bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of novel bifunctional chelators for diagnostic 64Cu PET imaging in Alzheimer’s disease
Authors: Mirica Liviu M
Published: December 2021

Background

Metal radiotracers exhibit beneficial properties that can improve in vivo positron emission tomography (PET) imaging over traditional radionuclides, such as longer half‐lives, facile last‐stage radiolabeling steps, and the potential for dual imaging‐therapy applications. Among such radionuclides, 64Cu exhibits a longer half‐life (t1/2 = 12.7 h) that allows for later PET imaging times and the ability to distribute 64Cu imaging agents to facilities that do not have an on‐site cyclotron.

Method

The employed approach uses a bifunctional chelator with two Aβ‐interacting fragments that dramatically improves the Aβ‐binding affinity and lipophilicity for favorable blood‐brain barrier (BBB) penetration, while the use of optimized‐length spacers between the Cu‐chelating group and the Aβ‐interacting fragments further improves the in vivo Aβ‐binding specificity and brain uptake of the corresponding 64Cu PET imaging agent.

Result

Herein, we report to the best of our knowledge the first 64Cu PET imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta‐amyloid aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice.

Conclusion

64Cu PET imaging agents can be used for in vivo imaging of beta‐amyloid aggregates.
Contribution of amyloid and tau to cerebrospinal fluid fatty acid indices in preclinical and prodromal Alzheimer’s participants
Authors: Fonteh Alfred N. , Arakaki Xianghong , Cipolla Matthew , Chui Helena C. , Harrington Michael G.
Published: December 2021

Background

Since Aβ42 derives from membrane‐bound amyloid precursor protein (APP), we propose that membrane lipid composition may influence how APP is processed. Therefore, we aim to determine if fluctuations in fatty acid metabolism accompany amyloid and tau pathology.

Method

Using neuropsychology and ELISA‐based Aβ42/T‐tau measures in CSF, we classify five groups of elderly subjects:
c
ognitively
h
ealthy with
n
ormal
Aβ

42/T‐
t
au (CH‐NAT, n=36 ), cognitively healthy with pathological Aβ42/T‐tau (CH‐PAT, n=34), and MCI participants with normal or pathological Aβ42/T‐tau (MCI‐NAT, n= 26; MCI‐PAT, n=12), and Alzheimer’s (n=25). We determined the unesterified fatty acid (UFA) levels and the fatty acid composition of CSF nanoparticulate (NP) fraction and supernatant fluid (SF) using GC/MS. We calculated the chain length, unsaturation, and peroxidation indices and the ratio of monounsaturated fatty acid (C18:1, oleic acid) to saturated fatty acid (C18:0, stearic acid) designated the stearoyl‐CoA desaturase (SCD) index.

Result

Unesterified chain length, unsaturation, peroxidation, and desaturase indices are higher MCI‐NAT/PAT than in AD. In the SF fraction, fatty acid indices are higher in the prodromal MCI‐PAT state than AD. To determine if SCD could account for differences in unsaturation, we quantified the primary SCD substrate (C18:0) and product (C18:1) in CSF fractions. We found that unesterified C18:0 was lower while C18:1 was higher in MCI‐NAT than the other clinical groups. These changes in C18:0 and C18:1 levels resulted in a higher desaturase index in MCI‐NAT (0.35± 0.15) than in CH‐PAT (0.26±0.16, adjusted p‐value (q) = 0.0230) and AD (0.16±0.11, q < 0.0001). In the SF fraction, C18:0 levels are lower in MCI‐PAT than AD concomitant with a higher C18:1 in MCI‐PAT than AD. These fatty acid differences result in a significantly higher desaturase index in the prodromal MCI‐PAT (0.46±0.15) than in AD (0.28±0.11, q = 0.0067).

Conclusion

These studies show an increase in the unsaturation and peroxidation indices in early AD that may result from enhanced brain desaturase activity. These data suggest that fatty acid indices are potential biomarkers of preclinical or prodromal AD. The increase in fatty acid indices followed by a decrease in dementia indicate a need for state or stage‐specific combinatorial preventive therapies.
Do fine motor impairments constitute a key feature of mild cognitive impairment? A systematic review and meta‐analysis
Authors: Lodha Neha , McCarthy Sarah
Published: December 2021

Background

Typical symptoms of mild cognitive impairment (MCI) include impairments in memory, executive function, and visuospatial skills. While impairments in these cognitive domains are highly apparent after MCI, impairments in motor domain are not so conspicuous. Converging evidence suggests that individuals with MCI demonstrate motor impairments in lower extremity such as reduced balance and impaired gait performance. However, the impact of MCI on upper extremity motor impairments is not well understood. In the current meta‐analysis, we examine whether fine motor impairments are a key feature of mild cognitive impairment.

Method

We performed a systematic search of electronic databases for articles published between 1990 and 2019. The meta‐analysis included studies that compared healthy older adults and adults with a clinical diagnosis of MCI on fine motor tasks such as handwriting, finger tapping, and hand dexterity.

Result

Ten studies with over 800 participants qualified for inclusion. Rigorous meta‐analytic techniques using random effects model, forest and funnels plots revealed a standardized mean difference effect of 0.48 (95% CI = 0.77 to 0.19, p=0.001). This moderate effect indicated deficits in fine motor control are a likely feature of MCI.

