bluuebunny/crossref_metadata_2025 huggingface dataset:
Young adulthood cardiovascular risk and MRI and amyloid PET in late‐life in a diverse cohort: The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M. , Whitmer Rachel A. , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M , Gilsanz Paola , Miles Sunita , Quesenberry Charles P , DeCarli Charles
Published: December 2020

Background

Mid‐life cardiovascular (CVD) risk factors have been associated with cognitive impairment, but CVD risk factors in young adulthood are not well characterized. We evaluated how young adulthood CVD factors influence late‐life brain health in The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort.

Method

KHANDLE is a multi‐ethnic study of 1,712 long‐term Kaiser Permanente North California members ages 65 and older. To date, 165 participants (25% Asian, 21% Black, 24% Latino, and 30% White) received MRI and PET imaging as part of an imaging sub‐study. MRI analyses included regional gray matter and total WMH volumes. Amyloid PET used AV45 and standard SUVR analysis with cerebellar gray matter as the reference region. Participants underwent neuropsychologic testing and received diagnoses of cognitively normal or dementia/mild cognitive impairment (MCI). CVD risk factors were measured during Multiphasic Health Checkups (MHC) between 1964‐1992 where body mass index (BMI), blood pressure, and total cholesterol were measured. The association of young adulthood CVD factors with imaging measures and syndrome were assessed using linear and logistic regressions with adjustment for age, years since MHC, gender, education and race/ethnicity.

Result

Participants had a mean age of 31+6 at MHC and 75+6 at KHANDLE. Being overweight or obese at MHC was negatively associated with hippocampal volume [β:‐0.42(‐0.81, ‐0.03)] and marginally associated with cerebral gray matter [β:‐0.37(‐0.75, 0.01)] and temporal cortex [β: ‐0.39(‐0.78, 0.01)] volumes. Continuous BMI was negatively associated with cerebral gray [β:‐0.07(‐0.14, ‐0.01)], hippocampal [β:‐0.07(‐0.14, ‐0.01)], and temporal cortex [β:‐0.39(‐0.78, 0.01)] volumes. Hypertension at MHC was negatively associated with cerebral [β:‐0.34(‐0.61, ‐0.06)] and occipital cortex [β:‐0.36(‐0.66, ‐0.06)] volumes. Hypercholesteremia at MHC was negatively associated with cerebral volume [β:‐0.50(‐0.81, ‐0.19)] and hippocampal volume [β:‐0.36(‐0.72, ‐0.01)]. A standard deviation increase in total cholesterol was negatively associated with hippocampal volume [β:‐0.16(‐0.31, ‐0.01)] and associated with greater amyloid burden [β:0.19(0.02, 0.36)].

Conclusion

CVD risk factors of overweight/obesity, hypertension, and hypercholesteremia in young adulthood were negatively associated with measures of late‐life brain health in this diverse cohort of community‐dwelling older adults.
Plasma‐based biomarkers for Aβ and tau predict longitudinal brain atrophy in cognitively healthy elderly and in patients with Alzheimer’s disease
Authors: Leuzy Antoine , Ashton Nicholas J. , Karikari Thomas K. , Simrén Joel , Mårtensson Gustav , Benedet Andréa Lessa , Hye Abdul , Schöll Michael , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kłoszewska Iwona , Lovestone Simon , Aarsland Dag , Mattsson Niklas , Hansson Oskar , Westman Eric , Blennow Kaj , Zetterberg Henrik
Published: December 2020

Background

While the last two decades have seen important advances in the in vivo detection of Alzheimer’s disease (AD) pathology (i.e. β‐amyloid [Aβ] and Tau) using biomarkers (PET‐ and CSF‐based), the global use of these measures is quite limited due to high costs, insufficient availability and their invasive nature. Interest in blood‐based biomarkers for AD is growing due their greater accessibility and lower cost. We here aimed to investigate the relationship between ultrasensitive plasma‐based measures for AD and both cross‐sectional and longitudinal brain atrophy.

Methods

We evaluated cross‐sectional plasma samples for 307 participants (100 cognitively unimpaired (CU) elderly, and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) and 106 AD) from the European multicentre AddNeuroMed cohort. Single molecule array (Simoa) assays were performed for NfL, T‐tau, Aβ42, Aβ40 and GFAp. P‐tau181 was measured using an in‐house Simoa assay. Associations with longitudinal MRI (baseline, 3‐months, 12‐months) were performed using linear mixed models (adjusted for age, sex, education, APOE ε4 status, and interval between plasma and MRI). Three predefined MRI markers were selected: hippocampal volume (adjusted for intracranial volume), cortical thickness within a temporal meta‐ROI encompassing regions susceptible to AD (mean thickness in the bilateral entorhinal, inferior/middle temporal, and fusiform cortices) and whole‐brain cortical thickness.

Results

Cross‐sectionally, P‐tau181 and whole‐brain cortical thickness were the only significant association for CU. In CI subjects, Aβ42/Aβ40 and P‐tau181 were significantly associated with hippocampal volume and temporal meta‐ROI/whole‐brain cortical thickness (Table 1). Longitudinally, increased baseline P‐tau181 was associated with all three MRI measures in both CU and CI subjects (Table 1). Low Aβ42/Aβ40 was also associated with all three MRI measures, though only in CI subjects. Further analyses will associate these plasma measures at the voxel level.

