bluuebunny/crossref_metadata_2025 huggingface dataset:
Net Carbohydrate Consumption is Associated with Cortical Thickness in Cognitively Impaired Older Adults with Confirmed Amyloid Burden
Authors: Bramen Jennifer E. , Popa Emily S. , Rapozo Molly K. , Siddarth Prabha , Hodes John F. , Ganapathi Aarthi S. , Slyapich Colby B. , Glatt Ryan M. , Porter Verna R. , Wong Claudia L. , Bookheimer Susan Y. , Roach Jared C. , Merrill David A.
Published: December 2022

Background

A low carbohydrate diet has been suggested as a treatment for Alzheimer’s disease (AD)1,2. One of the features of AD is widespread cortical thinning3; however, no study has demonstrated that carbohydrate intake is linked to cortical thickness in patients with confirmed AD‐related neuropathology. The aim of this study is to test the hypothesis that higher carbohydrate intake is associated with thinner cortex.

Method

Cortical thickness was estimated from T1‐weighted MR images using FreeSurfer with an alpha of p<0.05 (vertex‐wise) and p<0.01 (cluster‐wise correction for multiple comparisons). We calculated net carbohydrate intake using a Food Frequency Questionnaire (FFQ) as input to the validated FFQ EPIC Tool for Analysis4 in 22 participants aged 57‐84 (mean = 70.1 years, SD = 6.2) with a diagnosis of mild cognitive impairment (MCI) or mild AD and confirmed amyloid burden.

Results

Participants, on average, ate moderate to low levels of net carbohydrates (mean = 124 g, SD = 66). No participant exceeded the USDA guidelines for net average daily carbohydrate intake5. Most ate less than CDC guidelines for managing diabetes6 (N = 19). Participants were drawn from the Pacific Brain Health Center, a clinical practice centered around addressing lifestyle and located in Santa Monica, California. We found that higher net carbohydrate intake was significantly associated with thinner cortex, accounting for age, within the left middle frontal gyrus (size = 2900 mm2). Uncorrected results (cluster size>100 mm2) showed that throughout the cortex, we saw a widespread pattern of cortical thinning, including regions within the middle temporal, fusiform, lingual, supramarginal, cingulate, superior parietal, postcentral, paracentral, orbitofrontal, inferior parietal, superior frontal gyri and insula. Only one region, the postcentral gyrus, showed a positive correlation, strongly suggesting the validity of these findings.

Conclusions

Higher carbohydrate intake was significantly associated with thinner cortex in this cross‐section of older adults with cognitive impairment and confirmed amyloid burden. Prior research in older adults eating a Mediterranean diet did not detect this association7. Our sample was unique in that they ate fewer carbohydrates and had a diagnosis of cognitive decline with confirmed amyloid burden. Future directions of this research will assess how longitudinal trajectories of cortical thinning are impacted by changes in net carbohydrate consumption.
Clusterin is associated with Alzheimer’s disease biomarkers and cognitive scores in the pre‐symptomatic phase of the disease.
Authors: Dauar Marina Tedeschi , Picard Cynthia , Rosa‐Neto Pedro , Villeneuve Sylvia , Poirier Judes ,   Prevent‐AD Research Group
Published: December 2022

Background

Clusterin (CLU) is one of the main genetic risk factors of late onset Alzheimer’s disease (AD), and different polymorphisms have been associated with the disease. A GWAS performed in a population isolate from eastern Canada has found the polymorphism rs11136000 of the CLU gene to be associated with increased risk for AD. For the present work, we used two different cohorts (the “at‐risk” pre‐symptomatic PREVENT‐AD and the symptomatic ROSMAP cohort) with the objective of exploring how the rs11136000 polymorphism is associated with clinical manifestations, biomarkers and neuropathology of AD at different disease stages.

Method

In the PREVENT‐AD cohort, ELISAs were used for Tau, phospho(181) Tau (p‐tau), and Aß CSF levels. Cognition was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were followed for at least 4 years. In the autopsied‐confirmed ROSMAP cohort, Aß load and NFT density in the cortex were measured with immunocytochemistry, and cognition was assessed with the Mini‐Mental State Examination (MMSE). Participants were followed throughout their adult life, until death.

Result

In the cognitively unimpaired PREVENT‐AD cohort, participants who are APOE4 positive and non‐carriers for the rs11136000 T variant had lower CSF Aß1‐42 (p=0.01) and higher CSF p‐tau (p=0.027) (Fig 1). Additionally, participants who are APOE4 positive and have 2 copies of the CLU rs11136000 T variant display significantly higher coding scores (p=0.003), attention scores (p=0.015) and visuospatial/constructional score (p= 0.026) (Fig 2). However, participants who are APOE4 negative and are homozygous for the rs11136000 T variant have lower semantic fluency score (p=0.001), list recall score (p=0.038) and language score (p=0.007) (fig 2). In the ROSMAP cohort, there was no association of the CLU rs11136000 variant with risk of developing dementia, MMSE scores or Braak or CERAD scores.