Conclusion

The cumulative evidence suggests that fine motor impairments are pervasive in MCI across a range of upper extremity motor tasks. Quantitative assessment of the decline in fine motor function in MCI may be promising approach to understand the changes in motor function that occur with the onset of Alzheimer’s disease and are clearly differentiated from normal aging‐related decline.
Digital speech‐based measures separate those with cognitive impairment from those without
Authors: Stegmann Gabriela M , Hahn Shira , Liss Julie , Berisha Visar , Mueller Kimberly D
Published: December 2021

Background

Measures of language have demonstrated value in the detection of cognitive decline. Here we automatically extracted speech (audio) and language (transcripts) features from Cookie Theft picture descriptions (BDAE) to develop two classification models separating healthy participants from those with mild cognitive impairment (MCI) and dementia.

Method

We used Dementia Bank and Wisconsin Registry for Alzheimer’s Prevention (WRAP) datasets and evaluated the first observation of Cookie Theft descriptions from 1011 healthy participants: 51 with MCI (based on MMSE scores) and 193 with dementia. From the samples, we automatically extracted metrics to fit two classification models, which: (1) separated healthy from MCI participants; and (2) separated healthy from dementia participants. To avoid overfitting and spurious patterns in the data, we used k‐fold cross‐validation, restricted the feature space to only clinically meaningful metrics, and used simple logistic regression models with no more than 5 predictors.

Result

The MCI classifier separated healthy and MCI groups (ROC AUC = .80; Figure 1). Predictors were: MATTR (proportion of unique words on 10‐word moving average; b = ‐16.0, z = ‐4.7, p‐val < .05); the ratio of pronouns to nouns (b = 28.1, p‐value < .05), and propositional density (b = ‐15.0, p‐value < .05). The dementia classifier separated healthy and dementia groups (ROC AUC = .89; Figure 2). The predictors were: parse tree height (sentence complexity; b = ‐1.3, p‐value < .05), mean length of word (surface form; b = ‐3.9, p‐val < .05), the proportion of relevant details correctly identified in a picture description (b = 10.7; p < .05), type‐to‐token ratio (proportion of unique words; b = ‐11.0; p‐value < .05), and the duration of pauses relative to the total speaking duration (b = 1.1, p‐value = .22).

Conclusion

Both classifiers separated groups with ROC AUC >= 0.80, with the dementia classifier performing better than MCI classifier. Features in the models were clinically meaningful and interpretable, and relate to vocabulary (MATTR, propositional density, TTR, mean word length), syntax (parse tree height), language processing (pause duration/speaking duration), and ability to convey relevant picture details.
Progression of neuropsychiatric symptoms in pre‐dementia GRN and C9orf72 mutation carriers
Authors: Chatterjee Atri , Lee Hyunwoo , Mackenzie Ian R , Wittenberg Dana , Rademakers Rosa , Hsiung Ging‐Yuek Robin
Published: December 2021

Background

Neuropsychiatric symptoms (NPS) are common in frontotemporal dementia (FTD) patients and may precede the clinical diagnosis of dementia. We hypothesized that GRN and C9orf72 mutation carriers have increased baseline burden and rates of progression of NPS compared to non‐carriers prior to the onset of dementia. To investigate, we examined a longitudinal cohort of FTD mutation carriers and non‐carrier family members.

Method

We analyzed data from 80 participants (21 C9orf72+ mutation carriers, 10 GRN+ mutation carriers, and 49 non‐carrier family members (NCs); mean±SD age in years: 47±13, 51±9, and 54±13 respectively) recruited through the University of British Columbia FTD Study. NPS were assessed annually with Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI) and Iowa Scale of Personality Change (ISPC) with a mean follow‐up of 5.8 years. For ISPC, we used both the “Change” (“Now” minus “Before”) and the “Now” measures. If a participant developed FTD during the follow‐up (N=2), we only analyzed observations collected before the conversion. We initially compared the baseline burden of NPI, FBI and ISPC adjusted for age and sex, among C9orf72+ carriers, GRN+ carriers and NCs. We then used random‐intercept mixed models to compare the rates of progression of NPS among genetic groups using total NPI, FBI, ISPC change and ISPC now scores as outcome measures and genetic status, sex, respective baseline scores, expected years to onset (EYO) and genetic group*EYO interaction term as dependent variables.

Result

There were no significant group differences in baseline demographic features or neuropsychiatric measures. In longitudinal assessments, NCs demonstrated minimal change in NPS measures. GRN+ carriers had significantly higher progression rates of NPI (p<0.0001) and ISPC “Now” (p=0.0004) compared to NCs. However, there were no significant differences in the NPS progression rates between C9orf72+ carriers and NCs.

Conclusion

Although there was no baseline difference in the burden of NPS among the genetic groups, GRN+ carriers had a faster progression of NPS compared to NCs prior to the onset of dementia. Future work is warranted to investigate the potential association between the NPS trajectories and structural/functional brain changes in FTD mutation carriers.
Plasma antioxidants and phospholipids and brain imaging biomarkers among non‐demented older adults
Authors: Koch Manja , Cronjé Héléne Toinét , Furtado Jeremy D , DeKosky Steven T , Fitzpatrick Annette L , Lopez Oscar L , Kuller Lewis H , Mukamal Ken J , Jensen Majken K
Published: December 2021

Background

Previous studies have linked dietary fatty acids and antioxidants to dementia risk and cognitive decline. The relationships of objective markers of fatty acid and antioxidant intakes with brain imaging biomarkers remain uncertain.

