bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting future regional tau accumulation in preclinical Alzheimer’s disease
Authors: Giorgio Joseph , Jagust William J. , Baker Suzanne L. , Landau Susan M. , Tino Peter , Kourtzi Zoe
Published: December 2020

Background

Current models of AD pathogenesis hypothesise that b‐amyloid induces downstream tau deposition leading to cognitive decline. Here, we use machine learning with baseline data to predict dynamic changes in cortical tau in preclinical AD populations.

Methods

Using individuals from the ADNI (n=307) we train a machine learning algorithm that derives a continuous index using baseline medial temporal atrophy, amyloid‐PET, and APOE genotype. The index is generated to discriminate between cognitively normal (CN) individuals who remained normal over ≥ 3 years (n=145) (34 amyloid positive at baseline) and non‐demented progressing (NDP) individuals (CN/MCI at baseline) who developed dementia (n=162) (135 amyloid positive at baseline) The index combines information from multivariate data to maximise between class separation and minimise within class variability. We test the hypothesis that this index is predictive of future tau accumulation in two out‐of‐sample cohorts. In a separate ADNI cohort (ADNI‐3; 72CN/43MCI) with longitudinal flortaucipir PET(FTP) scans we derived the index and related it to future tau accumulation (FTP‐PET slope over time in Desikan‐Killiany ROIs normalised to eroded subcortical white matter) for individuals classified as NDP. Next, for cognitively normal individuals from the Berkeley Aging Cohort Study (BACS; n=56) we derived the index and tested predictions of regional future rate of tau accumulation for individuals classified as NDP.

Results

The algorithm using baseline data separated CN from NDP individuals with high accuracy (86.4%). Testing on ADNI‐3 individuals classified 54/115 individuals as NDP. These NDP individuals accumulated global cortical tau 2.8 times faster than non‐NDP individuals (Figure 1); for NDP individuals this index also predicted individual variability in regional future tau accumulation (Figure 2a). For BACS participants classified as NDP (n=23), the individualised regional predictions explain up to 38.5% of the observed variance in longitudinal tau accumulation in the temporal cortex (mean=27%) and 32% of the variance in superior and medial regions of the posterior parietal cortex (mean=23%) (Figure 2b).

Conclusion

Machine learning derived a continuous prognostic index from baseline data that was capable of predicting changes in regional tau accumulation in both MCI and cognitively normal people. This could have clinical applications in developing clinical trials or furthering our understanding of AD pathophysiological mechanisms.
Associations of nutritional parameters with clinical progression in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease: The NUDAD project
Authors: Doorduijn Astrid S , de Leeuw Francisca A , de van der Schueren Marian , van de Rest Ondine , Hendriksen Heleen MA , Teunissen Charlotte E , Scheltens Philip , Visser Marjolein , van Der Flier Wiesje
Published: December 2020

Background

Poorer nutritional status is more often observed in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia compared to patients with subjective cognitive decline (SCD), but it is not known whether nutritional status contributes to clinical progression. Therefore, we investigated longitudinal associations of body mass index (BMI), fat‐free mass (FFM), modified Mini Nutritional Assessment (MNA) score and diet quality with clinical progression in a memory clinic cohort.

Method

We included 219 patients with SCD (age 61±8 years), 135 with MCI (66±8 years) and 197 with AD dementia (67±8 years), with a mean follow‐up of 2±1 years. Nutritional parameters at baseline were transformed into z‐scores. Progression was operationalized as presence of at least one of the following: 1) in SCD, progression to MCI or dementia; in MCI, progression to dementia; in AD dementia, an increase of ≥ 1 point on Clinical Dementia Rating scale; 2) passed away or admitted to a nursing home; 3) self‐reported progression of cognitive symptoms. We used age and sex adjusted Cox proportional hazard models in the total sample and stratified for baseline diagnosis. We performed a sensitivity analysis in amyloid positive patients to determine specificity of results for AD.

Result

Progression was observed in 25 (11%) patients with SCD, 45 (33%) MCI and 100 (51%) AD dementia. A lower modified MNA score was associated with a higher risk of clinical progression in the total sample (Table 1). Stratification revealed that the association was mainly attributable to patients with MCI and AD dementia. Lower BMI, FFM and diet quality score was associated with a higher risk of clinical progression in the total sample. After stratification on baseline diagnosis, significance was lost. In amyloid positive patients, a lower modified MNA score was associated with a higher risk of clinical progression, but there were no significant associations for BMI, FFM and diet quality with clinical progression.

Conclusion

Poorer nutritional status is associated with a higher risk of clinical progression, especially in patients with MCI and AD dementia. This observation provides support for future studies investigating whether improving nutritional status contributes to slowing down clinical progression.
Evaluation of the novel 18F‐labeled PET tracer SMBT‐1 for imaging astrogliosis in healthy elderly controls and A+/T+/(N+) Alzheimer's disease patients
Authors: Villemagne Victor LL , Harada Ryuichi , Dore Vincent , Furumoto Shozo , Mulligan Rachel S , Kudo Yukitsuka , Burnham Samantha C , Krishnadas Natasha , Huang Kun , Yanai Kazuhiko , Rowe Christopher C , Okamura Nobuyuki
Published: December 2020

Background

Neuroinflammatory changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer’s diseases (AD). Reactive astrocytes overexpress monoamine oxidase‐B (MAO‐B) in the outer mitochondrial membrane. For imaging astrogliosis in the human brain, we developed the novel MAO‐B PET tracer named 18F‐SMBT‐1. We aimed to investigate the binding properties of 18F‐SMBT‐1 in healthy elderly controls and AD patients.