Conclusion

Our results confirm the role of the CLU rs11136000 variant in the pathology of AD, particularly in the pre‐symptomatic phase of the disease when pathology begins to unfold.
Impact of pre‐analytical factors on blood‐based biomarkers of Alzheimer's disease
Authors: Kurz Carolin , Stöckl Laura , Schrurs Isabelle , Suridjan Ivonne , Guersel Selim , Bittner Tobias , Jethwa Alexander , Perneczky Robert
Published: December 2022

Background

Reliable blood‐based biomarkers (BBBMs) are urgently needed to allow for robust, cost‐effective pre‐screening of patients with suspected Alzheimer’s disease (AD) before referral for detailed assessments. We evaluated the effects of storage time and temperature, plastic tube types, and freeze/thaw (F/T) cycles in fresh, never frozen and previously frozen whole blood (WB) and plasma. Effects of anticoagulants and tube transfer were only studied in previously frozen plasma.

Method

WB samples from patients with clinically suspected AD were collected in ethylenediaminetetraacetic acid (EDTA) tubes and stored at room temperature (RT) or 4°C for ≤24hrs as WB or plasma. Separated plasma was transferred into polypropylene (PP) tubes to evaluate the effects of tube transfer and F/T cycles, or into low‐density polyethylene (PE‐LD) tubes to assess the effect of tube type. In addition to EDTA, lithium heparin (Li‐Hep) and sodium citrate (NaCit) tubes were used and effects of anticoagulants evaluated. Plasma levels of phosphorylated‐tau (pTau) 217, pTau181, amyloid‐β 1–42 (Aβ42), amyloid‐β 1–40 (Aβ40), apolipoprotein E4 (ApoE4), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured using automated Elecsys® prototype immunoassays (cobas e 601 analyzer; all Roche Diagnostics International Ltd).

Result

For all BBBMs, pre‐analytical effects were comparable between fresh, never frozen and previously frozen samples. All BBBMs were stable for ≤24hrs at 4°C in WB and EDTA plasma; Aβ42, Aβ40, and ApoE4 were unstable if stored for >2hrs at RT. Up to five tube transfers, or two F/T cycles, and both tested plastic tube types were acceptable for all BBBMs. For all BBBMs, except Aβ42 and Aβ40, analyte levels were comparable between EDTA, Li‐Hep, and NaCit tubes. Aβ42 and Aβ40 were most sensitive to pre‐analytical sample handling and the effects could only be partially compensated by the Aβ42/Aβ40 ratio.

Conclusion

We provide recommendations for an optimal handling protocol for blood collection and sample handling for analysis of BBBMs for AD based on measurement in fresh samples (Figure): WB and EDTA plasma should be stored at 4°C for ≤24hrs, while storage at RT should be avoided or limited to 2hrs maximum.
Robustness of CSF Aβ42/40 and Aβ42/P‐tau181 to detect AD related outcomes using fully automated immunoassays
Authors: Leuzy Antoine , Mattsson‐Carlgren Niklas , Cullen Nicholas , Stomrud Erik , Palmqvist Sebastian , La Joie Renaud , Iaccarino Leonardo , Zetterberg Henrik , Rabinovici Gil D. , Blennow Kaj , Janelidze Shorena , Hansson Oskar
Published: December 2022

Background

An obstacle to the broad implementation of CSF AD biomarkers is the identification of uniform cutoffs and measurement variability that can result in diagnostic uncertainty at the patient level. We aimed to determine the comparability of cut‐offs for CSF immunoassays for Aβ42/Aβ40 and Aβ42/P‐tau181 and to assess the effects of variability in CSF measurements on AD‐related outcomes (Aβ‐PET visual read and progression from MCI to AD dementia).

Methods

We studied 750 participants with/without cognitive impairment (CI) with CSF Aβ42/Aβ40 and Aβ42/P‐tau181 and Aβ‐PET from Swedish BioFINDER (n=172; 85 cognitively unimpaired (CU); 87 with CI), ADNI (n=318; 54 CU, 264 CI), and the UCSF Memory and Aging Center (n=260; 55 CU, 205 CI). Aβ‐PET was visually rated as normal/abnormal. Youden’s index (Aβ‐PET visual read as outcome) was used to identify cut‐offs for Aβ42/Aβ40 and Aβ42/P‐tau181. Using these, we calculated accuracy (percentage of correctly classified individuals). To identify a grey‐zone around cut‐points where there is a risk of misclassification, we calculated longitudinal variability of Aβ42/Aβ40 and Aβ42/P‐tau181 in Aβ‐negative CU individuals and then studied the effects of this variability on biomarker performance when predicting CSF status, Aβ‐PET visual read and MCI‐AD dementia conversion.

Results

Similar cut‐offs were found for Aβ42/Aβ40 and Aβ42/P‐tau181 across cohorts; accuracies of about 90% were achieved for both measures. Longitudinal variability of Aβ42/Aβ40 and Aβ42/P‐tau181 in Aβ‐negative CU was 11.18% and 19.35%, respectively. Using these values, we estimated the robustness of Aβ42/Aβ40 and Aβ42/P‐tau181 by calculating the percentage of participants with >5% chance of having a different predicted outcome due to measurement variability following two CSF measurements close in time. On average, 8.71% of participants fell within this interval for Aβ42/Aβ40, compared with 4.45% for Aβ42/P‐tau181 using Aβ‐PET status as outcome (Figure 1A). Similar findings were observed using conversion to AD dementia (21.13% vs 13.13%) as outcome (Figure 1B).