Method

We assessed the associations of antioxidants and phospholipids in plasma, collected in 2000‐2002, with brain amyloid‐ß deposition on PET scans and hippocampal and white matter lesion volume on MRIs in 2009 among 193 participants of the Ginkgo Evaluation of Memory Study who were free of clinical dementia. We used multivariable‐adjusted and inverse‐probability‐weighted robust linear regression models. We measured antioxidants by organic phase extraction followed by chromatographic analysis and individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection.

Result

A total of 20 participants (10%) had mild cognitive impairment at baseline and 134 participants (69%) used either multivitamin, vitamin A or β‐carotene, or vitamin E supplements (Table 1). Higher plasma retinol,α‐tocopherol, and total vitamin E were related to higher future amyloid‐ß deposition (Table 2). Higher α‐tocopherol and total vitamin E were also related to less white matter lesion volume. Carotenoids were not significantly related to any of the brain imaging biomarkers.

Higher concentrations of the saturated fatty acid margaric acid (17:0) were associated with more amyloid‐ß deposition (adjusted difference per 1 SD higher margaric acid: 0.10 standardized uptake value ratio; 95% CI: 0.02, 0.19) and smaller hippocampal volume (Table 3). In contrast, higher concentrations of the saturated fatty acid behenic acid (22:0) were associated with less white matter lesion volume. Higher oleic acid (18:1n‐9c, a major monounsaturated fatty acid), was related to more hippocampal volume. Higher concentrations of the n‐3 polyunsaturated fatty acid docosahexaenoic acid (22:6n‐3c) were associated with more amyloid‐ß deposition, while higher concentrations of linoleic acid (18:2n‐6cc; a major n‐6 polyunsaturated fatty acid) were associated with less amyloid‐ß deposition (adjusted difference per 1 SD higher linoleic acid: ‐0.10 standardized uptake value ratio; 95% CI:‐0.19, ‐0.01).

Conclusion

Specific antioxidants and phospholipids may be associated with brain imaging biomarkers, a hypothesis that requires formal testing in long‐term intervention studies and that represents a possible preventive intervention,
Gamma sensory stimulation in AD patients, a randomized controlled trial
Authors: Boasso Alyssa , Hempel Evan , Hajos Mihaly , Malchano Zach
Published: December 2021

Background

Preclinical studies in transgenic mice demonstrated that sub‐chronic 40 Hz gamma sensory stimulation effectively halted or reversed AD‐related pathology, increased synaptic density, improved cognitive function, and normalized circadian rhythm. The OVERTURE clinical trial (NCT03556280), funded by Cognito Therapeutics Inc., is a 2‐to‐1 randomized placebo‐controlled trial conducted to determine the safety, tolerability, and impact of gamma sensory stimulation on Alzheimer’s disease symptoms and biomarkers in humans.

Method

This US‐based 4‐site feasibility trial evaluated safety, tolerability, cognitive and functional symptoms, and biomarkers of target engagement, neurodegeneration, and AD pathology. The trial was conducted between June 2018 and July 2020. Participants age 50 and older with a diagnosis of mild‐to‐moderate Alzheimer’s disease (MMSE 14‐26) were randomly assigned (2‐to‐1: active‐control) to receive 6 months of 1‐hour daily 40 Hz audio‐visual or sham stimulation. Therapy was self‐administered at home with the help of a care partner, and patients, care partners, and assessment raters were blinded to group assignment.

Result

A total of 135 subjects were screened, of whom 74 (55%) were randomized and 53 completed (72%). Safety was evaluated by MRI, a suicidality scale, and physical and neurological exams at baseline, 12‐, and 24‐weeks, and monthly assessments of adverse events. Tolerability was measured by device use data, daily diary, and user experience interviews. Symptomatic changes were assessed daily via a diary, monthly via ADL, QOL, and care partner burden scales, and quarterly via the ADAS‐Cog14, NPI, CDR, and Clock Drawing Test, and the MMSE at baseline and week 24. Biomarkers, including Amyloid PET, Plasma amyloid‐β1‐42, ptau217, GFAP, and Neurofilament light, EEG, and volumetric MRI were examined at 3‐month increments. APOE status was characterized at baseline. Actigraphy devices were worn continuously throughout the trial to assess daytime and nighttime activity.

Conclusion

This feasibility trial is designed to demonstrate gamma sensory stimulation’s safety and tolerability, feasibility of daily in‐home use for AD patients, possible functional and symptomatic benefits, and both standard and novel biomarkers of AD pathology and neurodegenerative decline. Data will help inform the design of a larger study, including the development of patient selection algorithms, novel outcome measures and evidence of clinical efficacy.
Cognition and elevated blood pressure in community‐dwelling older adults with subjective cognitive decline: A cross‐sectional exploratory study
Authors: Silva Narlon Cassio Boa Sorte , Gill Dawn P , Owen Adrian M , Petrella Robert J
Published: December 2021

Background

The impact of blood pressure (BP) on cognition in older adults remains equivocal. We investigated the relationships between cognition (global and domain‐specific) and ambulatory blood pressure in older adults with subjective cognitive decline (SCD).

