bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal changes in the expression of Alzheimer’s disease‐related pattern and default mode network
Authors: Perovnik Matej , Tang Chris C , Šalamon Sandi , Eidelberg David ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

Background

The Alzheimer’s disease‐related pattern (ADRP) is an imaging biomarker of AD, for which expression levels correlate with cognitive impairment in individual patients. The default mode network (DMN) is a dominant metabolic network expressed in healthy individuals. Longitudinal changes in ADRP and DMN expression levels have not been comprehensively studied in patients with AD or mild cognitive impairment (MCI), or in cognitively normal (CN) subjects.

Method

We obtained longitudinal data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database of participants who were CN (n=59), or who had MCI (n=128) at baseline and underwent 3 or more FDG PET scans (nscans=704) and had CSF amyloid and APOE information available. Groups were divided based on the conversion status, i.e., if they developed MCI/dementia at follow‐up. There were 36 stable and 23 converting CN participants and 73 stable (sMCI) and 55 converting (cMCI) participants. Amyloid positivity was defined as CSF Aβ42 < 880 pg/mL and APOE positivity as presence of one or more APOE4 allele. We used an automated algorithm to calculate standardized ADRP and DMN expression levels for each scan. Repeated measurements ANOVA (RMANOVA) was used to evaluate longitudinal changes in network expression in each group, as well as network interactions with conversion status, amyloid and APOE positivity.

Results

ADRP expression increased over time, but at with different rates in the CN, sMCI and cMCI groups (p<0.001). The interaction effect was significant between CN and cMCI (p<0.001) and sMCI and cMCI (p=0.009), but not between CN and sMCI (p=0.51). There was no significant interaction between group and time on DMN expression (p=0.60). Analysis of each group separately revealed no significant interaction between APOE4 status and time on ADRP or DMN expression levels (all p>0.10). There was a significant interaction between conversion status and time on ADRP and DMN in CN group (p<0.04). There was also a significant main effect of time on ADRP and DMN in cMCI group (p<0.04) and a significant interaction between amyloid and time on DMN expression (p=0.03).

Conclusion

ADRP progression was faster in cMCI compared to CN and sMCI. The longitudinal changes in DMN were not significantly different across groups.
Evaluation of pathologies associated with hyperhomocysteinemia in human autopsy brain tissue
Authors: Weekman Erica M , Winder Zachary , Rogers Colin B , Abner Erin L , Patel Ela , Dugan Adam , Fister Shuling X , Wasek Brandi , Bottiglieri Teodoro , Fardo David W. , Wilcock Donna M
Published: December 2022

Background

Vascular contributions to cognitive impairment and dementia (VCID) are one of the leading causes of dementia; VCID affects roughly 10‐40% of all dementia patients. A major, yet underrecognized, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy). Defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy has been recognized as a risk factor for VCID, studies aimed at identifying pathologies associated with HHcy have been lacking.

Method

To determine pathologies associated with HHcy, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (>14μmol/L) and 18 had high plasma homocysteine levels (<14μmol/L). We then measured levels of homocysteine and related metabolites in both plasma samples taken closest to autopsy and frontal cortex. Next, we determined whether the level of plasma homocysteine was associated with several markers identified via immunohistochemistry, including Aβ, PHF‐1, IBA‐1 and GFAP. Plasma and brain protein markers for inflammation and angiogenesis were also measured to determine associations with plasma homocysteine. Finally, we used the Human Neuroinflammation NanoString panel to determine gene expression changes of inflammatory markers associated with high homocysteine levels in the frontal cortex and occipital lobe.

Result

Plasma metabolite analysis showed patients who had elevated levels of homocysteine also had increased levels of several homocysteine cycle metabolites such as cysteine, S‐adenosyl‐homocysteine, cystathionine and choline. Flt1, an angiogenic marker, and IL5, an inflammatory marker, had a positive correlation with increased plasma homocysteine. No correlation between IBA‐1 or GFAP immunohistochemistry with plasma homocysteine was found. Gene expression showed that most genes were downregulated in the presence of high plasma homocysteine, including many significant genes involved in apoptosis, growth factor and cytokine signaling, and the innate and adaptive immune response.