Conclusion

These results suggest that plasma‐based measurements of Aβ42/Aβ40 and P‐tau181 are associated with cross‐sectional atrophy levels and, more importantly, can predict brain atrophy over time, both in patients with AD and in CU elderly individuals. These findings add to a growing number of studies suggesting that these markers hold great promise, both as diagnostic tools as well as in research and clinical trials.
Depressive symptoms are associated with hippocampal neurodegeneration in preclinical autosomal dominant Alzheimer’s disease
Authors: Gatchel Jennifer R. , Lopera Francisco , Fox‐Fuller Joshua T. , Guzman‐Velez Edmarie , Bocanegra Yamile , Pardilla‐Delgado Enmanuelle , Vila‐Castelar Clara , Schoemaker Dorothee , Baena Ana , Torrico‐Teave Heirangi , Munera Diana , Vannini Patrizia , Hanseeuw Bernard , Johnson Keith A. , Sperling Reisa A. , Marshall Gad A. , Quiroz Yakeel T.
Published: December 2020

Background

Increasing evidence suggests that depressive symptoms may be among early behavioral changes in Alzheimer’s Disease (AD). However, the neurobiology of these symptoms in the preclinical stages of AD remains unclear, particularly in relation to markers of neurodegeneration. Studying depression in individuals who carry mutations for autosomal dominant AD (ADAD) is a compelling way to characterize depressive symptoms in preclinical AD, as virtually all ADAD mutation carriers develop dementia and have a well‐characterized trajectory from pre‐symptomatic to clinical disease stages.

Method

We evaluated cross‐sectional associations between the 15‐item Geriatric Depression Scale (GDS) and neurodegeneration of the hippocampus, one of the most vulnerable brain regions in ADAD and depression, in 27 cognitively unimpaired PSEN1 E280A mutation carriers and 26 matched non‐carrier family members of a Colombian kindred with ADAD. Global cognition was measured by the Mini‐Mental State Examination (MMSE); hippocampal volume was assessed by structural MRI. A general linear model with dependent variable GDS, predictor hippocampal volume, and covariates, age, sex, MMSE, and intracranial volume (ICV), was employed.

Result

PSEN1 E280A carriers and non‐carriers did not differ in GDS (carriers:2.2±2.6, non‐carriers:2.9±3.5; p=0.64), sex (carriers:70% females, non‐carriers:88% females; p=0.24), age (carriers:35.9±8.2 years, non‐carriers:37.0±6.5; p=0.56), ICV (carriers:1.4 x106 ±1.1 x 105 mm3, non‐carriers:1.4 x 106 ±1.3 x 105 mm3; p=0.16), or hippocampal volume (carriers: 3867±569 mm3, non‐carriers: 4090±371 mm3; p=0.20). Compared to non‐carriers, carriers had lower MMSE scores (carriers: 28.3±2.9, non‐carriers: 29.7±0.5; p=0.03). In carriers, GDS was negatively associated with hippocampal volume (β= ‐0.71, t= ‐2.6, p=0.02), but not with age, sex, MMSE, or ICV. This association between GDS and hippocampal volume was not observed in non‐carriers (β= ‐0.26, t= ‐1.2, p=0.25).

Conclusion

Depressive symptoms in cognitively‐unimpaired carriers of an ADAD mutation are significantly associated with early hippocampal neurodegeneration, years before the estimated onset of dementia. This provides some of the first evidence of a region‐specific neurodegenerative basis of depressive symptoms in preclinical ADAD. Future longitudinal investigation is needed to characterize the temporal sequence of depressive symptoms in relation to markers of brain pathology and cognitive decline in AD. Findings may have implications for early interventions to reduce depressive symptoms in individuals who have AD risk factors.
Double‐blind placebo‐controlled trial of the safety and efficacy of GM‐CSF/sargramostim in subjects with mild‐to‐moderate Alzheimer’s disease
Authors: Potter Huntington , Woodcock Jonathan H. , Boyd Timothy , Sillau Stefan H. , O'Shaugnessy John R. , Borges Thomas T , Thaker Ashesh A.
Published: December 2020

Background

Rheumatoid arthritis (RA) patients have a reduced risk of developing Alzheimer’s disease (AD), originally hypothesized to be attributable to their use of non‐steroidal anti‐inflammatory drugs (NSAIDs). However, clinical trials with NSAIDs were unsuccessful in both AD and Mild Cognitive Impairment (MCI) subjects. We hypothesized that intrinsic innate immune system factors associated with RA itself may underlie the AD protective effect(s). We tested several cytokines upregulated in RA blood and found that 20 daily injections of 5 μg granulocyte‐macrophage colony stimulating factor (GM‐CSF) reduced cerebral amyloidosis by greater than 50% and completely reversed the cognitive impairment of transgenic AD mice. In a retrospective study, we found that short‐term treatment with sargramostim/Leukine® (recombinant human GM‐CSF) plus G‐CSF improved cognition of leukemia patients following bone marrow chemoablation/hematopoietic cell transplant compared to patients who received G‐CSF alone.

Method

A double blind Phase II safety and efficacy trial of sargramostim in 40 mild‐to‐moderate AD subjects, half receiving placebo and half receiving 250 μg/m2/day sargramostim by subcutaneous injection five days/week for three weeks with follow‐up visits at 45 and 90 days post‐treatment is complete (NCT01409915). Neurological and neuropsychological assessments and MRI and amyloid‐PET scans were performed to assess the safety and efficacy of treatment.