Method

We conducted a cross‐sectional exploratory analysis of data collected from 230 community‐dwelling older adults (age mean [SD]: 69.3 [7.2], 57.8% female) with self‐reported SCD. We assessed global cognitive functioning, memory, concentration, planning, and reasoning using the computer‐based Cambridge Brain Sciences battery. Assessment of 24‐hour BP was performed using an automated, ambulatory BP monitoring device (SpacelabsModel 90207). Ambulatory BP was measured every 30 minutes between 6am and 10pm, and hourly between 10pm and 6am. We employed hierarchical regression models to examine associations between 24‐hour systolic BP and cognition. Further, we conducted ANCOVAs exploring dose‐response relationships by stratifying our sample using clinical cut‐offs for normal (≤120 mmHg, n = 52), preclinical (121 to 135 mmHg, n = 119), and hypertensive (>135 mmHg, n = 59) BP. All analyses were adjusted for age, sex, MoCA, years of education, and diagnosis of diabetes and/or hypertension.

Result

In our sample, 24‐hour systolic BP was negatively associated with reasoning scores (unstandardized B [95% CI] = ‐0.008 [‐0.016 to ‐0.001], R2Change = 0.016, p = 0.028). The dose‐response analysis revealed a main group effect (F[2,221] = 3.6, p = 0.029, ηp2= 0.032), with post‐hocpairwise comparisons indicating that individuals with normal BP levels outperformed those with preclinical (mean difference [95% CI] = 0.280 [0.068 to 0.492], p = 0.010), and hypertensive (0.265 [0.021 to 0.508], p = 0.034) BP levels. The tasks adopted to assess reasoning targeted specifically grammatical reasoning, conflict resolution, and deductive reasoning, which fall under the overall scope of executive function tasks. No other relevant associations or interactions were found.

Conclusion

In this sample of older adults with SCD, 24‐hour systolic BP levels above optimal clinical parameters were negatively associated with cognitive reasoning performance. Future research should investigate whether interventions that target BP control could mitigate impairment on reasoning performance.
Pilot clinical trial: Electronic Memory and Management Aid/smart home partnership increases aid use at three‐month follow‐up in individuals with mild cognitive impairment
Authors: Schmitter‐Edgecombe Maureen , Luna Catherine , Brown Katelyn , Cunningham Reanne , Sumida Catherine , Holder Lawrence , Cook Diane
Published: December 2021

Background

Cognitive changes experienced by individuals with mild cognitive impairment (MCI) can impact everyday functioning and lower self‐confidence. The Electronic Memory and Management Aid (EMMA) is a senior‐friendly iOS tablet application designed to support everyday activities. To examine whether learning and sustained app use could be improved, we partnered EMMA with a smart home that delivered activity‐aware prompting.

Method

In a pilot trial, participants with MCI were randomly assigned to learn to use EMMA with (N = 14; M age = 74) or without (N = 15; M age = 71) smart home prompting. Training consisted of 5‐6 (two‐hour) structured sessions delivered in a 4‐week timeframe by a clinician in the participant’s home (half turned into smart homes). Real‐time data were collected on participant use of EMMA, with metrics averaged across these intervals: weeks 1‐2 (early‐training), 5‐6 (post‐training), 10‐11 (prompting turned off) and 15‐16 (follow‐up; prompting back on). Baseline, post‐training and follow‐up clinical data (coping, life satisfaction, everyday functioning) were also compared.

Result

No group differences emerged in age, education, estimated pre‐morbid ability (High Average), memory (Low Average) or executive functioning (Average). Participants in the partnered condition engaged daily with EMMA more times post‐training (M = 5.0) compared to the control (not‐partnered) condition (M = 2.0). Participants in the partnered condition also maintained a high level of engagement with EMMA even after prompting stopped (M = 5.0, M = 3.8 at follow‐up). This contrasted with significantly lowered use (M = 1.2 and M = 0.6, respectively) in the control condition. Similar patterns were found for usage rates of app components (event scheduling, calendar use) and advanced features (searches, alarms, pictures). Clinical data showed self‐reported positive changes in coping and life satisfaction that did not differ by condition; no significant changes were self‐reported in everyday functioning.

Conclusion

Partnering EMMA with a smart home that cued app use at opportune times and after periods of non‐use improved habit formation and earlier mastery of the tool. Once a habit was established, turning off the prompts did not impact use of the EMMA app, demonstrating the importance of habit formation and early mastery to sustain tool use.
Sex differences in the association between plasma and CSF p‐tau
Authors: Tsiknia Amaryllis A. , Sundermann Erin E. , Galasko Doug R. , Andrews Murray , Banks Sarah J.
Published: December 2021

Background

Mounting evidence from cerebrospinal fluid (CSF) studies suggests that women on the AD spectrum have higher levels of pathological tau in the CSF than men. Several studies suggest that plasma tau phosphorylated at threonine 181 (p‐tau181) is strongly associated with CSF biomarkers of tau and may constitute an accessible and informative biomarker of AD. However, sex stratified analyses of plasma and CSF tau associations are lacking. Here, we examine the relationship between plasma and CSF p‐tau181 separately in 476 men and 422 women on the AD continuum.

Method

Our sample included 280 cognitively normal (CN), 453 mild cognitively impaired (MCI) and 165 AD dementia participants from ADNI with concurrent plasma p‐tau181 and CSF p‐tau181 determined by the Roche Elecsys assay. We stratified our sample by sex, to examine plasma p‐tau181 differences between diagnostic groups separately in men and women. Furthermore, we examined the association between plasma and CSF p‐tau181 separately in each sex, within each diagnostic group. Models were first adjusted for APOE ε4 status and age, and then additionally adjusted for amyloid status.