Conclusion

These preliminary data show that increased plasma homocysteine correlates with protein inflammatory and angiogenic markers and with a significant downregulation of inflammation‐related gene expression markers in the brain. Overall, this could reflect impaired normal immune function, providing possible mechanisms by which hyperhomocysteinemia induces cognitive deficits and cerebrovascular damage.
Re‐examining the impact of adjusting for education and sex the RBANS delayed memory score: Implications on the cut‐offs used to detect cognitive impairment in prodromal Alzheimer’s disease. Data from the EPAD‐LCS study.
Authors: Sánchez‐Benavides Gonzalo , Buongiorno Mariateresa , Brugulat‐Serrat Anna , Cañas‐Martínez Alba , Canals‐Gispert Lidia , Minguillón Carolina , Milà‐Alomà Marta , Grau‐Rivera Oriol ,   EPAD Consortium
Published: December 2022

Background

the RBANS is a multilingual brief cognitive battery commonly used in both clinical practice and research. Its delayed memory index has been used as entry criteria for clinical trials in early stages of Alzheimer’s disease (AD). Although several studies reported a significant effect of education and sex in RBANS scores, the published normative data only provide adjustments by age. We aimed at exploring the impact of sex and education in the age‐adjusted scores and studying the percentage of change in the classification of memory impairment, along with the association with AD biomarker status after adjusting for education and sex.

Methods

We analyzed data from the EPAD baseline Longitudinal Cohort Study (n = 1,716 [Clinical Dementia Rating [CDR] = 0 n = 1,233; CDR = 0.5 n = 483]), see Table 1. We used multiple regression to assess the impact of years of education and sex on the age‐adjusted delayed memory index within the CDR = 0 sample. The coefficients obtained were used to generate sex‐, education‐ and age‐adjusted scores. The whole sample was classified as having/not having memory impairment (<85 points) with published and full adjusted scores. Within CDR = 0.5 group, the concordance between presence of memory impairment and pathologic amyloid‐β (A+; cut‐off = 1000 pg/ml) and p‐tau levels (T+; cut‐off = 27 pg/ml) in cerebrospinal fluid was assessed.

Results

Education and sex (being a woman) had significant positive effects (p<0.001) on the age‐adjusted delayed memory scores (Partial eta2 = 0.035 and 0.010). We observed a change of up to 10 points after sex and education adjustment (mean[SD] change = 0.83 [2.6]). The use of fully adjusted scores increased the number of individuals classified as having memory impairment by 1.7%. Within the CDR = 0.5 group, these scores identified 2.5% individuals with memory impairment that were considered within the normal range using the regular norms, and increased the concordance between memory impairment and A+T+ biomarkers by almost 5% (regular norms = 65.2%, adjusted norms = 69.7%).

Conclusion

Although small, education and sex exert a relevant effect in the delayed memory score of the RBANS and improve clinical and biomarker concordance of the conclusions on the cognitive status derived from them. Adding education and sex adjustments to the RBANS measures may improve the selection of individuals for clinical trials.
Insulin and hippocampal subregion volume in older adults
Authors: Twisselmann Alicia M , Tubi Meral A , Hall Brandon J , Hazra Nalini , Matsiyevskiy Elizabeth , Wheeler Koral , Johnson Leigh , Yaffe Kristine , Toga Arthur W. , O'Bryant Sid E. , Braskie Meredith N ,   for the HABS‐HD Study Team
Published: December 2022

Background

Type 2 diabetes (DM) is a risk factor for Alzheimer's disease (AD) and other dementias. DM, which is more common in Mexican Americans (MA) than non‐Hispanic Whites (NHW), is associated with high blood glucose levels and often with hyperinsulinemia. Hippocampal volume is an early neuroimaging marker of AD. We examined the relationship of blood insulin with hippocampal subregion volumes in MA and NHW.

Method

In a sample of 1588 older adults without dementia (age: 50‐92 years; 826 MA, 762 NHW; 387 DM, 1201 non‐DM; 1344 cognitively normal, 244 mild cognitive impairment; 613M/975F) from the Health and Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort, we assessed whether fasting plasma insulin and glucose levels were associated with the volume of left and right hippocampal body subregions (CA1, CA23DG, subiculum) using hippocampal high resolution 3T MRI scans (Siemens 3T). We further examined the significant insulin relationship with CA23DG volume by ethnicity and diabetes diagnostic group. We used a multiple linear regression model, covarying for age, sex, cognitive diagnosis, diabetic status, years of education, number of MRI slices segmented, and intracranial volume. All p values were FDR corrected for multiple comparisons across regions.