Methods

After in silico preclinical evaluation were performed for the assessment of binding affinity and selectivity of 18F‐SMBT‐1, 9 participants, 5 healthy elderly controls (3F/2M, 78.5±6.0 yrs, 3 A‐/T‐/(N‐) and 2 A+/T‐/(N‐)) and 4 A+/T+/(N+) AD patients (3F/1M, 76.8±1.4 yrs), underwent 18F‐SMBT‐1 PET, amyloid PET with 18F‐NAV4694, tau PET with either 18F‐MK6240 (n=7) or 18F‐PI2620 (n=2), and 3D‐MPRAGE MRI. While Ab burden was expressed in Centiloids, tau tissue ratios were generated using the cerebellar cortex as reference region. 18F‐SMBT‐1 studies were expressed as SUV or as tissue ratios using the cerebellar white matter as reference region. To ascertain 18F‐SMBT‐1 selective binding to MAO‐B, participants underwent a second 18F‐SMBT‐1 scan after receiving 5mg selegiline twice daily for 5 days.

Results

SMBT‐1 showed strong and reversible binding to MAO‐B, and low binding affinity to other enzymes, receptors and misfolded proteins such as amyloid‐β and tau.18F‐SMBT‐1 yielded high contrast images at 60‐90 min post injection, with high tracer retention in basal ganglia, intermediate in neocortical regions, and lowest in cerebellum which tightly follows the known regional brain distribution of MAO‐B (R2=0.82). In AD patients, 18F‐SMBT‐1 retention was significantly higher in parahippocampus, fusiform and inferior temporal gyrus. More than 85% of 18F‐SMBT‐1 signal was blocked and no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO‐B.

Conclusions

18F‐SMBT‐1 is the highly selective MAO‐B tracer, which will enable the assessment of astrogliosis in the human brain. The confirmation of these preliminary findings with 18F‐SMBT‐1 will require examination of a much larger series, including participants with MCI and prodromal AD.
AB42 and polyamines: Elucidating a potential mechanism of amyloid‐mediated apoptosis and aggregation
Authors: Sandberg Alexandra A. , Johnson Austin , Fudge Dylan , Melgar Stephanie , Hicks Carrie , Patterson David , Vacano Guido , Margittai Martin , Weismiller Hilary , Harvey Sebastian , Hernandez Luis , Caviedes Pablo , Ledreux Aurélie , Qin Yan , Granholm Ann‐Charlotte , Linseman Daniel , Paredes Daniel
Published: December 2020

Background

The dysfunctional accumulation of amyloid beta (Aβ) plaques in neuronal cells is widely regarded as a hallmark sign of Alzheimer’s disease (AD). However, the mechanisms by which Aβ causes the rampant apoptosis that leads to the characteristic memory loss and dementia observed in AD patients are much less understood. In this study, we investigated the regulatory relationship between Aβ42, a particularly toxic member of the Aβ peptide family, and polyamines (PA), a ubiquitous class of molecules associated with cell growth, proliferation, and immune response. Increasing evidence has suggested that the PA pathway is changed in AD. For example, increased levels of enzymes in the PA synthesis pathway and altered PA metabolomics have been found in the AD brain. Here, we sought to investigate the relationship between PA synthesis and disease pathogenesis, specifically Aβ aggregation and in turn, neuronal death.

Method

HT22 hippocampal cells were transiently transfected with bicistronic plasmids allowing for expression of DsRed alone or co‐expression with Aβ42. We then examined the effects of Aβ42 on expression of the rate limiting enzyme for PA synthesis, ornithine decarboxylase (ODC) and in turn, PA levels. Irreversible ODC inhibitor, L‐difluoromethylornithine (DFMO) was used to examine effects on Aβ42 aggregation and neuronal apoptosis. Hippocampal tissue from human sporadic AD and age matched controls were also assessed for PA concentration and ODC expression.

Results

We found that Aβ42 increased PA levels in a dose‐dependent fashion through enhanced expression of ODC in HT22 hippocampal cells. Treatment with DFMO significantly reduced this increase in PA as well as aggregation of Aβ42 and Aβ42‐induced apoptosis. Lastly, levels of spermidine and spermine as well as ODC expression were significantly increased in sporadic AD human hippocampal tissue in comparison to age‐matched controls.

Conclusion

These data suggest that increased intracellular concentrations of PA are not only a response to Aβ42, but they also promote Aβ42 toxicity by enhancing aggregation. Secondarily, DFMO may be a novel therapeutic to mitigate Aβ42 toxicity and reduce amyloid plaque load in patients with AD.
Evolution of unawareness of memory decline in individuals with autosomal dominant Alzheimer’s disease
Authors: Vannini Patrizia , Hanseeuw Bernard J. , Gatchel Jennifer R. , Sikkes Sietske A.M. , Alzate Diana , Zuluaga Yesica , Moreno Sonia , Mendez Luis , Baena Ana , Lopera Paula Ospina , Tirado Victoria , Henao Eliana , Acosta‐Baena Natalia , Giraldo Margarita , Lopera Francisco , Quiroz Yakeel T.
Published: December 2020

Background

While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease (AD) dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the pre‐dementia stages of the disease. Here, we investigated the evolution of memory awareness in the AD‐course in a large cohort of individuals who carry mutations for autosomal dominant AD (ADAD; a population that are genetically determined to develop early‐onset dementia, and have a well‐characterized disease trajectory from pre‐symptomatic to clinical stages) and compared it with family members who do not carry the mutation.

