a cohort of World Trade Center responders at midlife in order to determine the role for the two β-amyloid subtypes in the ATN model. Methods Ultrasensitive Simoa technology was utilized to measure neuropathology in plasma collected from a consecutive clinical sample (n =398). Generalized structural equation modeling was utilized for modeling linkages between pathological markers. Model fit was utilized to determine proposed directions of association. Results Our findings support the ATN neuropathological cascade model of AD and further identify an associative role for Aβ40 in A as playing a central role linking T to N. A strong correlation was found between CI and age, and it was found that women may be at increased risk of elevated T levels, with plasma NfL levels higher in responders with CI. Notably, our model reported associations between: Aβ42, CI and N; Aβ40, T and N; T and CI; Aβ42 and Aβ40. Conclusions The current ATN model of AD does not specify the subtype of β-amyloid to be considered, which may be overlooking the differential roles that these two subtypes serve in the pathogenesis of AD.

Background: More than half of the people with dementia live in lower-middle income countries (LMIC), yet we lack research and evidence-based knowledge to guide health promotion and prevention strategies for cognitive decline. In the Philippines, the prevalence of mild cognitive impairment (MCI) and cardiovascular risk factors among older persons are high, making this population at high risk for developing dementia. This protocol describes a cluster randomized controlled trial that aims to investigate the efficacy of a multicomponent intervention to maintain cognitive performance among high-risk population. Methods: This is a cluster-randomized, two-arm, single-blind trial of a multicomponent intervention that combines dance called INDAK (Improving Neurocognition through Dance and Kinesthetics), nutrition counseling, and vascular risk management. The intervention arm will receive 12 months (1-h, twice per week) of INDAK and every 3 months of nutrition counseling and intensive vascular risk management and monitoring. The control group will receive the usual vascular care advice and referral. A total of 605 (20-25 clusters per arm) community-dwelling Filipino older adults aged ≥ 60 years old with MCI will participate in the study and will be assessed at baseline, 6th- and 12th-month follow-up. The primary outcome is cognitive performance assessed by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), Mnemonic Similarity Tasks (MST), and executive function composite (EFC). Secondary outcomes are functional connectivity assessed through brain imaging, and measures of behavioral, functional level, and quality of life. Discussion: The study aims to provide scientific evidence on a public health intervention that is contextualized in a community setting to reduce dementia risk among older adults with MCI. This model can be an ecological, low-cost, and effective program, thereby conducive to widespread implementation in the Philippines as well as in other low-resource settings with similar public health challenges. The pilot phase was underway with eight villages (clusters), but temporarily interrupted by the pandemic. The full study is anticipated to start after community restrictions are eased. Ministry of Education (MOE) Published version This study was supported by grants from the Philippine Institute for Traditional and Alternative Health Care (PITHAC) of the Department of Health. The contributions of SC are partly supported by the Ministry of Education, Singapore, Academic Research Fund (MOE2019-T2-1-019).

Background The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer’s disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant’s clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI or AD proceeded through up to three review stages – independent review, collaborative review, and full committee review – requiring a unanimous decision and ratification by the chair. Results Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators’ clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80–90% for the remainder of the study. Conclusions The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure. Trial registration: NCT01931566

BackgroundThe COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs)forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19 we examined several scenarios in symptomatic and disease modification trials that could be made.MethodsWe identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trialsusing existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes.Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.ResultsTruncating both symptomatic and disease modification trials, led to underpowered trials.By contrast, adapting the trials byextending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.DiscussionThese analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies, and that adaptations can be made that maintain the trials validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect theoriginal effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