Result

Higher insulin levels were associated with a smaller volume in right and left CA23DG (right: FDR p=0.015, left: FDR p=0.015) across all participants. Glucose levels were not significantly associated with hippocampal subregion volume (Table 1). When we further investigated the significant relationship between insulin and CA23DG volume by ethnic group and diabetic status, we found that higher insulin was associated with lower CA23DG volume in NHW (right: p=0.014, left: p=0.013), MA (right only: p=0.034, left: p=0.115), and in non‐diabetics (right: p=0.027, left trend: p=0.056) (Figure 1).

Conclusion

Higher insulin levels were associated with lower CA23DG volume in older adults without dementia, with the strength of the negative association between blood insulin levels and hippocampal subfield volume varying by diabetic status.
A Quantitative‐EEG Assessment of Alpha‐1062, a Novel Pro‐Drug of Galantamine for the Treatment of Mild to Moderate Dementia Associated with Alzheimer’s Disease.
Authors: Kay Denis G , Stijl‐’t Hart Ellen , Bakker Charlotte , Linkenkaer‐Hansen Klaus , Sancilio Frederick D , Ortiz J. Bryce , Groeneveld Geert Jan , Poil Simon‐Shlomo
Published: December 2022

Background

Acetylcholinesterase inhibitors (AChEIs) enhance cognitive functioning in Alzheimer’s disease (AD). The use of AChEIs at therapeutic doses is limited by gastrointestinal (GI) side effects, such as nausea, vomiting and diarrhea. Alpha‐1062 is a pharmacologically inactive prodrug of the AChEI galantamine specifically designed to reduce or eliminate GI side effects and provide increased safety. In addition to its activity as an AChEI, galantamine exhibits a second important mechanism of action, binding allosterically to nicotinic cholinergic receptors enhancing their responsiveness to acetylcholine. In Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) trials in young and elderly healthy subjects, Alpha‐1062 demonstrated both evidence of an improved GI side effect profile and enhanced cognition. Here we extend the findings of the SAD and MAD studies with an additional analysis of the effects of Alpha‐1062 on quantitative‐EEG (qEEG) data collected as part of the MAD study.

Methods

Subjects (n = 12/dose) were administered two doses per day of Alpha‐1062 for 7 consecutive days. Pharmaco‐EEG measurements were performed for 4 min eyes closed / 4 min eyes open, on day 1 and day 7 at various timepoints both pre‐dose and post‐dose using a standard 10‐20 electrode montage with 21 channels. qEEG data analysis was conducted using qEEG indices developed using a machine learning algorithm based on the analysis of 39 AD patients administered galantamine (Sci Rep
7, 5775 [2017]). These were an AD index and a galantamine index, which were expected to be sensitive to the effects of Alpha 1062 administration.

Results

In healthy elderly subjects, Alpha‐1062 administration improved response on the AD index (p <0.05) compared to placebo, at the pre‐dose timepoint on day 7. The AD index was also reduced at all post‐dose timepoints on day 7 relative to placebo. Changes in several other relevant measures of qEEG function suggested Alpha‐1062 improved brain function.

Conclusion

These data demonstrate the potential benefit Alpha‐1062 in the treatment of AD. Alpha‐1062 was safe in the dose range investigated, and influenced pharmaco‐EEG outcomes in healthy elderly subjects that were consistent with the previously documented positive effects in tests related to sustained attention and working memory.
Autopsy Results from the ENGAGE Trial of Aducanumab: Lessons from Co‐pathology
Authors: Horiki Sheena , VandeVrede Lawren , La Joie Renaud , Ljubenkov Peter A. , Koestler Mary , Rojas Julio C. , Rabinovici Gil D. , Boxer Adam L. , Seeley William W.
Published: December 2022

Background

Aducanumab, a monoclonal antibody that clears amyloid aggregates, received FDA approval for early‐stage Alzheimer’s Disease (AD). Clinicopathologic studies from patients treated with aducanumab are as yet unavailable, and may inform clinical use. Therefore, we report the clinical course, PET, and autopsy results from two patients treated with aducanumab.