Methods

Pseudo‐longitudinal analyses using linear mixed‐effect models was used to predict self‐awareness (assessed using an awareness index based on the discrepancy score between participant and study‐partner report on the Memory Complaint Scale (Spanish version),in a total of 2,379 members of a Colombian kindred including 396 ADAD (14.9% impaired) and 1,983 non‐carrier family members (Table 1). Age was entered as a fixed and random factor in the models.

Results

The mutation carriers complained significantly more than their study‐partner until the mean age of 35, and complained significantly less (unawareness/anosognosia) than their study‐partner around the age of 43 (Figure 1A), approximately 6 years prior to their estimated median age of dementia onset (49yo). Cognitively‐unimpaired non‐carriers complained significantly more than their study‐partners (heightened awareness/hypernosognosia) between ages 20‐60 (Figure 1B). Using the awareness index (Figure 2) we observed a decrease with age (est.=‐0.04 discrepant‐points/year,se=0.02,t=‐2.2,p=0.03) in the non‐carriers and an even steeper decline in the mutation carriers (est.=‐0.21 discrepant‐points/year,se=0.04,t=‐5.1,p=2.8*e‐7). The awareness index was significantly different between groups from age 22.5, indicating less awareness of memory in the mutation carriers as compared to the non‐carriers.

Conclusion

Hypernosognosia was observed in both groups, indicating that heightened awareness of memory function is common and non‐specific in this cohort. In mutation‐carriers, awareness of memory decreased in the pre‐dementia stages, reaching anosognosia 6 years before dementia onset. These findings provide further support for the usefulness of informant‐reported cognitive decline and add to the sporadic AD literature suggesting that individuals who become unaware of cognitive change in preclinical stages may represent a specific risk group to develop AD dementia.
Neuropathologically‐defined subtypes of Alzheimer’s disease
Authors: Murray Melissa E
Published: December 2020

Background

Neuropathologic studies have demonstrated the importance of recognizing atypical patterns of neurofibrillary tangle pathology in Alzheimer’s disease (AD). Utilizing corticolimbic patterns to operationally classify neuropathologically‐diagnosed AD cases, we identified three subtypes: hippocampal sparing AD, typical AD, and limbic predominant AD (Murray 2011). While amyloid‐β plaque pathology does not differ across AD subtypes (Murray 2015), the frequency of co‐existing pathology does differ.

Method

The FLorida Autopsied Multi‐Ethnic (FLAME) AD cohort was reviewed (Hanna Al‐Shaikh 2019). Co‐existing α‐synucleinopathies was examined, including Lewy body disease and the presence of amygdala predominant Lewy bodies which are often observed in the context of severe AD pathology. The severity of cerebrovascular disease was examined using the modified Kalaria score (Deramecourt 2012), which provides a score from 0‐10.

Result

Out of 1361 AD cases, 175 (13%) were classified as hippocampal sparing AD, 1014 (74%) as typical AD, and 172 (13%) as limbic predominant AD. Limbic predominant AD cases were older at death (86 years) compared to typical AD (81 years) and hippocampal sparing AD (72 years) (p<0.001). A higher proportion of limbic predominant AD (26%) and typical AD (26%) had co‐existing Lewy body disease compared to hippocampal sparing AD (14%) (p=0.003). Amygdala predominant Lewy bodies were more frequently observed in limbic predominant AD (25%) compared to typical AD (17%) and hippocampal sparing AD (12%) (p=0.006). Limbic predominant AD has more severe cerebrovascular disease score (median=5, interquartile range 2‐6) compared to typical AD (4, 2‐6) and hippocampal sparing AD (4, 2‐5).

Conclusion

Corticolimbic patterns of neurofibrillary tangle pathology provide key insight into the neurobiology underlying clinical heterogeneity of AD. We observed a greater frequency of co‐existing pathologies in limbic predominant AD and typical AD. Future biomarker studies and efforts of targeted therapeutics should consider the effect of multiple comorbid pathologies. It will be of great interest to examine how these co‐existing pathologies influence clinical progression and heterogeneity of clinical presentations in Alzheimer’s disease patients.
Social connection, not loneliness, predicts dementia risk in Swedish older adults
Authors: Beam Christopher R , Kim Alice J
Published: December 2020

Background

Greater loneliness has been found to predict increased dementia risk in older adult populations. Yet, factors rather than loneliness, like objective social connections and depressive symptomatology, may explain away effects of loneliness on dementia risk. In a longitudinal sample of Swedish twins, we examined whether baseline scores and change in loneliness predict dementia risk. Additionally, we examined whether familial factors (shared genes and/or environments) confound the predictive utility of loneliness on dementia status. Finally, we hypothesized the observed effects of loneliness on dementia risk would be greater in women than men.

Method

The sample included 2,543 adult Swedish twins who completed baseline measures of loneliness and survived beyond age 60. Twins were followed until they were diagnosed with dementia, deceased, or lost to follow‐up. Analyses included first fitting latent growth curve models to evaluate change in loneliness over time; Cox regression models to test whether baseline and change in loneliness predicted dementia risk; and biometric regression models to test whether genetic and environmental pathways mediated effects of loneliness on dementia status.

Result

Latent growth curve models suggest that loneliness did not change over time. Baseline loneliness did not correlate with dementia status (r = .02, t = 0.82, df = 2574, p = .413), although greater number of close friends/family predicted lower odds of dementia (Odds Ratio: 0.63, .95CI: [0.45,0.88]). As loneliness did not correlate with dementia risk), which were confirmed in biometric regression models: loneliness did not correlate with dementia via genetic or environmental pathways. The only gender difference observed was that women reporting the highest levels of loneliness were diagnosed with dementia at significantly greater rates than men reporting the highest levels of loneliness.