Result

Clinical and imaging analyses showed no drug‐related serious adverse events, including no amyloid‐related imaging abnormalities (ARIAs; micro‐hemorrhage or vasogenic edema). At the end of treatment, the mean Mini‐Mental State Examination (MMSE) score in the sargramostim group was improved relative to baseline (p=0.0074) and to the placebo group (p=0.037) by repeated measures mixed model analysis. The beneficial effect of sargramostim on MMSE, compared to placebo, was retained at the first follow‐up visit at 45 days after the end of treatment (p=0.0272). In contrast, there was a single poorer ADAS‐Cog‐13 (Alzheimer’s Disease Assessment Scale‐Cognitive Subscale‐13) mean score in the sargramostim group compared to placebo–at the first follow‐up visit 45 days after the end of treatment. Amyloid and volumetric brain scans are being analyzed.

Conclusion

These results indicate that GM‐CSF/sargramostim shows promise as a potential treatment for AD and that our Alzheimer’s Association “Part the Cloud”‐funded 24‐week treatment trial is warranted.
Neuroprotective effects of fecal microbiota transplantation in a mouse model of Alzheimer’s disease
Authors: Holsinger R.M. Damian , Elangovan Shalini
Published: December 2020

Background

The efficacy of fecal microbiota transplantation (FMT) as a therapeutic in Alzheimer's disease was evaluated in the 5XFAD mouse model.

Method

We treated sixteen, 36‐week‐old 5XFAD transgenic mice with fecal slurry from healthy, wild‐type donors of similar age (n = 8; Old Tg‐FO) or from younger (8‐10‐week old) healthy, wild‐type donors (n = 8; Old Tg‐FY) for seven days. Mice were incubated for 21 days and were then subjected to cognitive tests to examine the effects of FMT on memory. Mice were sacrificed and brain tissue was examined for amyloid plaque load.

Result

Improved spatial and recognition memory in Old Tg‐FY and enhanced recognition memory in Old Tg‐FO mice were observed when compared to Old Tg‐Control mice treated with saline. Importantly, there were significant decreases in cortical Ab loading following seven days of FMT in all treated mice.

Conclusion

Our results demonstrate the capability FMT in improving cognition and reducing amyloid pathology in the 5XFAD mouse model of Alzheimer’s.
Retinal inhibition of glycogen synthase kinase 3 beta protects against tau phosphorylation and stabilises microtubule assembly
Authors: Chitranshi Nitin , Rajput Rashi , Garthwaite Linda , Thananthirige Kanshika Pushpitha Maha , Mirzaei Mehdi , Sheriff Samran , Godinez Angela , Gupta Veer , Graham Stuart , Gupta Vivek K.
Published: December 2020

Background

The microtubule associated protein tau is known to have several important functions like assembly and stabilisation of microtubules, axonal transport and neurite outgrowth in neurodegenerative diseases. Gsk3β, glycogen synthase kinase, plays a key role in regulating tau protein activity. There is little understanding of tau and Gsk3β association in the neurogenerative disorders affecting retina. Shp2, the mitogenic phosphatase, is associated with regulation of growth factor signalling pathways in the central nervous system. In this study we demonstrate that Gsk3β inhibition can suppress tau hyperphosphorylation and rescue the inner retinal degenerative changes induced by Shp2 overexpression (OE).

Methods

Adult Sprague‐Dawley rats were subjected to intravitreal injection of adeno‐associated viral vector (AAV2) overexpressing either Shp2 or eGFP alone (3.4x1012 GC/ml; n=8). These animals were also subjected to weekly (8 weeks) intravitreal injections of Gsk3β inhibitor (10 nM) and control. Electrophysiology and positive scotopic threshold response (pSTR) (‐4.3 log cd s/m2) were measured using Phoenix Ganzfield two months following intra‐ocular injections. The amplitude of each component was measured and analysed. Immunohistochemistry (IHC) and Western blot (WB) were performed for pTau Ser404, Tau, pGsk3β Ser9, Gsk3β, Ac‐tubulin and Tyr‐tubulin.

Results

Shp2OE in the rat eye significantly reduced the pSTR amplitudes (44%±3.1%) compared to PBS and GFP control. However, animals treated with Gsk3β inhibitor in Shp2OE retina demonstrated significant protection of pSTR amplitudes (81±5 % protection; n=32, p<0.05). IHC analysis demonstrated increased pTau Ser404 and decreased pGsk3β Ser9 immunoreactivity in the Shp2OE RGCs whereas pharmacological inhibition of Gsk3β for 8 weeks reversed the phosphorylation status of tau and Gsk3β in animals recieving AAV‐Shp2. We found that Shp2OE led to a markedly reduced expression of Ac‐tubulin (stable microtubules) and increased expression of Tyr‐tubulin (unstable microtubules) compared with control retina. Remarkably, the effects of Shp2OE on microtubules assembly was reversed upon Gsk3β inhibitor administration.

Conclusion

Shp2OE in the retina led to abnormal tau hyperphosphorylation via Gsk3β activation causing deficits in RGCs visual function through the disruption of microtubular assembly. Shp2 may thus be an attractive therapeutic target to counter RGC neurodegeneration by reducing tau hyperphosphorylation in Alzheimer’s disease.
The Preventing Dementia Massive Open Online Course results in behaviour change associated with reduced dementia risk: The My INdex of DEmentia Risk (MINDER) study
Authors: Farrow Maree , Klekociuk Shannon Z , Bindoff Aidan , Vickers James C
Published: December 2020

Background

Several multi‐domain dementia prevention interventions are being trialled, often involving intensive programs targeting older adults. To reach the wider population at risk of dementia, accessible and scalable interventions are also needed. The Preventing Dementia Massive Open Online Course (PD‐MOOC) aims to build knowledge of dementia risk factors, self‐efficacy in management of modifiable risk factors, and an ability to appraise evidence. Since 2016, the PD‐MOOC has attracted over 99,000 enrolments.