Postoperative cognitive dysfunction (POCD) is a decline in cognitive test performance which persists months after surgery. There has been great interest in the anesthesia community regarding whether variables generated by commercially available processed EEG monitors originally marketed to prevent awareness under anesthesia can be used to guide intraoperative anesthetic management to prevent POCD. Processed EEG monitors represent an opportunity for anesthesiologists to directly monitor the brain even if they have not been trained to interpret EEG waveforms. There is continued equipoise regarding whether any of the variables generated by the machines' interpretation of raw data are associated with POCD. Most literature has focused on the depth of anesthesia number, however recent studies have shown that processed depth may not be accurate in older age groups due to reduced alpha band power. Burst suppression is an encephalographic pattern of high voltage activity alternating with periods of electrical silence and is another marker of depth which can be obtained from commercial processed EEG monitors. We performed a prospective cohort study to determine whether burst suppression and burst suppression ratio as measured by the BIS Monitor (Bispectral Index, BIS Medtronic, Boulder CO), is associated with cognitive dysfunction 3 months after surgery. We recruited 167 elective surgery patients, 65 years of age and older, anticipated to require at least 2 day inpatient admission. Our main outcome measure was cognitive decline in composite z-score on the Alzheimer's Disease Research Center UDS Battery of at least 1 standard deviation 3 months after surgery relative to preoperative baseline. 14% experienced POCD, this group was older (72 [70, 74] versus 70 [67, 75] years), and had frailty scores as measured by the FRAIL Scale (2 [0, 3] versus 1 [0, 2]) and lower baseline z-scores (- 0.2 [- 0.6, 0.5] versus 0.1 [- 0.3, 0.5]). There was a univariable association between suppression ratio > 10 (SR > 10) and POCD (4.8 [0, 37.3] versus 15.4 [4.0-142.4] min), p = .038. However, after adjustment this relationship did not persist, only anesthetic technique, age, and pain remained in the model. In our cohort of older elective noncardiac surgery patients we found a marginal association between processed burst suppression (total burst suppression p = .067, SR > 5 p = .052, SR > 10.038) which did not persist in a multivariable model. Patients with POCD had almost twice the number of minutes of burst suppression, and three times the amount of time for SR > 5 and > 10. Our finding may be a limitation of the monitor's ability to detect burst suppression. The consistent trend towards more intraoperative burst suppression in patients who developed POCD suggests that future studies are needed to investigate the relationship of raw intraoperative burst suppression and POCD.Trial registry Clinical trial number and registry URL: Optimizing Postoperative Cognitive Dysfunction in the Elderly-PRESERVE, Clinical Trials Gov# NCT02650687; https://clinicaltrials.gov/ct2/show/NCT02650687 .

Objectives: This report describes the efficacy and utility of recruiting older individuals by mail to participate in research on cognitive health and aging using Electronic Health Records (EHR). Methods: Individuals age 65 or older identified by EHR in the Mount Sinai Health System as likely to have Mild Cognitive Impairment (MCI) were sent a general recruitment letter (N=12,951). A comparison group of individuals with comparable age and matched for gender also received the letter (N=3,001). Results: Of the 15,952 individuals who received the mailing, 953 (6.0%) responded. 215 (1.3%) declined further contact. Overall rate of expression of interest was 4.6%. Of the 738 individuals who responded positively to further contact, 321 indicated preference for further contact by telephone. Follow-up of these individuals yielded 30 enrollments (0.2% of 15,952). No differences in response rate were noted between MCI and comparison groups, but the comparison group yielded higher enrollment. 6 individuals who were not the intended recipients of mailing but nevertheless contacted our study were also enrolled. Conclusions: Mailings to individuals identified through a trusted source, such as a medical center from which they have received clinical care, may be a viable means of reaching individuals within this age group as this effort yielded a low rejection rate. However, EHR information did not enhance study enrollment. Implications for improving recruitment are discussed.

Objective Apathy is common in Alzheimer disease (AD) and has a far-reaching impact on patients’ clinical course and management needs. However, it is unclear if apathy is an integral component of AD or a manifestation of depression in cognitive decline. This study aims to examine interrelationships between apathy, depression, and function. Methods This was a cross-sectional study of well-characterized AD patients in the National Alzheimer's Coordinating Center Uniform Data Set with a Clinical Dementia Rating (CDR) between 0.5 and 2. Participants’ function was measured using the Functional Assessment Questionnaire. Apathy and depression were measured using clinician judgment and informant-reported Neuropsychiatric Inventory–Questionnaire. Dementia severity was categorized by CDR. Results Sample included 7,679 participants (55.7% men) with a mean (standard deviation) age of 74.9 (9.7) years; 3,197 (41.6%) had apathy based on clinician judgment. Among those with apathy, approximately half had no depression. Presence of apathy was associated with 21%, 10%, and 3% worsening in function compared with those without apathy in CDR 0.5, 1, and 2 groups, respectively. Depression was not independently associated with functional status. Results revealed no interaction between apathy and depression. Conclusion Apathy, but not depression, was significantly associated with worse function, with the strongest effects in mild dementia. Results emphasize the need for separate assessments of apathy and depression in the evaluation and treatment of patients with dementia. Understanding their independent effects on function will help identify patients who may benefit from more targeted management strategies.