Conclusion

Loneliness did not predict dementia risk over a 30‐year follow‐up period. Despite these null findings, women reporting the highest levels of loneliness appeared to confer greater dementia risk compared to their male counterparts. Consistent with previous results, social connection (as measured by greater number of close ties) lowered dementia risk, suggesting that measures of social network density may provide greater clinical utility than perceived social isolation.
Tracking neurodegeneration in frontotemporal dementia and Alzheimer’s disease: A comparative study of plasma tau and neurofilament light chain
Authors: Illán‐Gala Ignacio , Lleó Alberto , Karydas Anna M. , Staffaroni Adam M. , Zetterberg Henrik , Sivasankaran Rajeev , Grinberg Lea Tenenholz , Spina Salvatore , Kramer Joel H. , Ramos Eliana Marisa , Coppolla Giovanni , Joie Renaud , Rabinovici Gil D. , Perry David C. , Tempini Maria Luisa Gorno , Seeley William W. , Rosen Howard J. , Boxer Adam L. , Rojas Julio C.
Published: December 2020

Background

The comparative clinical utility of plasma Tau and neurofilament light chain (NfL) in frontotemporal lobar degeneration syndromes (FTLD‐S) and Alzheimer’s disease (AD) was determined.

Method

We measured plasma Tau and NfL with Simoa in 265 participants: 167 FTLD‐S, 43 AD and 55 healthy controls (HC), including 82 pathology‐proven cases (50 FTLD‐Tau, 18 FTLD‐TDP, 2 FTLD‐FUS and 12 AD) and 98 participants with amyloid PET. We compared cross‐sectional and longitudinal biomarker concentrations between groups, and studied their correlation with baseline clinical measures of disease severity and cortical thickness and their ability to predict disease progression and survival.

Result

Plasma NfL, but not plasma Tau, discriminated between FTLD‐S, AD and HC (AUC = .97, 95% CI .95 – .99, p < .001 for FTLD‐S vs HC, and AUC = .94, 95 CI .89 ‐ .98, p < .001 for AD vs HC). In pathologically‐confirmed cases, plasma NfL levels were higher in FTLD‐TDP (85.6 ± 46 pg/mL), compared to FTLD‐Tau (50.4 ± 26 pg/mL), after accounting for age, and disease severity (p < .001; partial η
2 = .20). High plasma NfL, but not plasma Tau, predicted disease progression in both FTLD‐S (2.3 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.4 – 4, FDR‐corrected, p=.007) and AD (2.9 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.2 – 5.6, FDR‐corrected, p = .035) and shorter survival (Log‐Rank = 14.4, p < .001) in FLTD‐S. Plasma NfL, but not plasma Tau, correlated with reduced cortical thickness in frontal regions in FLTD‐S and temporoparietal regions in AD. The combination of plasma NfL with plasma Tau did not improve the diagnostic prognostic performance of plasma NfL alone.

Conclusion

Plasma Tau has limited diagnostic and prognostic value. Plasma NfL discriminates FTLD and AD from healthy individuals and is associated with disease progression in FTLD and AD and may be have important clinical value for prognostic purposes.
Serum cortisol, cerebral amyloidosis, and neurodegeneration: A longitudinal study
Authors: Kim Jeongsim , Byun Min Soo , Lee Jun Ho , Yi Dahyun , Jeon So Yeon , Byeon Gihwan , Shin Seong A , Kim Yu Kyeong , Sohn Chul‐Ho , Lee Dong Young ,   the KBASE Research Group
Published: December 2020

Background

Although elevated blood cortisol has been repeatedly associated with Alzheimer`s disease (AD) and related cognitive decline, the pathological links underlying the association remain poorly understood. In this context, we aimed to investigate the relationship between serum cortisol and AD neuroimaging markers including amyloid beta protein (Aβ) deposition, tau deposition, AD‐signature region cerebral glucose metabolism (AD‐CM), AD‐signature region cortical thickness (AD‐CT), and adjusted hippocampal volume (HVa).

Method

This study was part of the of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study. A total of 503 middle‐aged and elderly adults, including cognitively normal adults and individuals with mild cognitive impairment and AD dementia, underwent comprehensive clinical and neuropsychological assessments, 11C‐Pittsburgh compound B (PiB)‐PET, 18F‐deoxyglucose (FDG)‐PET, MRI, and serum cortisol level quantification at baseline and 2 years later. A subset of subjects also received 18F‐AV‐1451 PET during the follow‐up evaluation.

Result

At baseline, a significant positive association was found between serum cortisol level and global cerebral Aβ deposition after controlling for the effects of potential confounders (i.e., age, sex, APOE4 status, cognitive status, vascular risk, and depression). In addition, cortisol level showed significant inverse association with AD‐CM even after controlling for global Aβ retention as well as the confounders. There was no significant relationship between cortisol and cerebral tau deposition. In regard of longitudinal changes of AD markers, baseline cortisol level also had significant positive association with increase of cerebral Aβ deposition over 2 years, but not with changes of any neurodegeneration markers.

Conclusion

The findings indicate that high serum cortisol contribute to AD processes through pathological cerebral Aβ deposition. Additionally, cortisol appears to directly affect neurodegeneration in AD‐signature brain regions via Aβ‐independent mechanisms.
Improved centiloid robustness using non‐negative matrix factorization
Authors: Bourgeat Pierrick , Dore Vincent , Ames David , Martins Ralph N , Masters Colin L , Rowe Christopher C , Fripp Jurgen , Villemagne Victor LL ,   the AIBL Research Group
Published: December 2020

Background

Centiloid was introduced to harmonise Amyloid PET quantification across different tracers, scanners and analysis techniques. Unfortunately, Centiloid suffers from quantification disparities in longitudinal analysis when switching from different tracers or scanners. In this work, we aim to reduce such variability using a different analysis technique on the existing calibration data.