Methods

Patients were seen at UCSF and enrolled in ENGAGE (NCT02477800). Florbetapir (FBP) PET was obtained, including the initial six‐month treatment interval. Additional data, including flortaucipir (FTP) PET, was available through UCSF ADRC. PET was analyzed locally, and neuropathological analyses were performed by the UCSF Neurodegenerative Disease Brain Bank.

Results

Patient 1: 77‐year‐old male (ApoE3/3) with vascular risk factors; onset age 63 with slowed processing, memory loss, and executive dysfunction. Fourteen doses aducanumab (6mg/kg) were administered in ENGAGE and 3 doses (1mg/kg) in EMBARK (NCT04241068). FBP demonstrated 8% reduction in amyloid centiloids (67.8→62.7). FTP encompassing four‐year interval from diagnosis to ENGAGE closure showed increase in metatemporal SUVR (1.175→1.273), with progression of cortical atrophy on MRI. He died of myocardial infarction (FBP‐to‐autopsy interval: 577d). Autopsy revealed intermediate ADNC (Thal 3, Braak 5, CERAD frequent), and substantial vascular pathology including chronic multifocal microinfarcts.

Patient 2: 64‐year‐old female (ApoE4/4); onset age 55 with rapid forgetting, executive dysfunction, prominent anxiety, and dream enactment. Fourteen doses aducanumab (10mg/kg) were administered prior to early‐termination due to disease progression. FBP showed 38% reduction in amyloid centiloids (42.1→26.2). After discontinuation, she developed dysautonomia, parkinsonism, and paranoia, later dying in status epilepticus (FBP‐to‐autopsy interval: 1120d). Autopsy revealed high ADNC (Thal 5, Braak 6, CERAD frequent), extensive cortical Lewy bodies disease (LBD, Braak 6), moderate cerebral amyloid angiopathy, and amygdalar TDP‐43 (LATE‐NC Stage 1).

Conclusion

Vascular disease and LBD, both common co‐pathologies in AD, likely contributed to the clinical phenomenology and course of these patients. In the first case, low‐dose aducanumab did not substantially reduce amyloid, and the patient later died from unrelated heart disease. In the second case, despite substantial amyloid clearance on high‐dose, co‐morbid LBD led to clinical progression and discontinuation. Additional autopsy studies are needed to clarify the neuropathological effects of aducanumab, and the role of AD co‐pathology.
Plasma biomarkers associations with cognitive change in preclinical Alzheimer’s disease
Authors: Milà‐Alomà Marta , Sánchez‐Benavides Gonzalo , Ashton Nicholas J. , Ortiz‐Romero Paula , Montoliu‐Gaya Laia , Benedet Andréa Lessa , Karikari Thomas K , Rodriguez Juan Lantero , Brugulat‐Serrat Anna , Escalante Armand González , Vanmechelen Eugeen , Day Theresa A. , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Dage Jeffrey L. , Zetterberg Henrik , Gispert Juan Domingo , Blennow Kaj , Suárez‐Calvet Marc ,   for the ALFA Study
Published: December 2022

Background

Blood biomarkers to detect Alzheimer’s disease pathology are needed as screening tools and to predict the onset of cognitive decline. Although there is increasing data on their potential usefulness across AD continuum, comprehensive comparisons of their ability to predict cognitive decline in cognitively unimpaired (CU) populations are still lacking.

Method

We studied 214 CU individuals from the ALFA+ cohort (Table 1), which had baseline measurements of plasma p‐tau181, p‐tau217, p‐tau231, t‐tau, GFAP, NfL and Ab42/40. All biomarkers were measured with Simoa, except for plasma p‐tau217 and t‐tau that were MSD‐based assay measures (Eli Lilly and Company ). Longitudinal measures of cognition (Preclinical Alzheimer Cognitive Composite [PACC]) at 3 years’ follow‐up were available. All participants remained CU at follow‐up.

We tested the associations of baseline plasma biomarkers with PACC scores change (delta score computed as V2‐V1) using linear regression models adjusted by age, sex, education and time between neuropsychological visits. We further stratified by CSF Aβ‐status (Aβ+ if CSF Aβ42/40 <0.071) and interaction terms between each biomarker and Aβ‐status were evaluated. Finally, we studied the associations between baseline plasma biomarkers and cognitive change specifically in participants that displayed the steepest (<1SD) cognitive decline (“decliners”).