Conclusions

Similar cutoffs could be applied to CSF immunoassays for Aβ42/Aβ40 and Aβ42/P‐tau181. Compared to Aβ42/Aβ40, Aβ42/P‐tau181 was more robust to the effects of measurement variability in terms of AD‐related outcomes. These findings suggest that Aβ42/P‐tau181 may be the preferred measure in clinical practice and trials.
Air pollution has a more deleterious effect on Alzheimer’s disease biomarkers in genetic predisposition to larger hippocampal volumes
Authors: Vilor‐Tejedor Natalia , Genius Patricia , Rodríguez‐Fernández Blanca , Minguillón Carolina , Crous‐Bou Marta , Suárez‐Calvet Marc , Milà‐Alomà Marta , Cirach Marta , Nieuwenhuijsen Mark , Sunyer Jordi , Fauria Karine , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Esteller Manel , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Guigó Roderic , Navarro Arcadi , Gispert Juan Domingo ,   for the ALFA study
Published: December 2022

Background

Gene‐environment interactions are important in understanding Alzheimer’s disease (AD) etiology. Current research is limited, possibly due to weak effects of individual genetic variants. We analysed interaction between genetics of hippocampal volume, environmental exposures and levels of AD biomarkers in cognitively unimpaired individuals at increased risk of AD.

Method

A total of 319 cognitively unimpaired, middle‐age participants from the Alzheimer’s and Families (ALFA) study with data for genotyping, environmental exposures, and cerebrospinal fluid (CSF) biomarkers were included. Genome‐wide genotyping was performed using Infinium Neuro Consortium (NeuroChip) Array. Genetic variants that passed a quality control/imputation procedure were used to calculate polygenic risk scores (PRS) using PRSice version 2. Land use regression estimated residential exposure to particulate matter (PM2.5, PM10), and nitrogen dioxide (NO2). NeuroToolKit robust prototype assays and Elecsys® immunoassays (both Roche Diagnostics International Ltd, Rotkreuz, Switzerland) were used to measure CSF biomarkers, and amyloid positivity was defined as amyloid‐beta(Aβ)42/40 ratio <0.071. Associations between PRSs and environmental factors were investigated and estimated using multiple logistic/linear regression models adjusted for age and sex; CSF biomarkers were included as outcomes.

Result

PRS‐hippocampal volume (HV)×PM10 and PRS‐HV×NO2 were significantly associated with p‐tau (p = 0.045 and p = 0.025, respectively) (Figure 1). Individuals at high genetic predisposition for larger hippocampal volumes had lower levels of p‐tau at low levels of air pollution compared to individuals at low/null genetic predisposition; as the level of exposure to PM10 and NO2 increased, higher values of p‐tau were observed compared to low‐risk individuals.

Conclusion

Our results showed that air pollution may have a deleterious effect on biological mechanisms of AD, in cognitively unimpaired individuals with higher genetic liability for larger hippocampal volumes. Further research is needed to elucidate the biological mechanism involved in such associations.
Macrophage Scavenger Receptor 1 in the CSF pre‐symptomatic with a parental history of AD and in the cortex of autopsy‐confirmed Alzheimer’s Disease cases.
Authors: Aumont‐Rodrigue Gabriel , Picard Cynthia , Rosa‐Neto Pedro , Miron Justin , Poirier Judes ,   PREVENT‐AD research Group
Published: December 2022

Background

The macrophage scavenger receptor 1 (MSR1) also known as SCARA1, is a gene that encodes for a macrophage/microglia cell surface receptor. Its primary function is to mediate the endocytosis of modified (acetylated or oxidized) low density lipoproteins (LDLs)(Frenkel, Wilkinson et al. 2013). Interestingly, MSR1 has been found to bind to soluble β‐amyloid (Aβ) and it is thought that it participates to its clearance via a microglia‐mediated process (PrabhuDas, Baldwin et al. 2017). Using multiple cohorts covering a wide range of brain health stages, MSR1 gene expression and protein level alterations were investigated to map the associations between MSR1 and Alzheimer’s disease (AD) pathophysiology.

Method

MSR1 CSF protein levels were assessed in the PREVENT‐AD (PRe‐symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease) cohort which is composed of subjects with parental history of AD. MSR1 has been measured with a primer extension assay using Olink technology (J. Alz. Dis., In press). ELISA has been used to quantify the MSR1 protein levels in frontal cortex homogenates of 86 brains from the Douglas Bell Canada Brain Bank (DBCBB) whereas MSR1 mRNA prevalence was measured using Gene Chip Clarium D human microarray. All data compilation and statistical analysis has been made using JMP pro 15.1 software.

Result

Strong correlations between MSR1 CSF protein levels and CSF AD biomarkers, notably phosphorylated Tau (R2=0.108; p=0.0007) and Aβ42 (R2=0.055; p=0.0175) have been found in the PREVENT‐AD cohort. An APOEε4‐independent correlation was observed between CSF MSR1 and APOE (R2=0.156; p˂0.0001) in these cognitively unaffected subjects. In autopsy‐confirmed cortical homogenates, MSR1 protein levels display negative correlations with both Aβ plaques (R2=0.035; p=0.1768) and neurofibrillary tangles (R2=0.136; p=0.0067). On the other hand, MSR1 mRNA levels of the same samples are not correlated with plaques (R2=0.008; p=0.5255) and tangles (R2=0.009; p=0.4971) density. Studies are underway to contrast MSR1 levels with amyloid‐42, p(181)tau and total tau in the same tissues.