Method

All the PET images from the calibration dataset, along with 3658 PET images from the AIBL study were analysed using the recommended SPM pipeline. All the images were SUVR normalised using the whole cerebellum and skull stripped. The nomalised PiB images were decomposed into 6 components using non‐negative matrix factorisation (NMF). NMF is similar to a PCA decomposition but imposes that all components and associated coefficients remain positive. The NMF coefficients related to the first component were strongly correlated with global SUVR (R2 = 0.93), and were subsequently used as a surrogate for Aβ retention. The NMF coefficients were calibrated to Centiloid using the anchoring groups in the PiB calibration dataset. For each tracer of the calibration dataset, a NMF decomposition was computed, where the coefficients of the 1st component were fixed, and set to those of their corresponding PiB, hence forcing the 1st component of the NMF decomposition to match across tracers. All PET images from AIBL were subsequently decomposed using the computed NMF, and their coefficients transformed into Centiloids.

Result

In AIBL, the correlation between the standard Centiloid and the novel CentiloidNMF was high in each tracer with 0.93 in 11C‐PiB, 0.97 in 18F‐NAV, 0.96 in 18F‐FBB, 0.91 in 18F‐FLUTE and 0.86 in 18F‐AV45. The longitudinal consistency was assessed using average fitting error of a linear regression model applied to each subject with 3 or more timepoints, and also by measuring the number of subjects with longitudinal changes >20CL/year, which are physiologically implausible and likely caused by noise. The average fitting error was decreased by 15%, and the number of subjects with changes >20CL/year was halved from 41 to 20.

Conclusion

We have proposed an image driven method to measure Centiloids. The method is highly correlated with standard Centiloids and reduces its longitudinal variability when switching scanners and tracers.
The electronic person specific outcome measure (ePSOM) programme: Overview and survey results
Authors: Saunders Stina , Sheehan Shane , Evans Alison , Luz Saturnino , Ritchie Craig W. , Terrera Graciela Muniz
Published: December 2020

Background

The ePSOM programme is a collaboration between the University of Edinburgh and Alzheimer’s Research UK. prompted by the recognition that outcome measures currently used in clinical trials in prodromal and preclinical neurodegenerative diseases do not capture the research participants’ views of effectiveness. This led to a 4‐stage programme. [1] Evidence review and programme methodology [2] Focus groups to identify key domains of importance to people at various degrees of neurodegenerative disease [3] National online survey and [4] App development which can be used as an outcome measure in trials. Here we present stage [3] of the programme.

Method

The online survey captured free text responses in 5 predefined domains. Self‐reported clinical details and sociodemographic data were captured to analyse responses by key variables whilst keeping the survey short (around 15 minutes). The survey received ethical approval and ran August – November 2019. Using clustering and natural language processing techniques we identified clusters of response by domain and across domains. A specific question about the steps individuals take to ‘maintain brain health’ was also included.

Result

5807 people completed the survey. Most were female (76.9%), married (63.4%) and living in an urban area (61.8%). The mean age in women was 57.35 (SD=13.8) and 62.88 (SD=13.08) in men. 73% had supported a relative with dementia but only 15.4% had sought help for their own brain health. On a 10‐point scale (10 = best level of health), the mean score for self‐rated brain health was 9.32 (SD=1.97). We consider that the population undertaking the survey was exactly as intended as a primary or secondary prevention population. Thirty distinct clusters of response were identified across all domain and will be presented. The most common activities undertaken to maintain brain health were ‘trying to keep brain active’ (86.6%) followed by ‘trying to keep physically active’ (70.8%).

Conclusion

The survey was successful in capturing a large number of people from a population at higher risk of neurodegenerative disease. The respondents understood the objectives of the survey and relevant clusters and items emerged which will guide the 4th phase of App development.
Relationship between vestibular dysfunction and dementia in elderly patients: Peripheral vertigo or central vertigo
Authors: Lee Jong Yoon
Published: December 2020

Background

Recent research suggests an association between vestibular impairment and dementia. Mild cognitive impairment (MCI) and dementia patients are associated with increased rate of vestibular loss. The vestibular system consists of the peripheral vestibular organs and the associated extensive vestibular cortical pathway. We investigate whether vertigo (peripheral vertigo or central vertigo) is correlated with an increased risk of dementia and clinical relevance of vertigo types to dementia.

Method

From August 2019 to January 2020, 300 patients, aged ≥ 50 years and vertigo symptom were retrospectively enrolled. Multivariate a Multivariate analysis was performed for vertigo types that showed a significant difference between dementia and non‐dementia groups. First, we reviewed vertigo with previous diagnosed 177 dementia and 123 healthy controls, and the differences in vertigo types between these groups were examined. Second, the patients with vertigo were classified into 2 groups: peripheral (Acute vestibular neuritis, Meniere's disease, Benign paroxysmal positional vertigo, Autonomic related vertigo, and so on) or central (Stroke, Vertiginous migraine and Epilepsy vertigo) types. Third, dementia groups included AD, VaD and Mixed types. Finally, this study evaluated risk factors for vertigo in cognitive impairment patients.