Result

In the whole sample, higher baseline plasma p‐tau181 (P=0.003) and t‐tau (P=0.007) were significantly associated with lower PACC scores at follow‐up. In CSF Aβ‐positive individuals, plasma p‐tau181, p‐tau231, t‐tau and NfL at baseline were significantly associated with cognitive decline while no significant associations were found in the Aβ‐negative group. The interaction with CSF Aβ status was significant only for plasma p‐tau231 (P=0.028) (Figure 1). In individuals that displayed a steeper decline (n = 33 [16% of the sample], Table 2), plasma p‐tau181, p‐tau217 and t‐tau were significantly associated with longitudinal change in PACC scores (Figure 2).

Conclusion

In preclinical AD, baseline plasma levels of p‐tau181, tau231, t‐tau and NfL are associated with cognitive decline at follow‐up. In the group of decliners, higher p‐tau181, p‐tau217 and t‐tau at baseline associate with cognitive change. These results have important implications for the consideration of plasma biomarkers for clinical trials targeting asymptomatic individuals or individuals with subtle cognitive decline.
Subtle cognitive deficits assessed by means of CANTAB in a cohort of subjects with CSF AD profile
Authors: Chipi Elena , Salvadori Nicola , Montanucci Chiara , Toja Andrea , Siena Elisa , Paoletti Federico Paolini , Bellomo Giovanni , Parnetti Lucilla
Published: December 2022

Background

In order to make successful disease‐modifying treatments, it is needed to shift Alzheimer’s disease (AD) diagnosis toward individuals with subtle cognitive deficits not yet fulfilling MCI criteria (pre‐MCI), entity associated with AD biomarkers positivity and increased risk of progression (Parnetti et al.,2019). This might allow to identify the individuals candidate to biomarker assessment. The detection of subtle cognitive impairment is limited by the sensitivity of standard neuropsychological measures (Wolfsgruber et al.,2020; Chipi et al.,2019). Cambridge Neuropsychological Test Automated Battery (CANTAB) represents an advanced computerized tool for the assessment of non‐verbal frontal‐subcortical functioning (Robbins et al.,1994). We aimed to explore the frequency of cerebrospinal fluid (CSF) AD‐like profile in pre‐MCI subjects defined as those obtaining low scores (≥‐1 SD) in at least one CANTAB test.

Method

We retrospectively analyzed 64 consecutive subjects (31 males, 33 females, mean age = 67±7.9) referring to our Memory Clinic for subjective cognitive complaints. All participants performed a comprehensive standard neuropsychological battery, reporting normal scores, and tests from CANTAB (Paired Associated Learning‐PAL; Pattern Recognition Memory‐PRM; Spatial Working Memory‐SWM). Pathological performance at CANTAB (CANTAB+) was defined as scores ≥‐1 SD in at least one task. All of them underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). By applying the A/T/(N) classification scheme (Jack et al.,2018), AD CSF profile was defined as A+/T+. As A biomarker, we considered the Aβ42/40 ratio.

Result

Out of 64 subjects, 43 performed ≥‐1SD in at least one test from CANTAB. In those 43 CANTAB+ subjects, 10 (23%) were A+/T+, 4 (9%) A+, and 22 (51%) A‐/T‐. Among CANTAB‐ (N = 21), 3 (14%) were A+/T+; 3 (14%) A+; 13 (61%) A‐/T‐. Among CANTAB+ subjects with A+/T+ (N = 10), 8 (80%) showed deficit in PAL, 4 at SWM and none of them showed altered scores at PRM.

Conclusion

Consistent proportion (23%) of pre‐MCI subjects with at least one altered score at CANTAB showed a CSF pattern compatible with AD. Since PAL test was altered in 80% of these subjects, if confirmed in independent cohorts, it might represent a sensitive neuropsychological measure to identify subjects with subtle cognitive deficits who may deserve CSF analysis for detecting preclinical AD.
A new flortaucipir PET biomarker based on graph theory for early detection of CTE in former American football players
Authors: Protas Hillary D. , Su Yi , Luo Ji , Chen Kewei , Alosco Michael L , Adler Charles , Balcer Laura , Bernick Charles B. , Au Rhoda , Banks Sarah J , Barr William , Coleman Michael J , Dodick David W. , Katz Douglas I , Marek Ken , Mariani Megan , McClean Michael D , McKee Ann C. , Mez Jesse B. , Palmisano Joseph , Peskind Elaine R , Turner Robert W. , Wethe Jennifer , Rabinovici Gil D. , Johnson Keith A. , Tripodis Yorghos , Cummings Jeffrey , Shenton Martha E , Stern Robert A , Reiman Eric M. ,   for the DIAGNOSE CTE Research Project
Published: December 2022

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.