Conclusion

MSR1 plays a significant role in the pathophysiology of AD and recent evidence suggests that elevated MSR1 protein observed in the early stages of AD are followed by a progressive decline that coincides with the emergence of Tau pathology.
Characterizing progressive speech changes in prodromal‐to‐mild Alzheimer’s disease using natural language processing
Authors: Robin Jessica , Xu Mengdan , Balagopalan Aparna , Novikova Jekaterina , Kahn Laura , Oday Abdi , Hejrati Mohsen , Hashemifar Somaye , Negahdar Mohammadreza , Simpson Bill , Teng Edmond
Published: December 2022

Background

Novel automated tools for analyzing speech and language may provide new insights into Alzheimer’s disease (AD). Although speech and language changes occur in AD and other neurodegenerative diseases, current clinical assessments to monitor these symptoms can be burdensome and may have limited sensitivity. Through analyses of open‐ended naturalistic speech collected from a standardized clinical interview, we developed a novel measure to characterize progressive speech changes in AD.

Methods

We analyzed Clinical Dementia Rating (CDR) recordings from a subset of 101 participants (58F, 43M, mean age=69 years, SD=7) from the Tauriel trial of semorinemab in prodromal‐to‐mild AD. CDR recordings were collected at the baseline, 6‐month, 12‐month and 18‐month timepoints. Recordings were processed using the Winterlight speech analysis platform which generates >500 acoustic and linguistic features. After controlling for age, sex and level of education, we identified multiple features that had significant linear effects of time (indicating progressive longitudinal change). These speech features were combined into an unweighted composite speech score, which was compared with other clinical endpoints.

Results

The novel speech composite score included six linguistic features (related to word duration, word frequency, syntactic depth, use of nouns, pronouns and particles) and three acoustic features (related to the power spectrum of the vocal recordings). When compared with clinical endpoints, the speech composite had a similar effect size for detecting longitudinal change (β=0.29) compared to the CDR‐Sum of Boxes (CDR‐SB; β=0.30) and Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog; β=0.22). Notably, it had a significantly greater longitudinal effect size compared to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; β=‐0.15, p<0.01) and the language subscales of the ADAS‐Cog measuring word finding difficulty (β=0.12, p<0.01) and spoken language ability (β=0.09, p<0.01).

Conclusions

Progressive speech changes are detectable in early AD and measurable via automated language processing tools. Speech composite scores have the potential to be more sensitive measures of disease progression and/or treatment response for speech‐related symptoms in AD that do not contribute to additional patient burden. Further validation is needed to replicate these findings and confirm the clinical and neuropathological relevance of this novel measure.
The fluid biomarker landscape in genetic FTD
Authors: van Swieten John C ,   GENFI consortium
Published: December 2022

Background

There is an increasing need for the use of fluid biomarkers in clinical management and future therapeutic trials of patients with genetic FTD.

Method

Several fluid biomarkers have been investigated in the largest longitudinal cohort of patients with genetic FTD (GENFI; n > 1000) associated with mutations in the progranulin (GRN), MAPtau and C9orf72 gene. Concentration changes in neurofilament light and neurofilament high protein (NfL and pNfH), neuronal pentraxin (NPTX2), glial fibrillary acidic protein (GFAP), dipeptides, complement factors and miRNAs have been correlated with disease onset and progression, disease severity and grey matter volume loss in pre‐ and symptomatic carriers. Sequences of biomarker abnormalities were analyzed using discriminative event‐based modelling (DEBM).

Result

A number of promising fluid biomarkers have been identified in all or in specific genetic subtypes of FTD, with a specific sequence of biomarker changes over time from pre‐ to symptomatic stage. The next step will bet he development of a multi‐modal prediction tool at individual level, which may improve patient stratification and track the efficacy of therapeutic interventions.

Conclusion

Major scientific achievements have been made in fluid biomarker studies of the largest cohort of genetic FTD (GENFI).
Circadian age, chronological age, and Alzheimer’s dementia
Authors: Li Peng , Sun Haoqi , Gao Chenlu , Gao Lei , Yu Lei , Yang Jingyun , Bennett David A , Buchman Aron S , Hu Kun
Published: December 2022

Background

In older adults, circadian rhythms show alterations in multiple dimensions with aging and during Alzheimer’s dementia progression. We propose that circadian function may serve as a unique gauge of biological age (i.e., circadian age), and that individuals with greater circadian age than chronological age have increased risk of Alzheimer’s dementia.

Method

We constructed a regression model with chronological age as the predicting target. The model prediction was termed circadian age. A softplus activation function was used to ensure positivity. The model was optimized to minimize the mean‐squared prediction error while penalizing the covariance between chronological age and prediction error. Cosinor analysis, nonparametric analysis, uniform phase empirical mode decomposition, and detrended fluctuation analysis were performed on baseline actigraphy data of 882 participants (age: 80.1±7.3; female/male: 692/190) from the Rush Memory and Aging Project who were cognitively intact and were not taking sleep medications. These analyses resulted in 23 features for circadian daily activity patterns as model inputs. The optimal model was trained through cross‐validation for the penalization parameter and applied to follow‐up actigraphy data. We compared circadian age among participants at different cognitive stages, evaluated the longitudinal change of circadian age, and examined the association of circadian age with incident Alzheimer’s dementia.