Result

Among 177 dementia patients with a mean age of 75.30 years, 56 (31.63%) developed vertigo. The frequency of vertigo types (peripheral vertigo or central vertigo) was different in dementia with vertiginous patients compared to non dementia groups {peripheral: central 55.35% vs 44.64%; 81.30% vs 18.69}. In this study, total 56 vertigo patients were divided into two groups based on peripheral type (n = 31) or central type (n = 25). There was no significant difference in vertigo classification between peripheral and central according to dementia subtype. On the other hand, 121 individuals with dementia were not found symptom of vertigo. Among, 123 non dementia patients with vertigo, there were 100 of peripheral vertigo (81.30%) and 23 of central vertigo (18.69%).

Conclusion

The classification of vertigo is different depending on dementia or not. The proportion of central vertigo has a tendency to increase with dementia groups. The findings of our study may provide direction for potentially useful diagnostic tests and vestibular‐targeted therapy such problem in dementia patients.
The validity of the good spirit, good quality‐of‐life tool for older Aboriginal Australians
Authors: Gilchrist Lianne , Bessarab Dawn , Douglas Harry , LoGiudice Dina , Ratcliffe Julie , Flicker Leon , Hyde Zoe , Smith Kate
Published: December 2020

Background

Enhancing quality of life (QoL) is the primary goal of aged care services for older people with dementia. Despite this, there are no culturally appropriate QoL measures for older Indigenous peoples with or without dementia. This study aims to address this gap.

Method

The Good Spirit, Good Life (GSGL) tool was co‐developed with older Aboriginal Australians and services in Perth and Melbourne, Australia. Adaptations were made following face validity with Aboriginal participants with dementia or cognitive impairment. Quantitative data collected by Aboriginal researchers included demographic information, GSGL tool (12 items, total score 60), KICA Cog (Indigenous cognitive assessment), EQ‐5D‐5L (health‐related QoL tool), ICECAP‐O (generic wellbeing tool for older people), Geriatric Anxiety Inventory‐Short Form (GAI‐SF), KICA‐Dep (Indigenous depression scale), Aboriginal Resilience and Recovery Questionnaire (ARRQ‐25), and GSGL Carers version.

Result

120 Aboriginal people aged 45‐86 years participated in the GSGL validity study, 68% were women. The mean total GSGL score was 48.7/60. 11% of participants had cognitive impairment or dementia. GSGL internal (Spearman‐Brown 0.83, Cronbach’s alpha 0.75) and inter‐rater (ICC 0.69‐0.95) reliability was strong. Concurrent validity is supported by strong correlation with ICECAP‐O (Spearman’s Rho (ρ)=0.61, p<0.05). GSGL was weakly correlated with health‐related EQ‐5D‐5L (ρ=‐0.32, p<0.05). Known‐groups validity was supported by significant difference in GSGL scores between participants with (40%) and without anxiety (Student’s t test t=4.3, p<0.05) and with (44%) and without depression (t=4.1, p<0.05). GSGL scores did not differ significantly for participants with and without cognitive impairment. Following multivariate regression, resilience (β=0.55, 95%CI [0.39, 0.70]) and GAI‐SF score (β=‐0.22, [‐0.38, ‐0.06]) were associated with total GSGL score. There was significant difference in GSGL item scores (p<0.05; Hotelling’s T2 test), with the ‘Country’ item having the lowest mean score (3.05/5, p<0.05).

Conclusion

The GSGL is a culturally valid tool for measuring quality of life in older Aboriginal Australians. Items are based on the quality of life priorities of Aboriginal Australians with and without dementia. Interventions targeted at building resilience and treating anxiety and depression may improve the quality of life of older Aboriginal Australians. More could be done by services and families to facilitate older people’s connection to Country.
The validation of the adapted Kimberley Indigenous Cognitive Assessment in a Brazilian indigenous community of older adults from Amazonas
Authors: Souza‐Talarico Juliana Nery , Carvalho Anna Paula , Nitrini Ricardo , Ferretti‐Rebustini Renata Eloah de Lucena , LoGiudice Dina , MD Brucki Sonia
Published: December 2020

Background

Dementia detection in indigenous populations, represents a challenge worldwide, due to the absence of culturally adapted cognitive tests. The Kimberley Indigenous Cognitive Assessment (KICA) was developed and validated to evaluate global cognitive performance in Aboriginal Australians. We aimed to determine reliability and validity of the KICA, and specificity and sensitivity in detecting cognitive impairment in a Brazilian indigenous community.

Method

The KICA was translated and back translated into Portuguese by independent translators. The translated version was revised by an experts committee and pre‐tested. Healthy indigenous older adults (n=123, Age mean=63.7, SD=±9.1; Education mean=1.5, SD±2.3) and indigenous patients with cognitive impairment (n=94; Age mean=65.0, SD±11.5; Education mean=1.1, SD±11.5) from Amazonas, Brazil, were administered the KICA and Mini‐Mental State Examination (MMSE). Cognitive impairment classification was based on the DSM‐IV and ICD‐10 criteria. The KICA reliability and validity was analyzed using Cronbach's alpha and Pearson correlation coefficient between KICA and MMSE scores. Sensitivity and specificity were calculated at several cutoff values and the area under the Receiver Operator Characteristic (ROC) curve was calculated.

Result

The KICA demonstrated moderate internal consistency (Cronbach's alpha coefficient=0.787) and was significantly correlated with MMSE scores (r=0.660; p<0.001; Pearson coefficient). The best equilibrium was at the cutoff value of 26/27 out of 39 showing 72% sensitivity and 73% specificity; the area under the ROC curve was 0.78 (95% CI: 0.72‐0.84).