Result

Participants with AD dementia had higher levels of plasma p‐tau181 than controls in both sexes, while MCIs had higher plasma p‐tau than normal controls only among women. In the CN group, higher plasma p‐tau181 correlated with higher CSF p‐tau181 in women (β=0.18, P=0.025), but not men (β=0.025, P=0.75). In the MCI group, higher plasma p‐tau181 was associated with higher CSF p‐tau181 in both men (β=0.22, P=0.001) and women (β=0.56, P<0.001), but the association was significantly stronger in women (z=2.47, P=0.007). In the AD dementia group, higher plasma p‐tau181 was associated with higher CSF p‐tau181 in men (β=0.6, P=0.001) but not women (β=0.33, P=0.19). Our result

Conclusion

These findings suggest that in women, associations between p‐tau181 levels in plasma and CSF are strongest early in the disease and weaker at later stages, while the opposite is true for men. Sex should be taken into account when interpreting plasma tau findings, and further investigation into sex‐specific relationships between plasma tau and CSF tau are warranted.
The effects of exercise on blood pressure and cognitive function in older adults with hypertension and subjective cognitive decline
Authors: Silva Narlon Cassio Boa Sorte , Petrella Andrea FM , Gill Dawn P , Owen Adrian M , Petrella Robert J
Published: December 2021

Background

The impact of exercise on cognition in older adults with hypertension and subjective cognitive decline (SCD) is unclear. In this study, we examined the influence of high‐intensity interval training (HIIT) combined with mind‐motor training on cognition and systolic blood pressure (BP) in older adults with hypertension and SCD.

Method

We randomized 128 community‐dwelling older adults (age mean [SD]: 71.1 [6.7], 47.7% females) with history of hypertension and SCD to either HIIT or a moderate‐intensity continuous training (MCT) group. Both groups received 15 minutes of mind‐motor training followed by 45 minutes of either HIIT or MCT. Participants exercised in total 60 minutes/day, 3 days/week for 6 months. We assessed changes in global cognitive functioning (GCF), Trail‐Making Test (TMT), systolic and diastolic BP, and cardiorespiratory fitness, using linear mixed regression models for repeated measurements. We also determined whether changes in cardiorespiratory fitness would be associated with changes in cognition and BP using hierarchical regression models adjusting for age and years of education.

Result

After 6 months, participants in both groups had improved cardiorespiratory fitness (F[1, 69]= 34.795, p < 0.001), TMT A (F[1, 81.51]= 26.871, p < 0.001) and B (F[1, 79.49]= 23.107, p < 0.001). Both groups also had improved diastolic BP (F[1, 87.32] = 4.392, p = 0.039), with greatest effect within the HIIT group (estimated mean change [95% CI]: ‐2.64 mmHg, [‐4.79 to ‐0.48], p = 0.017),but no between‐group differences were noted. Improvement in cardiorespiratory fitness across groups was associated with improved TMT A (unstandardized B = 0.21, p = 0.044), but not TMT B (unstandardized B = 0.002, p = 0.84) or diastolic BP (unstandardized B = ‐0.070, p = 0.58). There were no within‐ or between‐group differences in GCF or systolic BP.

Conclusion

Exercise of high‐ or moderate‐intensity seems to impart modest but positive effects on vascular health and lower‐level cognitive processing. The association between improvements in cardiorespiratory fitness and lower‐level cognition suggest a mechanistic effect. Future research in older adults with hypertension should consider modulating other aspects of exercise training or employ other exercise modalities to benefit cognition.
Machine learning algorithm selects transcripts in blood to distinguish Alzheimer’s disease and other neurodegenerative diseases
Authors: Huseby Carol J. , Delvaux Elaine , Brokaw Danielle , Coleman Paul D.
Published: December 2021

Background

Clinical diagnosis of neurodegenerative diseases is notoriously inaccurate and current methods are often expensive, time‐consuming, or invasive. Simple inexpensive and noninvasive methods of diagnosis could provide valuable support for clinicians when combined with cognitive assessment scores thereby reducing health care costs by ruling out or streamlining additional tests such as imaging. Biological processes leading to neuropathology are reflected in both the central nervous system and vascular peripheral system and progress silently for many years. Because Alzheimer’s disease (AD) symptoms often overlap with common disorders that may be treatable or reversible, an accurate diagnosis at the earliest time is crucial. A blood‐based screen to distinguish and classify neurodegenerative diseases is especially interesting having low cost, minimal invasiveness, and accessibility to almost any world clinic. Additionally, an inexpensive blood panel could also monitor disease progression, for example, marking the advancement beyond mild cognitive impairment (MCI).

Method

The study of blood‐based changes in mRNA gene expression presents a good strategy for differentiating patients of any neurodegenerative disease regardless of the proteins or their post‐translational modifications occurring in disease. Information about features selected for the classification may also guide insight into possible treatment strategies. Using existing public datasets, we developed a machine learning algorithm for application on transcripts present in blood.

Result

Our machine learning algorithm generated small sets of transcripts which distinguish a number of neurodegenerative diseases with high sensitivity and specificity.