Method

The graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.

Result

Entorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).

Conclusion

While there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.
Update on the TOGETHER study: a patient‐ and investigator‐blind, randomized, placebo‐controlled study evaluating the efficacy, safety and tolerability of bepranemab, UCB0107, in prodromal‐to‐mild Alzheimer’s disease
Authors: Barton Matthew E , Steen Bart Van Den , Van Tricht Hans L.G , Byrnes William , Purcell Fiona E , Southcott Sarah Ann , Raby Daniel , Starshinov Yaroslav Iurievich , Ewen Colin
Published: December 2022

Background

Bepranemab is a recombinant, humanized, full‐length IgG4 monoclonal antibody that binds to a central tau epitope (amino acids 235‐250). Here, we update on the progress of the TOGETHER study (AH0003; NCT04867616) with bepranemab in early Alzheimer’s disease (AD).

Method

TOGETHER is a global, multicenter, double‐blind, placebo‐controlled, parallel‐group study investigating the efficacy, safety and tolerability of bepranemab versus placebo. Patients with prodromal (National Institute on Aging‐Alzheimer’s Association [NIA‐AA] Stage 3) or mild (NIA‐AA Stage 4) AD (target N = 450) will be randomized (1:1:1) to receive one of two doses of bepranemab or placebo (intravenous, every 4 weeks), over an 80‐week treatment period, followed by an optional 48‐week open‐label‐extension period. Participants will have a global Clinical Dementia Rating (CDR) score of 0.5 (prodromal AD) or 0.5–1.0 (mild AD) and a CDR‐Memory Box score ≥0.5 at screening and baseline, a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), mini‐mental state examination (MMSE) ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read positron emission tomography (PET) scan or a positive cerebrospinal fluid (CSF) pTau181/Aβ1‐42 ratio. The primary endpoint is change from baseline to Week 80 in CDR scale Sum of Boxes total score. Secondary endpoints include: pharmacokinetics; safety and tolerability; tau PET imaging and change from baseline in AD Assessment Scale‐Cognitive Subscale 14, Amsterdam Instrumental Activities of Daily Living questionnaire and MMSE at Weeks 56 and 80.

Result

As of March 1, 2022, 56/125 planned centers have enrolled participants across 8 countries: Belgium, Canada, France, Netherlands, Poland, Spain, UK and USA. Of the 538 participants who entered screening, 62 have been randomized so far and 334 failed screening. Predominant reasons for screen failure include not meeting RBANS, MMSE or Aβ positivity (CSF or PET) criteria.

Conclusion

This proof‐of‐concept study employs clinical outcome measures, imaging, pharmacokinetics, and biomarkers to assess the ability of bepranemab to slow progression of AD when administered in the early stages of disease. Enrollment and randomization are underway with nearly half of the study centers active.
Associations between Depression and Subjective Cognitive Decline: Results from the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA) and HCHS/SOL
Authors: Guareña Lesley A. , Paredes Alejandra Morlett , Tarraf Wassim , Kuwayama Sayaka , Zlatar Zvinka , Stickel Ariana M , Gonzalez‐Pardo Roberto , Perreira Krista M , Wassertheil‐Smoller Sylvia , Zeng Donglin , Gallo Linda C , Daviglus Martha L , Isasi Carmen R , González Hector M
Published: December 2022

Background

Many aging Hispanic/Latino persons are worried about memory loss. Prior research suggests that subjective cognitive decline (SCD) and depression, might have common pathways, and could be precursors to cognitive impairment. We examined associations between depression and domains of SCD in a large sample of diverse Hispanics/Latinos.

Methods

Data included n = 6,189 (unweighted) middle‐aged and older Hispanics/Latinos (Age M = 63.4‐years, SD = 8.2; 55% female; 40.5% with more than High School education) from 6‐heritage groups participating in the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA), an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We used survey generalized linear regression to model the associations between depressive symptoms, captured at baseline (2008‐2011) with the Center for Epidemiological Studies‐Depression 10‐Item Scale (CES‐D‐10), and SCD was measured, on average 7‐years later, via the Everyday Cognition Short‐Form (ECog‐12).