Conclusion

Our results indicate that the KICA is a reliable tool and can be used for screening cognitive impairment in Brazilian indigenous with low education background.
Phenome‐wide associations with an Alzheimer’s disease genetic risk score in UK Biobank: Identifying early indicators of disease
Authors: Zimmerman Scott C , Ackley Sarah F , Brenowitz Willa D , Graff Rebecca E , Glymour M Maria
Published: December 2020

Background

There is a pressing need to identify early indicators of Alzheimer’s disease and Alzheimer’s disease‐related dementias (AD/ADRD) to understand the time course of disease and help target potential secondary prevention measures. A phenome‐wide association study (PHeWAS) could be used to rapidly screen numerous possible leading indicators of AD/ADRD based on phenotypes predicted by an Alzheimer’s Disease genetic risk score (ADGRS). We conducted a preliminary PheWAS to evaluate associations with an ADGRS, considering multiple phenotypic domains relevant to AD/ADRD.

Method

We calculated an ADGRS as a weighted sum of 23 previously identified AD‐related single nucleotide polymorphisms in individuals of European ancestry. We conducted a PheWAS of 373,225 UK Biobank participants of European ancestry aged 50‐69 years at enrollment. Using the open‐source tool PHEnome Scan ANalysis Tool (github.com/MRCIEU/PHESANT), we tested the ADGRS against 434 phenotypes: 183 neuroimaging, 100 cognitive, 84 mental health, 31 psychosocial, and 14 behavioral. PHESANT regresses the ADGRS on each phenotype adjusted for baseline age, sex, genotype chip, and 10 genetic ancestry principal components.

Result

Using a global Bonferroni threshold (p<1.15E‐4) significance criterion, we found 34 phenotype‐ADGRS associations. The three most significant associations were with cognitive functioning from a symbol digit substitution test: Duration to entering value (0.029, 95%CI=[0.023, 0.035]; p=2.58E‐06), number of matches made correctly (‐0.029, 95%CI=[‐0.035,‐0.022]; p=7.56E‐05), and number of matches attempted (‐0.028, 95%CI=[‐0.033,‐0.021]; p=2.63E‐08). Overall, 11 behavioral (69%), 21 cognitive (21%), 1 psychosocial (2%), and 1 mental health (2%) variables were significantly associated with the ADGRS. None of the neuroimaging variables were significant, but sample sizes were small (18,314‐20,827). Using category‐specific Bonferroni‐adjustments, 13 behavioral (81%), 23 cognitive (23%), 2 psychosocial (2%), and 2 mental health (2%) variables were significant.

Conclusion

In a largely healthy and cognitively normal sample, the PheWAS identified cognitive assessments that may be leading indicators of AD/ADRD and identified novel associations of ADGRS with 1 mental health, 1 psychosocial, and 11 behavioral variables. PHeWAS using AD/ADRD genetic profiles may have potential for identifying early indicators of AD/ADRD.
FC gamma receptor activation is related to neuronal and microglial toxicity mediated by palmitic acid
Authors: Phitthayaphong Phansa , Kumfu Sirinart , Chattipakorn Siriporn C. , Chattipakorn Nipon
Published: December 2020

Background

A high‐fat diet (HFD) rich in saturated fatty acid, particularly palmitic acid (PA), promotes pathophysiological changes in the brain. HFD induces cognitive impairment due to abnormal Alzheimer’s‐related protein production and increases the upregulation of hyperphosphorylation of Tau and Aβ peptides. Moreover, the progression of neuroinflammation and activated microglia were driven after HFD consumption. Activated microglia are able to eliminate abnormal proteins by using surface receptors called FcγR. These receptors have been found to mediate tissue injury within the CNS. However, the expression and activation of FcγRs, the presence of Alzheimer’s‐related proteins, proinflammatory cytokines as well as cell viability of neurons and microglia under PA exposure have not been investigated.

Method

SH‐SY5Y, the human neuroblastoma cell line, and HMC3, the human microglia clone 3 cell line, were exposed to 200 and 400 µM of PA‐conjugated BSA. After 24 hours of exposure, Alzheimer’s‐related proteins, including Aβ, APP, BACE1, IDE, p‐Tau and Tau, as well as the production of proinflammatory cytokines composed of TNFα, IL‐1β and IL‐6, were investigated. FcγRs levels with signaling and cell viability were determined.

Result

After exposure of PA‐conjugated BSA for 24 hours, SH‐SY5Y and HMC3 cells increased Alzheimer’s‐related protein production including Aβ, APP, BACE1, and decreased IDE. While p‐Tau/Tau ratio was increased only in SH‐SY5Y cells. Furthermore, both cell lines increased TNFα, IL‐1β and IL‐6 production after PA‐conjugated BSA exposure. Interestingly, an increase in FcγRs expression was only found in HMC3 cells, whereas FcγRs signaling significantly increased in both cell lines. The viability of SH‐SY5Y and HMC3 cells were decreased in a dose‐dependent manner with PA exposure.

Conclusion

PA increased Alzheimer’s‐related protein production, inflammation and FcγRs activation, which related to the presence of neuronal and microglial cell death. These findings suggest that the blockage of FcγRs should restrain further progression of Alzheimer’s pathology and neuroinflammation in HFD‐induced cognitive decline.
Texture of brain magnetic resonance images is associated with tau accumulation but not with amyloid accumulation in Alzheimer’s disease
Authors: Lee Subin , Kim Ki Woong
Published: December 2020

Background

Spatial variations in signal intensity on magnetic resonance images (MRI), as measured by texture analysis, has been reported to be able to discriminate and predict progression to Alzheimer’s disease (AD). In this study, we investigated associations between the MRI signal intensity variations and hallmark AD pathologies (amyloid and tau accumulation).