Introduction There is an unmet need for effective methods for conducting dementia prevention trials. Methods Home-based assessment study compared feasibility and efficiency, ability to capture change over time using in-home instruments, and ability to predict cognitive conversion using predefined triggers in a randomized clinical trial in (1) mail-in questionnaire/live telephone interviews, (2) automated telephone/interactive voice recognition, and (3) internet-based computer Kiosk technologies. Primary endpoint was defined as cognitive conversion. Results Analysis followed a modified intent-to-treat principle. Dropout rates were low and similar across technologies but participants in Kiosk were more likely to dropout earlier. Staff resources needed were higher in Kiosk. In-home instruments distinguished conversion and stable groups. Cognitively stable group showed improvement in cognitive measures. Triggering was associated with higher likelihood of conversion but statistically significant only in mail-in questionnaire/live telephone interviews. Discussion Relatively low efficiency of internet-based assessment compared with testing by live-assessors has implications for internet-based recruitment and assessment efforts currently proposed for diverse populations.

Introduction Chronic posttraumatic stress disorder (PTSD) is associated with poor memory and increased burden of various degenerative cerebral neuropathologies. The goal of this pilot study was to determine whether PTSD was associated with changes in plasma-based neuropathological biomarkers of neurodegeneration among World Trade Center (WTC) responders. Methods Thirty-four WTC responders had blood drawn and flash-frozen within 15 minutes of retrieval. PTSD symptoms were assessed at that time. Age, sex, and WTC exposure duration were obtained from medical records. Plasma was assayed in duplicate using an ultra-sensitive single-molecule enzyme-linked immunosorbent assay to examine the distribution of amyloid-β (Aβ) 42/40 ratios, total Aβ, total tau, and neurofilament light (NfL). The comparison group was drawn from a bank of healthy controls collected and assayed at the same facility. Results The average age of WTC responders at blood draw was 53 years. Half were PTSD positive (PTSD+) as indicated by symptom severity. WTC responders had lower Aβ42/Aβ40 ratios but higher total tau and NfL levels in the plasma than healthy controls. PTSD+ status was associated with lower plasma Aβ load and higher Aβ42/Aβ40 ratios. Discussion Findings suggest that PTSD may be associated with alterations in plasma markers related to Aβ, tau, and NfL, highlighting the potential association between PTSD status and neurodegenerative neuropathology in WTC responders.

Introduction Associations of some risk factors with poor cognition, identified prior to age 75, are reduced or reversed in very old age. The Protected Survivor Model predicts this interaction due to enhanced survival of those with extended risk factor duration. In a younger sample, this study examines the association of cognition with the mean hemoglobin A1c risk factor over the time at risk, according to its duration. Methods The interaction of mean hemoglobin A1c (average = 9.8%), evaluated over duration (average = 116.8 months), was examined for overall cognition and three cognitive domains in a sample of 150 “young-old” veterans (mean age = 70) with type 2 diabetes. Results The predicted interactions were significant for overall cognition and attention, but not executive functions/language and memory. Discussion Findings extend the Protected Survivor Model to a “young-old” sample, from the very old. This model suggests focusing on individuals with good cognition despite prolonged high risk when seeking protective factors.

OBJECTIVE: Depression and cognitive impairment are highly prevalent in type 2 diabetes (T2D) yet little is known about how their relationship varies by sex. DESIGN: Population-based cross-sectional study. SETTING: Community. PARTICIPANTS: Eight hundred and ninety seven non-demented elderly with type 2 diabetes aged ≥ 65 participating in the Israel Diabetes and Cognitive Decline (IDCD) Study. MEASUREMENTS: Cognition was evaluated by a comprehensive neuropsychological battery and depressive symptoms were assessed by the Geriatric Depression Scale (GDS). RESULTS: In all but the executive function domain, the association of depressive symptoms with poorer cognitive function was stronger in women than men, with a significant interaction for language/semantic categorization and missed significance for episodic memory. Using a cutoff of GDS≥ 6 for clinical depression, women with depression had significantly poorer language/semantic categorization, memory and overall cognitive function. Inclusion of anti-depressants in the model did not alter substantively the associations. CONCLUSION: Our results suggest that depressed T2D women may have poorer cognitive performance, highlighting the significance of sex-specific personalized management of depression in elderly diabetics.