Results

Higher depressive symptoms at baseline were linked to worse global (B = .37, SE = .02) and domain specific SCD [Memory (B = .34, SE = .02), Visual Spatial Planning (B = .28, SE = .02), Executive (B = .33, SE = .02)] (ps<0.001) after adjusting for cardiovascular risk and demographic covariates. These associations were more pronounced in individuals who were concerned about their attention, concentration or memory. Hispanic/Latino background (i.e., Dominican, Central American, Cuban, Mexican, Puerto‐Rican, South American, Other) did not modify the associations between depression symptoms and measures of SCD (ps>0.05).

Conclusion

Elevated depressive symptoms were consistently linked to global and domain specific subjective cognitive decline across Hispanics/Latinos of diverse heritages, particularly in the presence of attention, concentration or memory concerns. Our findings underscore the importance of assessing depression when evaluating Hispanics/Latinos with cognitive complaints.
Exploring Combination Therapies in AD: Additive Effects of the QPCT Inhibitor Varoglutamstat and Aducanumab on Aβ Pathology and Biomarkers In Vivo
Authors: Hoffmann Torsten , Schenk Mathias , Gnoth Kathrin , Ilse Victoria , Brunner Daniela , Rahfeld Jens‐Ulrich , Schilling Stephan , Schaeffer Michael
Published: December 2022

Background

Pyroglutamate‐3Aβ (N3pE), a toxic Aβ variant formed by the activity of glutaminyl gyclase (QPCT) has been shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Recently, we demonstrated that a combination of the QPCT inhibitor varoglutamstat (PQ912) with the N3pE‐specific antibody m6 has an additive effect on lowering of N3pE in vivo. Here, we analyzed whether a similar additive effect could be achieved when combining varoglutamstat with the Aβ‐aggregate‐specific antibody aducanumab.

Method

Nine‐months old APPxhQC mice were treated with either varoglutamstat (1.6 g/kg chow, ad libitum), chimeric aducanumab (chAdu, ≈10 mg/kg i.p. weekly) or a combination of both for 16 weeks. Brain Aβ accumulation (ELISA and immunohistochemistry) and AD biomarkers in the water‐soluble brain fractions (neurogranin, BACE‐1, YKL‐40; ELISA) were analyzed and compared to a vehicle‐treated group.

Result

Treatment with either varoglutamstat or chAdu significantly reduced the accumulation of both total Aβ and N3pE in the brain. The effect of chAdu was more pronounced for total Aβ (‐35% vs. ‐21% for varoglutamstat), while varoglutamstat treatment resulted in a stronger decrease of N3pE (‐28% vs. ‐19% for chAdu). The combination treatment generally led to a stronger decrease of Aβ vs. single agent treatment (Bliss combination index (CI) = 0.88 for soluble Aβ42 and 1.23 for insoluble Aβ42). For insoluble N3pE, the observed effect was nearly additive (CI = 1.09). Treatment with chAdu, varoglutamstat or both had different effects on the analyzed AD biomarkers. chAdu treatment significantly decreased BACE‐1 protein levels (‐30%), while varoglutamstat treatment significantly reduced levels of the brain inflammation marker YKL‐40 (‐27%), which is in line with earlier clinical Phase 2a study results.

Conclusion

Our data indicate that a combination of agents with different modes of action such as aducanumab, an Aβ aggregate‐specific antibody and varoglutamstat, a small molecule designed to block formation of toxic, aggregation‐prone N3pE, can act additively to decrease total Aβ and N3pE levels in the brain. Our results also provide a rationale for investigating different potential combination regimens, including an initial antibody‐mediated Aβ clearance followed by long‐term suppression of N3pE formation and inflammation by varoglutamstat (“treat and maintain”).
Cellular senescence profiling reveals distinct sub‐types of neurofibrillary tangle bearing neurons.
Authors: Orr Miranda E , Orr Timothy C , Dehkordi Shiva Kazempour , Zare Habil , Walker Jamie M. , Keene C Dirk
Published: December 2022

Background

Neurons with tau‐containing neurofibrillary tangles (NFTs) closely correlate with Alzheimer’s disease (AD) progression and severity. Our prior work determined that NFT‐bearing neurons undergo a change in cell fate consistent with cellular senescence. The goal of this project was to determine whether senescent NFT‐bearing neurons differ from quiescent NFT‐bearing neurons.