Conclusion

Neurodegenerative diseases such as AD are associated with changes in specific molecular pathways and signatures. Using RNA expression as blood biomarkers can also provide information for a pathophysiological relationship with disease and gives us the advantage of using the vast knowledge of gene expression to not only predict disease but also analyze the pathways involved. Our chosen transcripts reveal that neurodegenerative diseases have common themes which after removal bare the unique transcripts of each disease.
Assessing the needs of Black/African American dementia caregivers seeking emotional support
Authors: Fields Julie A , Forsberg Leah K , Knutson Matthew , Seifert Sara J , Farah‐Milller Emily A , Melius Jodi L , Miller Joel K , Knopman David S , Boeve Bradley F , Petersen Ronald C , Kramer Kevin M , Lunde Angela M
Published: December 2021

Background

Black/African Americans (B/AA) are nearly twice as likely as White/European Americans (W/EA) to have Alzheimer’s or other dementias and are more likely to provide care for persons with dementia (PwD). Evidence indicates that B/AA desire having someone to talk with who understands their caregiving challenges, yet are less likely than W/EA to ask for support. Further, community resources supporting caregivers’ ability to maintain health and well‐being developed with input from B/AA are lacking. We aimed to determine how a technology‐assisted caregiver matching service designed with user input could address diverse caregiver needs.

Methods

For this Phase I project, 32 caregivers of PwD (31% B/AA) participated in semi‐structured focus groups and completed surveys to provide input regarding characteristics deemed valuable in someone they would choose to be connected with for emotional support. Through an iterative process as new information emerged, a web‐based prototype and matching algorithm were developed.

Results

Age and sex distribution were similar between B/AA and W/EA (71 and 68 yrs; 90% and 86%, respectively). W/EA were most likely caring for a spouse/significant other (73%) whereas B/AA were caring for spouse/significant other (30%), a parent (30%;18% W/EA), a sibling (10%; 0% W/EA), or other (30%; 9%W/EA). Level of emotional support was rated “poor” (50% B/AA, 18% W/EA); “average” (0% B/AA, 14% W/EA); “good” (40% B/AA, 41% W/EA); and “excellent” (10%, 27% W/EA). Characteristics B/AA deemed “very important” or “absolutely essential” for a supportive match included living in close proximity, same ethnicity, similar lifestyle, and common values. Alternatively, W/EA selected similar age, living in close proximity, same sex, similar lifestyle, common values and interests, having the same caregiving relationship, and having the same diagnosis in their PwD (see chart).

Conclusion

In this cohort, B/AA reported poorer levels of emotional support than W/EA. B/AA were equally likely to be supporting a spouse/significant other as a parent or other acquaintance, whereas W/EA provided support primarily for a spouse/significant other. Characteristics B/AA and W/EA consider important in a supportive caregiver match show important differences that should be considered when optimizing caregiving resources. Phase II will explore further in a much larger sample.
rPOP: Robust PET‐only processing and quantification of community‐acquired amyloid‐PET from the IDEAS Study
Authors: Iaccarino Leonardo , La Joie Renaud , Koeppe Robert , Siegel Barry A , Hillner Bruce E , Gatsonis Constantine , Whitmer Rachel A. , Carrillo Maria C. , Apgar Charles , Camacho Monica R , Nosheny Rachel L , Weiner Mike W. , Rabinovici Gil D. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

Background

The Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) Study collected over 15,000 community‐acquired amyloid‐PET scans, without structural MRI and with different acquisition times, tracers and scanners. Here we describe and validate rPOP (robust PET‐Only Processing), a pipeline for 18F‐Florbetapir (FBP), 18F‐Florbetaben (FBB) and 18F‐Flutemetamol (FLUTE) scans collected in IDEAS.

Method

Each image undergoes automatic origin reset to center of mass, spatial normalization based on weighted PET templates (with SPM12) and data‐driven differential smoothing (with AFNI). We received n=740 (514 FBP, 182 FBB, 44 FLUTE) amyloid‐PET scans from the IDEAS–Brain Health Registry substudy (IDEAS‐BHR), with amyloid‐PET local visual reads available for N=663 scans. We performed semi‐quantification via rPOP and estimated neocortical Centiloids after tracer‐specific calibrations using the GAAIN VOIs with whole cerebellum reference. Centiloids were calculated for clinical groups (MCI or dementia), to compare rPOP‐based amyloid‐status (centiloids≥24.4) with visual reads. The pipeline was validated with n=1518 ADNI scans (n=1249 FBP, n=269 FBB), using MRI‐based amyloid‐status as a reference and testing the associations between rPOP‐ and MRI‐based centiloids.

Result

rPOP successfully processed N=2233/2258 (98.9%) scans in the first pass, with N=24/25 warping‐related failures rescued with a manual reorientation and origin reset prior to warping. In IDEAS‐BHR, we observed the expected centiloids distribution (Figure 1A‐B) both according to visual reads and also stratifying by clinical stage amyloid‐negative, i.e. mean±sd Centiloids MCI/Dementia: 2±23/‐5±27; amyloid‐positive: MCI/Dementia: 65±42/80±37. There was high concordance (Table 1) between rPOP‐based amyloid status and both local visual reads (IDEAS‐BHR, Cohen’s k=0.72 [0.7‐0.74], ∼86% concordance). Very high concordance was also observed in the ADNI dataset (k=0.88 [0.87‐0.89], ∼94% concordance), with rPOP‐ and MRI‐based Centiloids being strongly linearly associated (R2:0.95, p<0.001), with a tighter relationship in images with better resolution (β= ‐0.016, p<0.001).