Objective In community dwelling older adults, depression and anxiety symptoms can be associated with early cognitive decline. Symptoms of depression and anxiety are common in older adults prior to surgery. However, their significance is unknown. Our objective was to determine whether preoperative depression and anxiety symptoms are associated with postoperative cognitive decline (POCD) and in‐hospital delirium, in older surgical patients. Methods We conducted a secondary data analysis of postoperative cognitive dysfunction in a cohort study of patients 65 and older undergoing elective noncardiac surgery. We used the Hospital Anxiety and Depression Scale (HADS) to screen for depression and anxiety symptoms at a home visit prior to surgery and 3 months after surgery. Patients with a history of psychiatric (major depressive disorder, bipolar disorder, and schizophrenia) or neurologic disorder (Parkinson's disease and stroke) were excluded from the parent study. Results Out of the 167 patients, 9.6% (n = 16) reported significant depressive symptoms and 21.6% (n = 36) reported significant anxiety symptoms on preoperative screening. There was no association between preoperative or new‐onset postoperative depression and anxiety symptoms and the incidence of delirium or POCD three months after surgery. Patients with preoperative depressive symptoms had higher preoperative pain (scores 69 vs. 35.7, p = .002) and frailty (56 vs. 14.6, p, Preoperative mood symptoms were related to physical pain and frailty. Taken together, these suggest that in patients without a formal psychiatric diagnosis, preoperative mood symptoms are related to physical state rather than a harbinger of early cognitive decline. Future studies are needed to understand the nature of the relationship between mood symptoms and physical state in surgical patients.

Author(s): Sano, Mary; Cummings, Jeffrey; Jeste, Dilip V; Finkel, Sanford; Reichman, William

Introduction Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. Methods The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

OBJECTIVE Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline. RESEARCH DESIGN AND METHODS Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications. RESULTS In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to 0.01). CONCLUSIONS Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes.

Introduction The objective of this study was to investigate associations between dementia in World Trade Center (WTC) responders and in vivo volumetric measures of hippocampal subfield volumes in WTC responders at midlife. Methods A sample of 99 WTC responders was divided into dementia and unimpaired groups. Participants underwent structural T1‐weighted magnetic resonance imaging. Volumetric measures included the overall hippocampus and eight subfields. Regression models examined volumetric measure of interest adjusting for confounders including intracranial volume. Results Dementia was associated with smaller hippocampal volume and with reductions across hippocampal subfields. Smaller hippocampal subfield volumes were associated with longer cumulative time worked at the WTC. Domain‐specific cognitive performance was associated with lower volumetric measures across hippocampal subregions. Conclusions This is the first study to investigate hippocampal subfield volumes in a sample of WTC responders at midlife. Selective hippocampal subfield volume reductions suggested abnormal cognition that were associated with WTC exposure duration.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting’s agenda and provide an overview of the presentation materials and group discussion.

Mobile technologies are becoming ubiquitous in the world, changing the way we communicate and provide patient care and services. Some of the most compelling benefits of mobile technologies are in the areas of disease prevention, health management, and care delivery. For all the advances that are occurring in mobile health, its full potential for older adults is only starting to emerge. Yet, existing mobile health applications have design flaws that may limit usability by older adults. The aim of this paper is to review barriers and identify knowledge gaps where more research is needed to improve the accessibility of mobile health use in aging populations. The same observations might apply to those who are not elderly, including individuals suffering from severe mental or medical illnesses.

Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.