Method

The My INdex of DEmentia Risk (MINDER) study aimed to investigate the impact of the PD‐MOOC on risk‐related behaviour and dementia worry, and associations between the two. PD‐MOOC participants completed the short form Australian National University Alzheimer’s Disease Risk Index (ANU‐ADRI) and the Dementia Worry Scale at 3 time points: pre‐MOOC (n = 4838), immediately post‐MOOC (n = 2546), and 6 months follow‐up (n = 906). Multinomial logistic regression models were used to estimate the probability of transition from one risk behaviour state (high/intermediate/low risk) to another, based on ANU‐ADRI sub‐scales for the seven modifiable factors assessed.

Result

At 6 months follow‐up, the probability that participants in the high‐risk state for depressive symptoms at baseline had moved to the low‐risk state was 0.58 (CI: 0.49 – 0.66). Dementia worry was significantly associated with risk state transitions only for depressive symptoms; those more worried were more likely to move from the high‐ to low‐risk state. The probability that heavy alcohol drinkers at baseline transitioned to moderate drinking at follow‐up was 0.49 (CI: 0.33 – 0.64), and the probability that current smokers transitioned to former smokers was 0.15 (CI: 0.05 – 0.23). The probability of moving from the highest risk state at baseline to a lower risk state at follow‐up was 0.36 (CI: 0.11 – 0.70) for social activity, 0.35 (CI: 0.25 – 0.44) for fish consumption, and 0.20 (CI: 0.15 – 0.13) for physical activity, and just 0.02 for cognitive activity.

Conclusion

These findings suggest the PD‐MOOC provides benefits beyond imparting knowledge and may contribute to self‐efficacy for sustained behaviour change. The PD‐MOOC may be considered an accessible, scalable and effective multi‐domain public health intervention for dementia risk reduction.
Cognitive reserve for memory performance is mediated by preclinical frontotemporal and limbic amyloid deposition in subjects with normal cognition in early MCI
Authors: Ali Doaa , Moga Daniela C , Khouli Riham H El , Martinez Ashley I , Abner Erin L , Jicha Gregory A
Published: December 2020

Background

The neuroanatomic substrate for cognitive reserve has been poorly elucidated. The development of antemortem biomarkers such as amyloid‐PET afford the potential to begin to explore regional pathologic burden with overt cognitive performance as well as cognitive resilience in relation to neuroanatomic distributions of pathology. The present study sought to identify the relationship between regional amyloid burden and objective measures of cognitive reserve for memory function.

Method

Sixty‐two subjects with normal cognition or mild cognitive impairment from the INCREASE randomized controlled trial (R01AG054130) underwent amyloid‐PET imaging with Amyvid® tracer, and regional SUVr was determined using the Siemens Syngo.via® Neurology software package. Participants underwent cognitive testing with the Montréal Cognitive Assessment (MOCA) and California Verbal Learning Test (CVLT) while challenged with 1.5mg transdermal scopolamine and four weeks later in an unchallenged state. Cognitive reserve (CR) was operationalized by subtracting the scopolamine‐challenged score from unchallenged test performance for CVLT trials 1‐5 total learning. The relationship between regional SUVr and unchallenged as well as CR cognitive test performance was analyzed using adjusted linear regression models.

Result

Subjects included 39 women (63%) and 23 men (37%) with a mean age of 73.1±6.2 years, education 16.5±2.7 years, MOCA 25.8± 2.5, and CVLT 45.2± 11.6. Global amyloid‐PET SUVr ranged from 0.9‐2.0 and CVLT CR scores ranged from ‐12 to 34. While, age and education adjusted linear regression analysis demonstrated that unchallenged MOCA and CVLT scores were not significantly related to global SUVr in this sample, reduced CVLT CR was associated with increased global SUVr (p<0.05). Regional analysis demonstrated that this effect was mediated by amyloid deposition in the frontal ((p=0.009), medial temporal (p=0.019), and limbic (p=0.030) regions.

Conclusion

These data demonstrate that cognitive reserve for memory functions is particularly sensitive to amyloid deposition in frontotemporal regions intrinsic or connected to the Papez circuit. While this finding is not surprising, it does provide convincing evidence that even preclinical amyloid deposition can have significant clinical consequences when neuroanatomic circuits are stressed. Further work investigating whether transient decline in memory performance at times of medical, emotional, or physical stress might be indicative of preclinical amyloid deposition is warranted.
Decreased task‐evoked functional connectivity in the descending pain modulatory network in Alzheimer’s disease
Authors: Atalla Sebastian W. , Iversen Larkin , Moss Karen , Wright Kathy , Monroe Todd B.
Published: December 2020

Background

People with Alzheimer’s disease (AD) may suffer from alterations in the descending pain modulatory network (DPMN). Adults with AD receive fewer analgesic pain medications and report pain less frequently than healthy controls. This study examines possible alterations in task‐evoked functional connectivity (TEFC) in response to thermal pain in several structures comprising the DPMN. We hypothesize that adults with AD will demonstrate decreased TEFC between DPMN regions.