Result

Chronological age explained 24.8% of the variance in circadian age. At analytical baseline, participants with Alzheimer’s dementia had significantly greater circadian–chronological age deviation (CCD) than cognitively normal participants (2.98±1.43 vs. ‐0.13±0.42 years, p=0.04). For each 1‐year increase in chronological age, circadian age increased by 1.05±0.06 years (p<0.001), suggesting accelerated circadian aging. Among baseline cognitively normal participants, greater CCD was associated with an increased risk of Alzheimer’s dementia independent from chronological age, sex, total daily activity, sleep fragmentation, vascular disease and risk factors, and depressive symptoms. For a 10‐year increase in CCD, the hazard ratio was 1.23 (95% CI: 1.06‐1.42).

Conclusion

Circadian daily patterns can be integrated to predict chronological age. Older circadian age than chronological age is an independent risk factor for Alzheimer’s dementia. Future work should refine the determination of health status for training dataset and examine whether circadian age links with endogenous circadian function.
Alzheimer’s Disease Patients, Especially ApoE4 Carriers, Have Significantly Reduced High‐density Lipoprotein Particle Size Revealed by Negative‐stained Transmission Electron Microscopy
Authors: Zheng Jack Jingyuan , Hong Brian V. , Agus Joanne , Guo Fei , Lebrilla Carlito B. , Jin Lee‐Way , Maezawa Izumi , Harvey Danielle J. , Zivkovic Angela M.
Published: December 2022

Background

High density lipoproteins (HDL) are protective against a wide array of diseases and have recently also been found to be associated with reduced risk of Alzheimer’s Disease (AD). However, the amount of circulating HDL‐cholesterol does not correlate closely with function, explaining only about 40% of the variance in HDL’s ability to perform its primary role of cholesterol efflux. HDL particle composition, size and structure are important determinants of functional capacity, however little is known about HDL particle physical characteristics in AD patients, in particular whether there are apolipoprotein E (APOE) genotype‐dependent effects.

Method

Plasma samples from a total of 172 APOE genotyped patients, n = 37 ApoE3/E3 and n = 34 ApoE3/E4 with diagnosed AD, n = 22 ApoE3/E3 and n = 18 ApoE3/E4 with diagnosed MCI, and n = 44 ApoE/E3 and n = 39 ApoE3/E4 age‐ and sex‐matched non‐AD controls were obtained from the UC Davis Alzheimer’s Disease Research Center biobank. HDL particles were isolated from plasma by sequential density‐adjusted ultracentrifugation followed by size‐exclusion chromatography. The size of HDL from each patient was characterized using negative‐stained transmission electron microscopy (NS‐TEM) followed by computational particle size analysis.

Result

On average, 34 TEM micrographs were obtained, and over 33,000 individual particles were selected and analyzed from each HDL sample using pre‐determined image quality and image selection criteria. The average particle size were compared between AD patients and controls stratified by APOE genotype. The mean particle diameter of HDL from MCI and AD patients was smaller compared to the control group (8.28 +/‐ 0.587, 8.30 +/‐ 0.662 vs. 8.84 +/‐ 0.587, respectively). The differences remained statistically significant when stratified by genotype. Both MCI and AD group had smaller HDL particle size compared to the control group in the ApoE3/E3 genotype (8.37 +/‐ 0.452, 8.48 +/‐ 0.613 vs. 8.90 +/‐ 0.602, respectively), and in the ApoE3/E4 genotype (8.17 +/‐ 0.707, 8.11 +/‐ 0.667 vs. 8.80 +/‐ 0.582, respectively).

Conclusion

These results reveal that patients with Alzheimer’s dementia and mild cognitive impairment have disrupted HDL particle distribution, with smaller average HDL particle size, highlighting the need for further studies of lipoprotein metabolism in AD.
Chronicling the diagnostic journey, symptom experiences, and disease impact in frontotemporal degeneration
Authors: Barker Megan S , Joyce Jillian L. , Dodge Shana G. , Niehoff Debra , Denny Sharon S. , Dacks Penny A. , Dickinson Susan , Cosentino Stephanie , Wheaton Dianna K.H.
Published: December 2022

Background

Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive decline or changes in cognition, language, behavior, and personality. The FTD Insights Survey was created with the aim of gathering information on the lived experience of FTD. Here we present a subset of survey data chronicling the diagnostic journey, symptoms experienced, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease course.

Method

In total, 1,796 individuals completed the survey. Persons reported as severe to profoundly impaired due to FTD, as well as past caregivers, were excluded for this analysis. The resulting cohort included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses (n = 395 behavioral variant frontotemporal dementia or Pick’s disease; n = 155 primary progressive aphasia; n = 61 progressive supranuclear palsy or corticobasal syndrome; n = 13 FTD with amyotrophic lateral sclerosis; n = 32 unknown).

Result

Around half of survey respondents saw three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses, including primary psychiatric disorders, Parkinson’s disease, or Alzheimer’s disease, were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was highly endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick’s disease. Participating independently in activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the significant disruption to daily living even at the mild and moderate stages of disease.