Older adults with type 2 diabetes (T2D) are at increased risk for depression, cognitive decline, and dementia compared to those without T2D. Little is known about the association of simultaneous changes in depression symptoms and cognitive decline over time.Subjects (n=1021; mean age 71.6 [SD=4.6]; 41.2% female) were initially cognitively normal participants of the Israel Diabetes and Cognitive Decline study who underwent evaluations of depression and cognition approximately every 18 months. Cognitive tests were summarized into four cognitive domains: episodic memory, attention/working memory, executive functions, and semantic categorization. The average of the z-scores of the four domains defined global cognition. Depression symptoms were assessed using the Geriatric Depression Scale, 15-item version. We fit a random coefficients model of changes in depression and in cognitive functions, adjusting for baseline sociodemographic and cardiovascular variables.Higher number of depression symptoms at baseline was significantly associated with lower baseline cognitive scores in global cognition (estimate = -0.1175, SE = 0.021, DF = 1,014, t = -5.59; p0.001), executive functions (estimate = -0.186, SE = 0.036, DF = 1,013, t = -5.15; p = 0.001), semantic categorization (estimate = -0.155, SE = 0.029, DF = 1,008, t = -5.3; p0.001), and episodic memory (estimate = -0.08165, SE = 0.027, DF = 1,035, t = -2.92; p = 0.0036), but not with rate of decline in any cognitive domain. During follow-up, a larger increase in number of depression symptoms, was associated with worse cognitive outcomes in global cognition (estimate = -0.1053, SE = 0.027, DF = 1,612, t = -3.77; p = 0.0002), semantic categorization (estimate = -0.123, SE = 0.036, DF = 1,583, t = -3.36; p = 0.0008), and in episodic memory (estimate = -0.165, SE = 0.055, DF = 1,622, t = -3.02; p = 0.003), but the size of this effect was constant over time.In elderly with T2D, increase in depression symptoms over time is associated with parallel cognitive decline, indicating that the natural course of the two conditions progresses concurrently and suggesting common underlying mechanisms".

Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.

Objective Establish whether POCD is associated with new disability after surgery, which would inform whether POCD impacts patient-centered outcomes. Background POCD is a decline in neuropsychiatric tests scores from presurgical baseline which occurs in approximately 15% of older patients 3 months after surgery. POCD is a research construct meant to investigate patient and family reports of older adults who were "never the same after surgery." However, many patients with POCD do not perceive difficulty with thinking and memory, and the question remains whether POCD impacts patient function. Methods We performed a prospective cohort study of 167 older adults undergoing major noncardiac surgery (requiring at least a 2-day hospital stay). Exclusion criteria were: history of dementia, cardiac or intracranial procedure, inability to consent for themselves, or emergency surgery. We administered formal neuropsychiatric testing (Alzheimer Disease Research Center UDS battery), basic and instrumental activities of daily living (Alzheimer Disease Research Center IADLs), pain (geriatric pain measure), and depression screening (hospital depression and anxiety scale) before and 3 months after surgery. We recorded all patient refined diagnostic related groups codes, blood pressure, anesthetics and narcotics administered, surgical and anesthesia duration, and measured complications and severity, length of stay, and readmissions. Results Patients with POCD (21/167, 14.1%) had twice the proportion of new impairment in IADL as compared to those without POCD (57% vs 27%, P = .01). The most common areas of decline were social activities, ability to find items around the house, remember appointments, shop and pay for items, do laundry, drive a car/use public transport, and do housework. Predictors of IADL change after surgery included POCD, presurgical cognition, presurgical function, postoperative depression, and the development of postoperative complications. Conclusions Patients with POCD experience a much higher incidence of new disability after surgery. Baseline cognitive or functional limitations are also risk factors for new disability. Many patients are not aware of their limitations before surgery. Future study is needed to identify practical ways to routinely screen patients and reduce risk. Patients need to be informed of their risk for new disability after surgery to inform their medical decision making.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Contains fulltext : 229856.pdf (Publisher’s version ) (Open Access) Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders.

Introduction This study examined cortical thickness (CTX) in World Trade Center (WTC) responders with cognitive impairment (CI). Methods WTC responders (N = 99) with/without CI, recruited from an epidemiologic study, completed a T1‐MPRAGE protocol. CTX was automatically computed in 34 regions of interest. Region‐based and surface‐based morphometry examined CTX in CI versus unimpaired responders. CTX was automatically computed in 34 regions of interest. Region‐based measures were also compared to published norms. Results Participants were 55.8 (SD = 0.52) years old; 48 had CI. Compared to unimpaired responders, global mean CTX was reduced in CI and across 21/34 cortical subregions. Surface‐based analyses revealed reduced CTX across frontal, temporal, and parietal lobes when adjusting for multiple comparisons. Both CI and unimpaired WTC groups had reduced CTX in the entorhinal and temporal cortices compared to published normative data. Discussion Results from the first structural magnetic resonance imaging study in WTC responders identified reduced CTX consistent with a neurodegenerative disease of unknown etiology.