Method

The sample consisted of 61 adults, 31 people with Alzheimer’s disease (AD; Mage  = 77) and 30 healthy controls (HC; Mage  = 73). The groups did not differ on socioeconomic status, current or average pain, or state or trait anxiety scores. Age and depression scores differed between groups and were controlled. Participants completed 4 pseudorandomized fMRI sessions using a passive thermal pain induction task consisting of warmth, mild pain, and moderate pain temperature thresholds. Regions of interest were selected a priori: bilateral primary somatosensory cortex (S1), bilateral anterior insula (aINS), bilateral posterior insula (pINS), anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). Psychophysiological interactions (PPI) analysis was completed using CONN v18.b. Motion correction was performed using Artifact Detection Tools and fMRI sessions for which greater than 20% of the timeseries exceeded 2 mm normalized motion were excluded from the analysis. Age and AD‐related differences in cerebral tissue volume were controlled. Contrasts for this analysis were chosen to be mild pain > warmth and moderate pain > warmth to subtract innocuous stimulus from noxious stimuli.

Result

Compared to healthy controls, adults with AD exhibited decreased TEFC between the R S1 and L S1 for mild pain > warmth (T = ‐2.03, p = 0.047), and decreased TEFC between the PAG and ACC for moderate pain > warmth (T = ‐2.18, p = 0.033).

Conclusion

Findings suggest that in people with AD, decreased connectivity between left and right S1 may indicate altered sensory processing of neural input. Evidence of decreased connectivity between the PAG and ACC in adults with AD may indicate an inability to modulate endogenous opioid systems within the brain and may lead to increased suffering from pain.
Traumatic brain injury and dementia risk: The role of sex, insurance and race
Authors: Nuno Miriam , Ugiliweneza Beatrice , Gilsanz Paola , Peterson Rachel , Eng Chloe W. , George Kristen M. , Whitmer Rachel A.
Published: December 2020

Background

Although traumatic brain injury (TBI) has been found to be associated with dementia in numerous studies, large‐scale studies of US non‐Veteran populations are scarce. The question of whether sex, insurance, and race influence the risk of dementia after a TBI is not well studied.

Methods

We analyzed data from 97,736 individuals with TBI age 55+ captured in the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database between January 1, 2000 and December 31, 2016. Dementia diagnosis was made from inpatient or outpatient visits during this period with a “wash out” period of one year. The risk of dementia after TBI was established using Cox proportional hazard models adjusted for age, sex, insurance, diabetes, cardiovascular disease, and birth decade. We censored cases at end of enrollment or date of last claim.

Results

Over a median follow‐up of 19.2 (IQR: 6‐42) months, 6417 (5.9%) individuals developed dementia. Older age at injury was associated with a higher risk of dementia in both mild and moderate/severe cases (Age 85+ vs. 55‐64: Mild HR 13.51, 95% CI: 7.97‐22.91; Moderate/Severe HR 6.88, 95% CI: 5.37‐8.83). Women with moderate/severe TBI had a significantly higher hazard of incident dementia compared to men with the same type of injury (HR 1.14, 95% CI: 1.07‐1.21). Individuals with Medicaid and Medicare coverage had a higher risk of dementia than Commercial insurance users independent of TBI severity. The presence of diabetes (Mild: HR 1.46, 95% CI: 1.24‐1.72; Moderate/Severe: 1.28, 95% CI: 1.03‐1.58) and cardiovascular disease (Mild: HR 1.28, 95% CI: 1.03‐1.58; Moderate/Severe: 1.17, 95% CI: 1.07‐1.29) were associated with an increased risk of dementia. A reduction in dementia risk was observed among Blacks (HR 0.85, 95% CI: 0.74‐0.99), and Hispanics/Others (HR 0.63, 95% CI: 0.51‐0.78) in patients covered by Medicaid (N=13304) when compared to non‐Hispanic whites.

Conclusion

Age at injury, sex and insurance type were associated with increased risk of dementia after a TBI. Blacks and Hispanics/Others covered by Medicaid experienced a lower risk of dementia compared to Whites. Greater efforts to identify factors to mitigate the burden of dementia in large diverse populations are needed.
A dementia risk assessment tool to facilitate risk‐related behaviour change: The dementia risk profile
Authors: Farrow Maree , Kim Sarang , Bindoff Aidan , Doherty Kathleen , Eccleston Claire , Vickers James C
Published: December 2020

Background

Several risk assessment tools have been developed to estimate an individual’s risk of developing dementia. These measure age, self‐report measures of risk‐related activity and health conditions, and/or physiological measures of vascular or genetic risk. An understanding of actions that one can undertake is required to facilitate individual risk reduction. We developed the Dementia Risk Profile (DRP), focusing on assessment of risk‐related behaviour rather than actual risk, with the aim of providing information to individuals to enable risk reduction.

Method

The WHO Guidelines for Risk Reduction of Cognitive Decline and Dementia recommend interventions for eight modifiable risk factors. For each of these we identified the behaviours associated with mitigating risk. We adapted relevant sections of the short form Australian National University Alzheimer’s Disease Risk Index to develop questions for the DRP and included questions to assess adherence to the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet. Item development focused on ease of understanding and responding, provision of feedback on actions that could be taken to reduce risk, and tracking behaviour change over time.