Conclusion

Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop new therapies that improve quality of life
Validation of a continuous model of amyloid‐β CSF/PET discordance across cohorts and PET tracers
Authors: Sala Arianna , Gispert Juan Domingo , Salvadó Gemma , Shekari Mahnaz , Bucci Marco , Collij Lyduine E. , García David Vállez , Garibotto Valentina , Barkhof Frederik , Nordberg Agneta K , Rodriguez‐Vieitez Elena ,   Alzheimer's Disease Neuroimaging Initiative, on behalf of the AMYPAD project
Published: December 2022

Background

Recently, we provided evidence that discordance in CSF vs. PET amyloid‐β biomarkers represents a natural phase in the progression of amyloid‐β pathology, with either CSF or PET biomarkers becoming abnormal first, based on well‐validated cut‐offs. We found that CSF‐/PET+ individuals had lower prevalence of APOE‐ε4 genotype and slower rate of amyloid‐β PET accumulation compared with CSF+/PET‐ individuals [1]. Given the methodological limitations of binary cut‐offs, here we aimed to validate a continuous model of imbalance in CSF vs. PET amyloid‐β biomarkers across cohorts and tracers, and to investigate biological factors underlying discordance in CSF and PET results.

Method

The study included n=944 participants from two independent cohorts: ADNI and AMYPAD. We selected n=822 individuals (73.0±7.4 yr‐old, 53% female, 45% APOE‐ε4 carriers, 16.3±2.6 yr‐education) from ADNI, ranging from cognitively‐normal to demented, with global cortical 18F‐florbetapir‐PET and CSF‐Aβ42 measurements available within 3‐months; all participants also had CSF‐Aβ38 and CSF‐Aβ40 available. We also selected n=112 individuals (65.6±7.0 years, 59.8% female, 30.6% APOE‐ε4 carriers, 15±3.5 yr‐education) ranging from cognitively‐normal to MCI from the AMYPAD Prospective and Natural History Study (PNHS) cohort with CSF‐Aβ42 and global cortical 18F‐flutemetamol (n=75) or 18F‐florbetaben (n=37) PET available within one‐year, expressed in Centiloids. In each cohort, we iteratively fitted the CSF/PET cross‐sectional data to a hyperbolic regression model with three parameters, by minimizing the Euclidean distance of the experimental points to the fitted line (Fig. 1). For each individual, we derived a measure of imbalance based on standardized residuals, with zimbalance>0 reflecting PET‐over‐CSF imbalance (zimbalance<0 reflecting CSF‐over‐PET imbalance).

Results

The hyperbolic model adequately fitted the CSF/PET data across cohorts and tracers (pseudo‐R2>0.90, Fig. 1). In ADNI, greater zimbalance (PET‐over‐CSF imbalance) was associated with lower APOE‐e4 prevalence, and higher levels of CSF‐Aβ42, CSF‐Aβ40 and CSF‐Aβ38, corrected for demographics and disease stage. Studies in the AMYPAD cohort are ongoing.

Conclusion

We tested a continuous model of amyloid‐β CSF vs. PET imbalance across cohorts and PET tracers. Imbalance in CSF vs. PET amyloid‐β values carries meaningful biological and genetic information, which allows to identify heterogeneous pathological trajectories in the AD continuum, with implications for clinical trials.

[1] Sala et al. (2021) Mol. Psychiatry 26(10):5864‐5874
INPP5D inhibition attenuates amyloid pathology through the regulation of microglial functions.
Authors: Lin Peter Bor‐Chian , Tsai Andy Po‐Yi , Soni Disha , Lee‐Goseelin Audrey , Nho Kwangsik , Lamb Bruce T , Oblak Adrian L
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome‐wide association studies recently highlighted a prominent role for microglia in late‐onset AD (LOAD). Specifically, inositol polyphosphate‐5‐phosphatase (INPP5D) is selectively expressed in brain microglia and one of its common intronic variants (rs35349669; OR=1.08, 95%CI=1.06‐1.11) has been reported to be associated with increased risk of LOAD. INPP5D is linked to the triggering receptor expressed on myeloid cells 2 (TREM2) signaling, but little is known about the function of INPP5D in microglia and how INPP5D regulates TREM2‐related AD pathogenesis. Therefore, we aim to understand the role of INPP5D in microglia and AD pathology.

Method

We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density using transcriptomic data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD) cohort. We also performed quantitative real‐time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression and microglial markers in the 5xFAD amyloid mouse model with INPP5D deficiency. Behavioral deficits were assessed by the Y‐maze assay in all animal cohorts at 4‐ and 6‐month of age. The primary microglial culture was used the evaluate the amyloid uptake ability of microglia.

Result

INPP5D gene expression was upregulated in LOAD and positively correlated with amyloid plaque density. Inpp5d expression increased as the disease progressed in the 5xFAD mice, and selectively in plaque‐associated microglia. Inpp5d deficiency mitigated the plaque burdens and neuropathology in the 5xFAD mice and further protected against behavioral deficits induced by amyloid pathology. Inpp5d deficiency modulates the microglial signaling, including Trem2 expression and Syk phosphorylation, and further upregulates the expression of the post‐synaptic marker. In the primary microglial culture, Inpp5d inhibition increased the uptake of fibril amyloid beta‐peptide.