Introduction Human studies on low-dose resveratrol are scarce. This study aims to evaluate the safety, tolerability, and efficacy of an oral preparation of resveratrol, glucose, and malate (RGM) in slowing the progression of Alzheimer's disease (AD). Methods Thirty-nine subjects with mild to moderate AD who were free of life-threatening disease and who did not have contraindications to the use of the study product were screened. Progression of AD was measured by change in the cognitive portion of the Alzheimer's Disease Assessment Scale–cognitive subscale. Secondary outcomes included Clinician's Global Impression of Change, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, and Neuropsychiatric Inventory. 15 mL of the following preparation per dose, i.e., 5 g dextrose, 5 g malate, and 5 mg resveratrol, or matching placebo was ingested with an 8 oz glass of commercial unsweetened grape juice twice a day for 1 year. Group differences in the rate of change in the outcome measures were examined using generalized estimating equations. Results The treatment and control groups were similar on all of the screening variables. At 12 months, change scores on Alzheimer's Disease Assessment Scale–cognitive subscale, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, or Neuropsychiatric Inventory all showed less deterioration in the treatment than the control group; however, none of the change scores reached statistical significance. The most common AE were falls, all in the control group. None of the falls were deemed to be study related. Conclusion Low-dose oral resveratrol is safe and well tolerated. Interpretation of the effects on clinical outcomes trajectories remains uncertain. A larger study is required to determine whether low-dose resveratrol may be beneficial. Trial Registration ClinicalTrials.gov ( NCT00678431 ), Registered 05/15/2008.

This study evaluated the effect of the alpha-2A-adrenoceptor agonist guanfacine on prefrontally mediated cognitive functions, as well as quality of life and global function in healthy older participants. One hundred twenty-three participants aged 75 years and older were randomly assigned to guanfacine 0.5 mg, 0.1 mg, or placebo daily for 12 weeks. The primary outcome measure was the change in z-score for 6 prefrontal executive function tasks over 12 weeks (PEF6). Neither dose of guanfacine improved PEF6 z-score relative to placebo. The rate of mean change (95% confidence interval) in PEF6 z-score over 12 weeks was 0.270 (0.159, 0.380) for placebo, compared with 0.121 (0.011, 0.232) for guanfacine 0.1 mg (p = 0.06, compared to placebo) and 0.213 (0.101, 0.324) for 0.5 mg (p = 0.47). Neither dose of guanfacine improved the quality of life or global function relative to placebo. Among common adverse events, only dry mouth was significantly more frequent on guanfacine compared to placebo. Guanfacine failed to ameliorate prefrontal cognitive function in older individuals, who were cognitively normal for age.

Background: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied. Objective: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D. Methods: In this cross-sectional study, we examined 738 participants, aged 65–88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education. Results: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p

Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well-characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction (POCD). This paper describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), that focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40 to 80 years old, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired prior, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale (PQRS) cognitive domain, than younger adults in the immediate post-anesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs.

Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. In 2015 IPA convened a transparent process to build a consensus definition of agitation and agreement on what elements should be included in the syndrome that resulted in publication of provisional guidelines. (Cummings et al, 2015) In the 2020-2021 year, the two co-chairs of this symposium have led a new workgroup to make the provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies and guide treatment final.Co-Chairs will discuss methods used in updating and findings and compare changes made to the provisional guidelines. Dr. Sano will present new findings on the biological basis of agitation in dementia and Dr. Mintzer will present on application of guidelines in the special circumstances of persons in palliative and hospice care. Dr. Rosenberg will discuss the special circumstance of agitation care in hospital emergency departments. Mr. Splaine will present findings about the utilization of the 2015 guidelines in the peer reviewed literature, professional and government dementia care guidance, and clinical trials.Cummings, J., Mintzer, J., Brodaty, H., Sano, M., Banerjee, S., Devanand, D., … Zhong, K. (2015). Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. International Psychogeriatrics, 27(1), 7-17. doi:10.1017/S1041610214001963