Result

The final DRP survey measures: diagnosis, regular checks and management for blood pressure, cholesterol and diabetes; body mass index; MIND diet adherence; frequency of engagement in cognitive activities; time spent engaging in walking, moderate and vigorous physical activity; frequency and amount of alcohol consumption and smoking tobacco. Algorithms calculate an individual’s risk state for each factor and a traffic light system informs the individual of their status (e.g. red = high risk). Change within a state (e.g. still smoking but smoking less) can also be indicated, to motivate ongoing risk‐reducing behaviour change. Written feedback for each factor is provided under the headings ‘What the science says’, ‘Your status’ and ‘What can you do?’ The DRP has been implemented in a randomised controlled trial (n=414) and a population‐level public health intervention (n=3269).

Conclusion

Initial DRP data and user feedback will inform development to ensure its capacity to inform individuals about their risk and facilitate behaviour change that has a positive impact on their dementia risk in addition to their overall health.
Conceptualizing the relationship between parental education and own cognition in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study
Authors: Eng Chloe W , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles , Whitmer Rachel A
Published: December 2020

Background

Few studies have considered how parental education influences late‐life cognition; those that have often focus on maternal and not paternal influences or as part of a broader SES index, which does not allow us to understand the functional form of the relationship between parental education and cognition. We assessed whether mother’s education dichotomized at 8th grade, a commonly used cutoff among similarly aged older adults to our sample, sufficiently captured effects of parental education by systematically evaluating conceptualizations of parental education.

Methods

Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study baseline participants, aged 65 years plus (n=1,633), self‐reported own and parents’ education at baseline. Parental education was operationalized separately as (1) mother’s only, (2) father’s only, (3) mother and father together; each operationalization was considered as categorical (missing, <=8th grade, incomplete high school, high school diploma, postsecondary education), as >8th grade (with missingness indicator and with missing included in “low”), and as high school completion (with and without missingness indicator). Parental (4) concordance (both high, high mother, high father, both low), (5) highest parental level, and (6) lowest parental level were also evaluated. Verbal episodic memory (VEM), semantic memory (SEM), and executive functioning (EF) from the Spanish and English Neuropsychological Assessment Scales (SENAS) were considered separately in covariate‐adjusted linear models. The lowest Bayesian Information Criterion (BIC) model was considered to provide the best fit.

Results

Across all parental education operationalizations, 8th grade cut‐offs performed best; categorical (5‐level) parent education performed the worst. Semantic memory was best predicted by the referent measure of mother’s education >8th (B̂: 0.33; 95% CI: 0.25, 0.42); however verbal memory was best predicted by mother’s education >8th grade (B̂: 0.14; 95% CI: 0.03, 0.24) plus missing indicator (B̂: ‐0.24; 95% CI: ‐0.37, ‐0.10) and executive function by both mother’s (B̂: 0.22; 95% CI: 0.12, 0.31) and father’s (B̂: 0.18; 95% CI: 0.09, 0.28) >8th together.

Conclusion

The preferable performance of parental education as >8th grade likely reflects historical education trends when KHANDLE participants’ parents were educated; whether preference for dichotomized measures over full categories reflects uncertainties in recall of parental education remains unclear.
The diffusion of dementia risk education
Authors: Fair Hannah , Eccleston Claire , Doherty Kathleen , Klekociuk Shannon Z , Farrow Maree
Published: December 2020

Background

The Preventing Dementia Massive Open Online Course (PD‐MOOC) is one of several initiatives aiming to increase dementia risk knowledge and promote risk‐reducing behaviour. These initiatives primarily reach advantaged individuals, increasing health inequities. Previously, thematic analysis of PD‐MOOC participant feedback identified frequent reports of sharing dementia risk information with others. Interpersonal communication often introduces information to people from a broader demographic and may increase the impact of dementia risk education. This study investigated the diffusion of dementia risk reduction knowledge and behaviour beyond PD‐MOOC participants.

Method

The PD‐MOOC attracted over 99,000 enrolments from 2016 to 2019. Responses to surveys completed by participants before (demographics) and after (course feedback) the PD‐MOOC were analysed. Qualitative statements were characterised using key word filtering and subsequent thematic analysis. Chi‐squared tests of homogeneity with Bonferroni adjustments for multiple comparisons were used to determine significant information sharing patterns.

Result

Older people, females, health sector workers and people with a post‐secondary education were over‐represented among PD‐MOOC participants. Participants expressed an eagerness to share the MOOC with others, with 98.8% of respondents agreeing they “would recommend the MOOC to others”. 25% of responding participants discussed sharing PD‐MOOC information in their response to the question “If you have already applied your MOOC learning, please tell us how”. Among those who reported sharing information with specific people, family members were mentioned most frequently, followed by friends and colleagues. Significantly more responses discussed sharing information with males than females (p < 0.001) and with people outside the health sector than within (p < 0.001). Some participants reported sharing information about specific risk domains; physical activity was mentioned most frequently, followed by cognitive stimulation and diet. Additionally, some reported that the person with whom they shared information altered their behaviour; increased physical activity was most commonly reported, followed by a general improved lifestyle and a change in diet.