Conclusion

With rPOP, we successfully derived Centiloids quantification from heterogeneous IDEAS amyloid‐PET scans and validated the pipeline with ADNI scans acquired in a research setting. These data show that community‐acquired amyloid‐PET scans can be successfully analyzed, enabling joint efforts by clinical sites and research centers.
Association of neighborhood socioeconomic disadvantage and cognitive decline
Authors: Marsh Karyn , Shao Yongzhao , Zhang Yian , Masurkar Arjun V , Vedvyas Alok , Chodosh Joshua
Published: December 2021

Background

There is increasing emphasis on research recruitment of persons of color to understand the influence of race/ethnicity on Alzheimer’s disease (AD) and AD‐related dementia (ADRD) risk. Normal persons with subjective cognitive decline (SCD) are considered at risk for future decline as SCD is thought to be a preclinical stage of AD/ADRD. Yet the validity of SCD across racial and ethnic groups is unclear. Race/ethnicity‐related conditions such as socio‐economic disadvantage, neighborhood segregation, and poor housing quality (neighborhood deprivation) are important factors in stress, discrimination and other social determinants of health and may provide more in‐depth explanations for SCD than race/ethnicity alone.

Method

We examined the role of neighborhood deprivation and compared this to the role of race/ethnicity in SCD using a validated instrument, the Brief Cognitive Rating Scale (BCRS). Using the Area Deprivation Index (ADI), we cross‐sectionally examined the relationship between neighborhood characteristics and SCD in a racially and ethnically diverse group of community‐residing older adults in New York City. For those having available addresses, we used data from participants with normal cognition in the NYU Alzheimer’s Disease Research Center (n=313) and conducted multivariable logistic regressions, comparing two models with the BCRS as our outcome: using the ADI without race/ethnicity and then with race/ethnicity, both adjusting for age, sex, education (years).

Result

Participant mean age was 72.8.0 ± 7.4 years; mean education was 16.3± 3.1 years. Seventy‐six percent of the cohort was female (n=232); 12.1% (n= 38) reported as Hispanic, 73.5% (n=230) non‐Hispanic (NH) White; 13.4% reported as NH Black or African‐American (n=42); and 3 were other. In multivariable logistic regressions of BCRS domain‐specific analysis, ADI was a significant predictor of BCRS‐measured SCD even when race/ethnicity was included as a covariate (p<0.05), suggesting independent influence of neighborhood deprivation.

Conclusion

Neighborhood characteristics may play an influential role in SCD regardless of race/ethnicity and thus are likely important risk factors for AD/ADRD. If larger and more diverse studies generate similar findings, neighborhood investment and recruitment goals for AD/ADRD studies will require more focus on neighborhoods with greater deprivation.
Comparison of plasma and CSF biomarkers across ethnoracial groups in ADNI
Authors: Windon Charles , Iaccarino Leonardo , Allen Isabel Elaine , Boxer Adam L. , Byrd Desiree , Okonkwo Ozioma C. , Weiner Mike W. , Mindt Monica Rivera , Rabinovici Gil D.
Published: December 2021

Background

Differences in CSF and plasma Alzheimer’s disease biomarkers between African Americans (AA), Latinos (LA), and non‐Hispanic Whites (NHW) have been reported. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) may offer insights into ethnoracial biomarker differences important for understanding disease trajectory variations among diverse populations.

Method

We queried the ADNI database for all participants with available plasma pTau181 and NfL (Simoa) and linked CSF biomarkers within 1 year of blood draw (Aβ42, pTau181, T‐tau, Elecsys). Baseline data for 47 AA and 43 LA with plasma biomarkers were matched to separate groups of NHW (1:3 nearest neighbor matching on propensity score), considering age, sex, education, CDR, APOE ε4 alleles and family history of dementia (Table 1). Cross‐sectional analyses compared biomarker levels between matched cohorts without (non‐parametric Mann‐Whitney U‐test) and with adjustment for demographics, clinical, biomarker, and medical characteristics (multi‐linear regression). Statistical threshold was set at two‐tailed p<0.05.

Result

Unadjusted comparisons between AA and NHW revealed no significant differences in plasma NfL [29.3 (IQR: 21.6‐42.5) vs 35.5 (27.0‐49.6), p=.12], plasma pTau181 [14.5 (9.4‐22.9) vs 15.5 (10.1‐22.8), p=.83], CSF Aβ42 [933.1 (649.5‐1590.8) vs 926.7 (677.7‐1697.8), p=.83], CSF T‐tau [214.6 (152.4‐290.7) vs 251.9 (194.5‐351.4), p=.17] or CSF pTau181 [19.6 (14.4‐27.3) vs 22.7 (17.0‐33.3), p=.32] (Fig. 1a‐b). No significant differences were identified in any of the biomarkers after adjustment for relevant covariates. Unadjusted comparisons between LA and NHW revealed no significant differences in plasma NfL [36.7 (24.4‐50.4) vs 35.6 (25.6‐47.1), p=1], plasma pTau181 [18.0 (11.3‐25.0) vs 15.7 (10.9‐23.4), p=.81], or CSF Aβ42 [852.7 (787.1‐1213.0) vs 951.6 (651.1‐1530.5), p=1]. A trend towards lower CSF T‐Tau [216.5 (147.1‐270.5) vs 257.2 (197.2‐360.9), p=.076] and CSF pTau181 [19.4 (13.6‐27.9) vs 24.7 (17.5‐33.4), p=.076] in LA was observed (Fig. 2a‐b). After adjustment for covariates, LA were found to have significantly lower levels of CSF T‐tau (β=0.154, p<.05) and CSF pTau181 (β=0.164, p<.05), while differences in plasma markers were not significant.