Method

Study participants consisted of 151 subjects from the Alzheimer’s Disease Neuroimaging Initiative 3 who had a T1‐weighted image, AV45 positron emission tomography (PET), and AV1451 PET. We extracted texture features from each of five regions: entorhinal cortex, hippocampus, posterior cingulate cortex, precuneus, and superior frontal cortex. Cerebral amyloid burden was measured as standardized uptake value ratio (SUVR) in AV45 positron emission tomography (PET), and cerebral tau burden was measured as SUVR in AV1451 PET. We investigated associations between each texture feature and AD pathological measures in each of the regions by using linear regression, controlling for the effects of age and gender. We also compared texture features and AD pathological burden among in vivo Braak stage groups.

Result

Regional texture were associated with regional tau burden but not with amyloid burden. Furthermore, the texture features that were associated with tau accumulation were different between regions with different cytoarchitecture. Significant group differences were observed for amyloid and tau accumulation, and certain texture features. Mean signal intensity showed an increasing trend across higher stage groups.

Conclusion

This study suggests that brain MRI texture may reflect microstructural changes related to tau accumulation, and has potential as an early non‐invasive imaging marker of AD. This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379 [A092077]).
Association between plasma neurofilament light chain levels and cognition in early Parkinson's disease
Authors: Yong Alisa C.W. , Tan Yi Jayne , Ng Ebonne YL , Lu Zhonghao , Ng Samuel YE , Chia Nicole SY , Choi Xinyi , Heng Dede , Neo Shermyn XM , Xu Zheyu , Tay Kay Yaw , Au Wing Lok , Tan Eng King , Tan Louis C.S. , Ng Adeline Su Lyn
Published: December 2020

Background

Plasma neurofilament light chain (NfL) levels reflect large calibre myelinated axonal loss; and has been proposed as a blood‐based biomarker for neurodegeneration in dementia and parkinsonian disorders. Recent studies have suggested an association between increased plasma NfL levels and worse global cognition in Parkinson’s Disease (PD) patients. However, its relationship with specific cognitive domains remain unclear. This study thus aims to investigate the association between plasma NfL and cognitive domains in early PD.

Method

Plasma NfL was measured using Quanterix’s Single Molecule Array (Simoa) technology in a total of 197 subjects (175 early PD patients and 22 healthy controls). Cognitive function was assessed using a standard battery of neuropsychological tests. This included the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) as tests of global cognition, as well as two tests for each of five relevant cognitive domains, namely episodic memory, language, working memory, visuospatial, and executive function.

Result

PD patients had higher plasma NfL levels (mean=16.3 pg/ml, SD=8.59) compared to healthy controls (mean=12.2 pg/ml, SD=4.18) (p=.023). Amongst PD patients, increased NfL levels associated significantly with worse global cognition scores (MMSE: b=‐1.11 p=.009; MoCA: b=‐1.27, p=.026). In particular, higher levels of plasma NfL significantly correlated with poorer episodic memory (b=‐.541, p=.003) and executive function scores (b=‐.427, p=.002). No significant associations were found between plasma NfL and cognitive measures in healthy controls.

Conclusion

Higher plasma NfL levels were found in PD patients compared to healthy controls and associated significantly with poorer global cognitive function in PD. Interestingly, higher NfL levels correlated with worse episodic memory and executive function. These results implicate plasma NfL’s role as a potential biomarker for cognition in PD. Further studies are required to validate these findings.
CSF biomarkers in neuropathological Alzheimer's disease
Authors: Leroy Melanie , Maurage Claude Alain , Pasquier Florence , Deramecourt Vincent , Lebouvier Thibaud
Published: December 2020

Background

Since the new ATN classification system positing a biological definition of Alzheimer’s disease (AD), cerebrospinal fluid (CSF) biomarkers are the keystone of AD diagnosis in countries where amyloid and tau positron emission tomography (PET) are not available. However, data confronting CSF biomarkers with pathology are still scarce.

Method

Among the 242 patients within Lille Brain bank, 23 patients had both CSF biomarkers and a neuropathologically confirmed AD. CSF collection was performed during follow up at the Lille Memory Clinic. CSF Ab42, Tau and pTau were measured and classified as pathological or normal regarding the cutoff at the time. The ATN profile (where A+ stands for pathological Ab42, T+ for pathological pTau and N+ for pathological Tau) was then determined.

Result

21/23 patients had early onset AD, the age at first symptoms, the delay between the first symptoms and the lumbar puncture (LP) as well as the the delay between the autopsy and the LP were not different between groups. The MMSE at LP was above 15 in the A+T+N‐ (23.8 ± 4.5), the A‐T‐N+ (22) and the A+T+N+ group, and was statistically different between A+T+N‐ vs A‐T‐N+ (p = 0.03) and A+T+N‐ vs A‐T+N+ (P = 0.01) groups. Among our pathologically proved AD cases, 14/23 were A+T+N+, while 7 patients had 2 pathological biomarkers (4 were A+T+N‐ and 3 were A‐T+N+) and 2 patients had one (one was A+T‐N‐ and one was A‐T‐N+). AD was the main neuropathological diagnosis in all cases except for the A‐T+N‐ case where progressive supranuclear palsy was the main diagnosis (Figure 1).

Conclusion

Despite neuropathological evidence of amyloid deposition, neuronal death and neurodegeneration at autopsy, only 60% of our AD patients had a full A+T+N+ CSF profile. CSF Ab42/40 ratio may improve correlations between biomarkers and pathology by reincorporating some of our A‐T+ patients into the A+T+ group. We are currently confirming these data by repeating the measures using modern fully‐automated assays, including CSF Ab42/40 ratio.