Conclusion

Information sharing transmits dementia risk information to, and promotes behaviour change among, people who are demographically less represented in the PD‐MOOC, extending the reach and impact of this educational intervention. The PD‐MOOC enables dementia risk reduction beyond those educated.
Applied co‐creation approach to the design and development of a socially assistive robot system to support hardware and software accessibility and acceptability needs of individuals with AD/ADRD and their caregivers
Authors: Kingsley Caroline , Stout Andrew , Herrera Nicolas , Mittelman Mary S , Niehaus James
Published: December 2020

Background

Commercially available socially‐assistive robots (SARs) serve as a promising new assistive technology platform for individuals with early and middle stage AD/ADRD and their caregivers, yet often fail to address the specific usability, accessibility, and acceptability needs of these user groups. Loneliness, social isolation, depression, anxiety, and overall diminished quality of life are symptoms that individuals with AD/ADRD and their caregivers often share. The emerging market of SARs brings an advantage over existing assistive technologies because they provide an opportunity for technology to empathetically and seamlessly provide affordable and scalable solutions to social isolation and loneliness that are often left unaddressed.

Method

Three rounds of co‐creation sessions, consisting of interviews with individuals with early and middle stage AD/ADRD and focus groups with AD/ADRD caregivers, to understand both groups' pain points, needs, methods/frequency of social interaction, experiences with technology, criteria for building trust in technology/systems, perception/opinions of SARs, and interest in and ideas for ways SARs can improve their daily lives, to drive co‐development of hardware and software solutions to adapt commercially available SARs to deliver useful experiences tuned to population‐specific requirements.

Result

We will present on the qualitative methods, analysis, and findings from our NIA‐funded IRB‐approved co‐creation user research and demonstrate our resultant prototype system, involving a commercial social robot with user‐centered software and hardware adaptations for increased accessibility and usability (e.g., large tactile buttons, large visual display, additional speakers and microphones). Additionally, we will discuss lessons learned from our co‐creation user research approach in the context of addressing two unique populations and recommendations for future approaches.

Conclusion

Individuals with early and middle stage AD/ADRD and their caregivers are generally receptive and excited by the potential for social robot technology and can greatly benefit from it when designed thoughtfully and inclusively. Current SARs provide promise, but must be adapted to the specific interaction needs of these populations to increase adoption and utility. An iterative, co‐creation user research and design process involving both individuals with AD/ADRD and their caregivers provides a promising approach to develop useful and acceptable in‐home social robot technology to enhance the social connectedness, well‐being, and quality of life of these populations.
Developing appropriate methodologies for effective clinical trial engagement in vascular cognitive impairment and dementia (VCID)
Authors: Schneider Lon
Published: December 2020

Background

Compared with the substantial advances in Alzheimer’s trials and methods, there have been only attenuated advances in trials for vascular cognitive impairment and dementia (VCID). From a broad perspective, a clinicaltrials.gov search yielded 621 clinical trials in Alzheimer’s, but only 75 interventional trials that included patients with vascular dementia of which 35 also included patients with a variety of dementias; and the interventions for the majority of the trials were not focused on cognitive or functional outcomes. Currently, there are no drugs with FDA marketing approval specifically for VCID.

Method

Qualitative and quantitative assessment of trials for VCI from the 1970s onward was undertaken to assess the evolution of drug development and trials. Diagnoses, drug interventions, targets, the use of biomarkers, and trials methods were examined in order to assess the current state and barriers to drug development for vascular brain injury.

Result

Preliminary assessment reveals that various diagnostic criteria, interventions, and inconsistent trials methods have been employed. It is often unclear how participants were identified or diagnosed. Sample sizes tend to be small, and outcomes various. The rationales for specific treatments are often not apparent. Mainly trials rely on a post‐stroke, multi‐infarct dependent diagnosis; a minority on a small vessel, ischemia‐based definition. In many diagnostic criteria are vague. Notable groupings include cholinesterase inhibitors and cerebral amyloid angiopathy. Most of the former group relied on NINCDS‐AIREN criteria, Alzheimer trials methods, and were intended for FDA regulatory consideration. No trial seemed to use vascular biomarkers or validated drug targets.

Conclusion

The lack of progress in VCID trials is intriguing considering its high prevalence and overlap with Alzheimer pathology. The various VCID diagnoses and conditions and their heterogeneity represents barriers to treatment development. As evidence is substantial that VCID is at least a modifier of Alzheimer pathology and expression, the development of valid drug targets, biomarkers, drugs, and regulatory pathways are essential. Noteworthy is a focus developing biomarkers for small vessel disease (Greenberg SM, et al https://markvcid.partners.org/). Despite the challenges, the field needs to move in a way that will engage regulatory agencies and pharma to develop pathways and therapeutic pipelines.
Epidemiology informs randomized clinical trials of cognitive impairment and late‐onset, sporadic dementias
Authors: Gustafson Deborah R.
Published: December 2020

Background

Despite strong and consistent evidence, criticisms of epidemiologic associations between vascular factors and cognitive impairments (CI) and late‐onset, sporadic Alzheimer’s Disease (LOAD), abound. A common critique is, “If vascular risk factors identified in observational epidemiology are real, why do clinical trials of treatments for vascular risk fail to improve cognition or prevent LOAD?’ Given the strengths of Dementia Epidemiology in identifying population‐level questions and solutions, how can there be a better translation to Randomized Controlled Trials (RCT)?

Method

Herein, it is proposed that greater attention to ‘real world’ epidemiology and ‘fit for purpose and fit for community’ approaches, can result in better planning of RCT. Facets of accomplishing this include the following considerations: 1) CI and LOAD result from exposures occurring over the life course; 2) definitions and terminology related to exposures and clinical outcomes; 3) characteristics of populations at risk and their variation over the life course, e.g., mid‐life to late‐life; 4) attaining data on latest life exposures and flux; 5) duration of exposure(s), such as medication adherence, that are required to achieve desired effects; 6) reverse causality; 7) birth cohort; 8) multimorbidities; and 9) genetic susceptibility.