Conclusion

No significant biomarker differences between AA and NHW were observed. Lower CSF pTau181 and CSF T‐Tau in LA compared to NHW after covariate adjustment may represent subtle differences driven by biological factors or unmeasured sociocultural determinants (income, occupation, neighborhood environment); larger studies are needed.
Study design of gamma sensory stimulation at multiple dose levels in MCI patients
Authors: Hempel Evan , Hajos Mihaly , Williams Martin , Malchano Zach
Published: December 2021

Background

Non‐invasive gamma sensory stimulation has been demonstrated to have beneficial effects on the hallmarks of AD pathophysiology in transgenic mouse models of AD. The Etude clinical trial is a translational clinical study examining dose‐ranging, safety, tolerability, and potential benefits of gamma sensory stimulation as a novel, non‐invasive treatment for Alzheimer’s disease.

Method

Two cohorts were planned to evaluate tolerability, safety and therapeutic effects by dose with results from the first cohort guiding dose escalation for the second. In the first cohort, 10 subjects were randomized to receive once or twice daily therapy for 12 months. When therapy was completed, safety and tolerability, as well as symptom progression, was evaluated and the second cohort was initiated; 3 subjects were enrolled at twice daily 1‐hour therapy for 12 months. All subjects received 40Hz audio‐visual therapy (Cognito Therapeutics, Cambridge MA) at home with assistance from a caregiver. Key criteria for subject enrolment were: adults 50 years and older, MMSE 24‐30, MCI due to AD diagnosis per NIA‐AA criteria, and an amyloid‐positive PET scan. Subjects were excluded for history of seizure, memantine use, alternate causes of cognitive impairment or MRI findings that prevented PET SUVr processing. Subjects were followed for safety, tolerability and changes to symptoms via clinical assessments, phone assessments, and electronic treatment diary. Tolerability was measured by device use, including treatment diary and device‐reported data, Zarit burden interview, and structured interviews at pre‐planned time points. Clinical progression was measured using MMSE, ADAS‐Cog, CDR, NPI, Clock‐Drawing Test, ADL, and QOL. Quantitative EEG, actigraphy, amyloid PET, volumetric MR are evaluated at regular intervals throughout the study as biomarkers.

Result

Thirty‐seven subjects were screened and 13 enrolled, of whom none terminated early and 3 are still active. An open‐label extension year was added to the protocol and 70% of subjects chose to re‐enroll. Review of MR imaging noted no ARIA and there were no unexpected related serious adverse events. Results on symptomatic and biomarker changes are being analyzed.

Conclusion

We describe the design and methods of a translational dosing study which evaluates a novel therapeutic modality. All evaluated dosing regiments were safe and well‐tolerated by subjects.
Associations in Alzheimer’s disease between intracranial vascular metrics from 4D‐flow MRI and β‐amyloid and tau PET
Authors: Rivera‐Rivera Leonardo A , Cody Karly Alex , Betthauser Tobey J , Cadman Robert V , Reher Thomas , Rowley Howard A. , Carlsson Cynthia M , Eisenmenger Laura , Johnson Sterling C. , Johnson Kevin M
Published: December 2021

Background

Cerebrovascular disease (CVD), has been linked with dementia stages of Alzheimer’s disease (AD); however, the question of whether CVD is associated with underlying AD pathophysiology remains unresolved. This work investigated the relationship between advanced MRI based cerebrovascular markers with AD biomarkers of β‐amyloid deposition and neurofibrillary tau tangles in subjects spanning the AD clinical spectrum.

Method

Subjects: Study groups are summarized in figure 1. MRI: Whole brain 4D‐Flow data were acquired on a 3.0T system using a 32‐channel head coil. From 4D‐Flow images, intracranial blood flow, trans‐capillary pulse wave delay, and low frequency oscillations (LFOs) were estimated. Trans‐capillary pulse wave delay was defined as the cardiac pulse wave transit time from intracranial arteries‐to‐capillaries‐to‐veins and was measured from cardiac wave time‐to‐upstroke differences in arteries and veins. White matter hyperintensity (WMH) lesion volumes were segmented from T2‐FLAIR images using the Lesion Segmentation Toolbox in SPM12. PET: Four groups were established based on clinical diagnosis and biomarker positivity. Subjects were classified as cognitively normal (CN) or impaired (IM) (MCI or dementia) based on a clinical consensus review. Amyloid (A) (+/‐) was determined using a previously established global PiB DVR threshold >1.19 and tau (T) (+/‐) was determined using a previously established entorhinal cortex MK‐6240 SUVR threshold >1.27. Pairwise statistical differences were assessed using ANOVA followed by post‐hoc analysis (P<0.05 significance).

Result

Trans‐capillary pulse wave delay was significantly longer in controls (A‐/T‐/CN) when compared with AD biomarker confirmed groups (fig 2 b) (P<0.001). Low frequency flow range and LFOs were significantly lower and diminished in A+T+ groups both cognitively normal and impaired (fig 3 P<0.001; fig 4 P=0.027, P=0.046, P=0.046). Linear regression analysis showed a weak correlation between trans‐capillary pulse wave delay and PiB and MK‐6240 (R2=0.12, R2=0.04), and between LFOs and PiB and MK‐6240 (R2=0.07, R2=0.03) (fig 5). No significant AT biomarker group differences were observed across other modalities such as traditional cardiovascular and cerebrovascular metrics, including WMH lesion volumes (fig 1).

Conclusion

Although more traditional measures of CVD were not related to biomarker groups, 4D‐Flow MRI based vascular markers suggest significant intracranial vascular stiffness and reduced autoregulation‐related vasomotion in AD biomarker positive subjects during preclinical AD.