Conclusion

Our findings show that INPP5D expression increases throughout the AD progression and is predominantly in plaque‐associated microglia. Importantly, INPP5D deficiency reduces Abeta pathology through the regulation of microglial functions, highlighting INPP5D as a potential therapeutic target.
A Population‐Based Meta‐Analysis of Plasma Glial Fibrillary Acidic Protein for Cognitive Decline and Incident Dementia
Authors: Gonzales Mitzi M , Wiedner Crystal , Wang Chen‐Pin , Bis Josh C , Li Zhiguang , Himali Jayandra J , Parent Danielle , Kautz Tiffany F , Pase Matthew P , Aparicio Hugo J , Beiser Alexa S , Launer Lenore J. , Fornage Myriam , Tracy Russell P. , Seshadri Sudha , Satizabal Claudia L
Published: December 2022

Background

Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, co‐localizes with neuropathology in the brain. Blood‐derived levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability and assess the biomarker’s potential efficacy in community settings.

Method

Plasma GFAP levels were assayed using a Simoa HD‐1 analyzer in 4,338 adults without prevalent dementia from four longitudinal cohort studies, the Framingham Heart Study (FHS), the Cardiovascular Health Study (CHS), the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES), and the Coronary Artery Risk Development in Young Adults Study (CARDIA). The associations between plasma GFAP levels with a general cognition score derived from multiple cognitive tests, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer’s disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random effects models with inverse variance weighting. The Sidik‐Jonkman estimator was used to report overall associations across studies.

Result

Meta‐analysis indicated that higher plasma GFAP associated with lower general cognition (ß=‐0.09, [95% confidence interval [CI]: ‐0.15 to ‐0.03], p=0.005), but not with total brain or hippocampal volume (p>0.05 for all). However, higher GFAP was significantly associated with a 2.5‐fold higher risk of incident all‐cause (Hazard Ratio [HR]: 2.47 (95% CI: 1.52‐4.01)) and Alzheimer’s disease dementia (HR: 2.54 (95% CI: 1.42‐4.53) per standard deviation increase over up to 15‐years of follow‐up.

Conclusion

The findings suggest that elevations in plasma GFAP may be detectable several years prior to a clinical diagnosis, highlighting the potential value of the biomarker for aiding dementia risk prediction at a population‐based level
Novel AD biomarker based on platelets tau: Expanding to plasma detection
Authors: González Andrea , Guzmán‐Martinez Leonardo , Maccioni Ricardo Benjamin
Published: December 2022

Background

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly. One of the major drawbacks of this disease is the lack of molecular biomarkers that could provide of an early detection, as the ones currently available are invasive (CSF biomarkers), not cost‐efficient (neuroimaging, PET scan) and do not provide an early detection. In this work we propose the novel biomarker Alz‐tau®, based on platelet tau, as a non‐invasive and cost‐efficient way for early detection of pathological events that may lead Alzheimer’s disease.

Methods

Plasma samples were obtained by centrifugation. Platelets were obtained from blood samples of AD patients and controls, lysed to obtain protein extracts and further processed for a western blot analysis. The immuno‐ detection was performed with a novel monoclonal antibody tau51, which detects two variants of tau protein: a high molecular weight variant (HMW) and a low molecular weight variant (LMW). The results obtained were subjected to a densitometric analysis with ImageJ and the algorithm HWM/LMW was obtained.

Results

We demonstrated that in platelets the algorithm HWM/LMW was statistically higher in AD patients when compared to controls. Similar results were obtained in plasma. Likewise, the platelet biomarker has a proven sensitivity of 71.43% and a specificity of 69.23%, while a sensibility of 80% and specificity of 66.5% was found in plasma samples.

Conclusions

Here, we demonstrate the efficiency and functionality of of a novel, non‐invasive, and cost‐efficient biomarker for early detection of AD, based on 4 clinical trials. The most relevant feature of this biomarker is that it is able to detect alterations before the patient presents any symptoms, thus it would be highly beneficial for prevention of AD.
The Gut Microbiota in Mild Cognitive Impairment in Community‐Dwelling Older Adults in Taiwan
Authors: Chuang Yi‐Fang
Published: December 2022

Background

Recent microbial studies of Alzheimer’s disease and mild cognitive impairment (MCI) have focused on the alterations of gut microbiota in cognitively impaired patients. However, related research remains limited and varies with analytical pipelines. This study aims to examine biodiversity and the differential abundance of gut flora in MCI.

Method

The study sample of 96 older adults was derived from a community‐based prospective cohort study, the Epidemiology of Mild Cognitive Impairment in Taiwan (EMCIT). Among them, 31 were ascertained as MCIs, matched with 65 cognitively normal individuals on age, gender and community. Fecal samples were analyzed by Illumina sequencing of the V3‐V4 regions of the 16S rRNA gene. The divisive amplicon denoising algorithm 2 (DADA2) pipeline was applied to the production of the amplicon sequence variant (ASV) table, and the SILVA database 138.1 was used to assign taxonomies.