Result

Two practical examples translating the observational epidemiology to the RCT will be provided. Both examples involve obesity as the exposure, and the outcomes include ADRD and Vascular Cognitive Impairment (VCI).

Conclusion

RCT must embrace more of the chaos (intra‐ and inter‐individual and ‐community variabilities) to better identify prevention strategies that work. This proposed presentation will address concerns that provide a natural segue for the scientific community to focus on, facilitate and feed forward future solutions and fill knowledge gaps.
Divergent effects of education and occupation history on age at onset within Alzheimer’s and frontotemporal dementia
Authors: Miller Zachary A. , Allen Isabel Elaine , Neylan Kyra D. , Diggs Ryan T. , Bogely Rian L. , Palser Eleanor , Perry David C. , Brown Jesse , Sturm Virginia , Rabinovici Gil D. , Rosen Howard J. , Kramer Joel H. , Rankin Katherine , Grinberg Lea Tenenholz , Seeley William W. , Gorno‐Tempini Marilu , Miller Bruce L.
Published: December 2020

Background

Cognitive reserve refers to the resilience education and life‐time mental activity confer against neurodegenerative disease. Mostly understood within Alzheimer’s disease (AD), we investigated the impact education and occupation history have within frontotemporal dementia (FTD).

Methods

Employing the United States Bureau of Labor Statistics (USBLS) job classification, we screened occupation histories in all participants who presented to the UCSF MAC from 1998‐2019 and met criteria for FTD (n=638; including behavioral variant FTD, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia) and compared to a sample of AD matched for age at symptom onset (n=600).

Results

Compared to AD, FTD possessed significantly higher amounts of years of education (15.7±2.9 vs. 15.3±3.5, p=0.03) and male sex (50.2% vs. 43.7%, p=0.02). Adjusting for these differences, seven of 23 USBLS categories differed between AD and FTD (Table 1). “Architecture & Engineering,” “Computer & Mathematical,” and “Life, Physical, & Social Science,” which together constitute the STEM (Science, Technology, Engineering, and Mathematics) professions, were increased in FTD. “Arts, Design, Entertainment, Sports, & Media,” “Personal Care & Services,” “Production,” and “Other” occupation categories were increased in AD (referred to here as AD‐Relevant). STEM occupations predict FTD over AD (OR, 2.3; 95% CI, 1.7 to 3.2), whereas AD‐Relevant occupations predict AD over FTD (OR, 2.2; 95% CI, 1.6 to 3.1). Survival curve analyses of STEM vs. AD‐Relevant vs. all remaining occupations revealed that STEM occupation associates with earlier symptom onset in FTD and later onset in AD and AD‐Relevant careers, the opposite. Furthermore, within FTD, disease duration was longest in the STEM cohort compared to all remaining and AD‐relevant careers (11.4 vs. 8.9 vs. 9.3, p=0.003).

Conclusions

We find that education and occupation history impact age at symptom onset within AD and FTD, in opposing manner. The cognitive reserve hypothesis was created to explain the delayed symptom onset and shortened disease duration increased years of education and occupational complexity bestow on individuals with AD. Within FTD, we observe the opposite ‐ earlier symptom onset and greater disease duration in STEM professionals ‐ suggesting a reciprocal process may be at work within FTD.
Subject selection and identification of optimal clinical outcome measures in dementia trials focused on vascular cognitive impairment and dementia
Authors: Peters Ruth
Published: December 2020

Background

Research into the understanding and identification of modifiable clinical and lifestyle related factors associated with increased risk of dementia has grown enormously over the past twenty years. The development of the field is now such that we have a general awareness of the main risk factors, and, in many areas, public health messaging is underway to support risk reduction. Given the overlap between the risk factors for dementia and those for other non‐communicable disease, for example, cardiovascular disease and cancer, the potential benefit of risk reduction activities is unequivocal. Despite this, the evidence base for dementia risk reduction is not strong and for several risk factors the clinical trial results have been mixed and inconclusive.

Method

To evaluate reasons for the inconsistency between the epidemiology and the clinical trial evidence we selected key modifiable risk factors that lend themselves to blinded pharmacological intervention and where trial results are available. E.g. antihypertensives, hormone replacement therapy, non‐steroidal anti‐inflammatories, statins and omega 3 supplementation. Experts in the field of dementia risk factor epidemiology, dementia risk reduction trials, and with statistical and clinical, Alzheimer’s and vascular dementia expertise were convened to critically appraise the evidence.

Result

Explanations for the discrepancies arise in both the trial and epidemiology evidence. E.g.; selection of trial populations from age or population groups that do not match the groups where the association between the risk factor and dementia outcome is strongest, a lack of understanding of the most appropriate dose of intervention or goal level of risk factor for the best cognitive outcome and the short duration of trials in the context of a disease process with a decades long prodromal phase. Conversely epidemiology that suffers from confounding by indication or that fails to fully account for confounding by key factors such as socioeconomic status, or to take account of the life‐course.

Conclusion

To fully understand the potential for risk reduction and to target resources accordingly will require both a new and more sophisticated evaluation of existing data and the delivery of new and better designed trials. Recommendations are made for the next steps.