Result

There is no significant difference in alpha‐ and beta‐ diversity between MCI and cognitively normal adults after adjusting for age, gender, community, education and hypertension. (Fig. 1). However, the results of linear discriminant analysis (LDA) effect size (LEfSe) showed a differential abundance of ASVs between two groups. Increased abundance of several genera within Firmicutes phylum and reduced abundance of Ruminococcus, Butyricimonas, Oxalobacter are associated with MCI. A ROC curve using these microbial genera of interest can distinguish MCI patients from controls with AUC = 84%. (Fig. 2)

Conclusion

Compared with cognitively normal older adults, the gut microbiota of older adults with MCI identified from the community was significantly altered, particularly manifesting in enriched genera from the Firmicutes phylum and decreased abundance of genera Ruminococcus, Butyricimonas, Oxalobacter.
Language Fluency and Premature Brain Aging
Authors: Busby Natalie , Newman‐Norlund Sarah , Sayers Sara , Newman‐Norlund Roger , Nemati Samaneh , Bonilha Leonardo , Fridriksson Julius
Published: December 2022

Background

Age‐related changes in the brain are often associated with general cognitive decline. Cognitive aging affects the ability to produce spoken language, with older adults experiencing increased difficulties in word‐finding1 and verbal fluency2,3. Neurodegenerative diseases such as Alzheimer’s disease are often attributed to an acceleration of typical aging processes (i.e., premature aging). Accelerated age‐related atrophy is present in mild cognitive impairment4,5 and premature brain aging may contribute to declining cognitive skills6,7. A recent study demonstrated that the disparity between chronological age and brain age (based on measures of cortical integrity) is a good predictor of early cognitive impairment8. Our aim was to extend these findings by investigating the role of brain age in overall cognition as well as language in particular.

Method

Participants included 216 healthy controls (age range 20–79) from the Aging Brain Cohort at the University of South Carolina9. Structural T1‐weighted MRI scans were collected, and participants completed the Montreal Cognitive Assessment (MoCA10). Brain age was calculated based on T1‐weighted structural data using the BrainAgeR analysis pipeline (github.com/james‐cole/brainageR). A brain age gap estimate (BrainAGE)11 was calculated as the difference between brain age and chronological age. This was used as the primary measure of advanced/delayed brain health, where positive values represent premature brain aging.

Result

Estimated brain age differences ranged from 22 years younger to 14 years older than chronological age. Pearson correlations revealed a negative correlation between MoCA total score and chronological age (r(209) = ‐0.41, p<0.001), but not in partial correlations using BrainAGE, accounting for chronological age (r(207) = ‐0.003, p = 0.48.). Regarding our language measure (words generated during the MoCA fluency task), we observed a negative correlation with BrainAGE, corrected for chronological age (r(208) = ‐0.133, p = 0.03), but no correlation with chronological age (r(210) = ‐0.04, p = 0.58).

Conclusion

Our data support the hypothesis that differences between chronological and brain age are related to cognition and language, and highlight the utility/importance of brain age in understanding cognitive impairment. Interestingly, findings suggest that there may be a particularly strong relationship between the brain age gap estimation and MRI‐based measure of brain aging and language in particular.
Feasibility Study for Detection of Retinal Amyloid in Clinical Trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Trial
Authors: Ngolab Jennifer , Korouri Shaina , Rissman Robert A.
Published: December 2022

Background

Alterations to the retina manifest in patients diagnosed with neurodegenerative diseases such as Alzheimer’s disease (AD). Retinal imaging techniques open the possibility for non‐invasive evaluation of AD pathology. Clinically AD diagnosed patients exhibit retinal amyloid deposits. Few studies monitoring preclinical individuals exist, limiting the assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection.

Method

We compared retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline.

Result

Participants from the A4 trial exhibited a greater number of retinal spots compared to those from the LEARN study. We report a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr).

Conclusion

The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.
Support for Dementia Care Partners using Telehealth: Tele‐STELLA Phase 1
Authors: Lindauer Allison , Gothard Sarah , Boardman Charles , Smith Samantha , Mattek Nora , McDaniel Delaney , Bernard Hannah , Tran Leslie , Tadesse Ruth
Published: December 2022

Background

Effective interventions that reduce dementia Care Partner stress and burden are available. but access to them is impeded by barriers such as distance, cost, behavioral symptoms of dementia, stigma and social anxiety.

Tele‐STELLA is a multi‐component, videoconference‐based intervention designed to provide easily‐accessible education and support for Care Partners.

The goal of this intervention is to diminish the frequency of behavioral symptoms that persons with dementia experience, and Care Partner reactivity to these symptoms. Here we report on the findings of Phase 1 of Tele‐STELLA.

Method

In Tele‐STELLA interventionists meet with Care Partners, via videoconferencing, to identify specific behavioral symptoms of dementia that are distressing for them. The interventionists and Care Partners meet, first individually and then in groups, to address these symptoms using an analytic approach. Care Partners are encouraged to contact each other for support.

Prior to, during, and after the 8‐week intervention we collect data on behavioral symptoms (frequency and Care Partner reactivity to the symptoms), depression, and burden using electronically‐administered surveys.

Result

Of the 26 Care Partners who completed 8 weeks of the intervention 19 (70%) were female, average age of 67; 25 (96%) identified as white; 14% lived in a rural area. Burden, as assessed on the Revised Memory and Behavior Problem Checklist, did not change significantly over the 8‐week intervention, nor did scores on depression, grief or quality of life measures. There was no change in behavior frequency, but we did appreciate a significant improvement in Care Partner reactivity to the two personalized target problems they identified (p<0.01 and p=0.025, respectively).

Conclusion

Significant improvement was seen in Care Partner reactivity to the specific behavioral problems chosen by the Care Partners. This suggests the intervention is effective when Care Partners work on the personalized problems they identified. The lack of significant improvement on the (depersonalized) surveys may be due to unbiased reporting by Care Partners using electronically‐administered surveys, small sample size, or stabilization of affective symptoms. Phase 1 will inform revisions for the remainder of the study (total n goal=150).