Method

Postmortem human AD brains were analyzed using GeoMx (NanoString, Inc) digital spatial profiling (DSP). Region of interest (ROI) selection included the presence or absence of neuronally expressed AT8 (phosphorylated tau, NFTs) and/or p19 (senescence). NFTs with or without p19 expression were compared to healthy neurons from the same cases. The expression of 86 proteins associated with neuropathology, inflammation, autophagy and cell typing was determined for each ROI and immediate environment (Fig. 1a‐b).

Result

NFT‐bearing neurons with p19 (senescent) were significantly different than NFT‐bearing neurons without p19 (quiescent). Senescent NFT‐bearing neurons appeared similar to neurons without tau pathology. In contrast quiescent NFT‐bearing neurons displayed signs of crisis (i.e. apoptosis). Additionally, we revealed significant differences in tau phosphorylation at multiple epitopes between the two classes of NFT‐bearing neurons (Fig. 1c‐h).

Conclusion

These data indicate the presence of distinct NFT‐bearing neuron subtypes in AD. Our ongoing studies are investigating (i) whether senescent or quiescent NFTs are more closely associated with pathogenesis, (ii) the transition between neuronal quiescence to senescence and (iii) which tau species contribute to this cell fate decision (self‐sacrificing versus disease propagating). More broadly, these results will provide a better understanding of distinct tau species in neurodegeneration which is critically important to clinical studies that are increasingly relying on tau biomarkers to predict disease onset, progression and target engagement in clinical trials.
A systematic review of locus coeruleus degeneration detected by neuromelanin sensitive MRI technique in patients with Alzheimer’s disease
Authors: Hou Ruihua , Chen Yuqing , Chen Teng
Published: December 2022

Background

The locus coeruleus(LC) is a bilateral nucleus located in the dorsal pontine tegmentum and is the major source of noradrenaline(NA), which plays a key role in cognition. While cognitive decline in Alzheimer disease(AD) has primarily been related to dysfunction within the cholinergic system in the nucleus basalis, there is considerable research evidence indicating extensive LC degeneration in AD, with some suggesting that it is among the earliest pathologies. Therefore, the early vulnerability of the LC to AD is of considerable clinical significance, as this raises the possibility that changes of the LC activity may provide early detection markers for diagnosis as well as early intervention targets to delay AD progression. However, the contribution of LC degeneration to cognitive decline in the development of AD has been underappreciated due to methodological difficulties, with most evidence coming from animal and post‐mortem studies. The absence of reliable non‐invasive direct measures of the LC remains the biggest challenge. Recent research indicates that LC visibility is driven by neuromelanin content of noradrenergic neurons and the intrinsic neuromelanin‐sensitive MRI technique enables direct visualisation of the LC.

Methods

A systematic search of the literature was performed on electronic databases including PubMed, Web of Science, and Embase. Human imaging studies employing neuromelanin‐sensitive MRI technique to measure LC degeneration were included in this review. Screening, data extraction, and quality assessment were undertaken following PRISMA guidelines for preferred reporting of systematic reviews.

Results

LC‐contrast ratio or LC‐signal intensity detected by the neuromelanin‐sensitive MRI were found to be significantly reduced in patient groups with Alzheimer's disease compared with the healthy control group in all included studies, with recent evidence indicating its significant association with levels of CSF amyloid.

Conclusions

The current systematic review strongly supports the use of the neuromelanin‐sensitive MRI technique to detect the LC degeneration as a biomarker for AD neuropathology. Future research are warranted to characterize how LC signals evolve at different stages of AD, which could lead to novel intervention approaches to delay or prevent cognitive decline.
Treating Alzheimer’s Disease via Donepezil Hydrochloride Loaded Nanoparticles: A Novel Approach for Brain Drug Delivery
Authors: Garg Yogesh , Bhatia Amit
Published: December 2022

Background

Many neuroprotective agents (like donepezil hydrochloride) have poor permeation to brain through blood brain barrier. Thus, there is a need to develop a new drug delivery system that can improvise the release of neuroprotective agents/drugs directly into brain avoiding blood brain barrier.

Method

Donepezil hydrochloride loaded chitosan nanoparticles were developed by ionic gelation method and optimized using Design of Experiment (DoE) approach.

Result

The optimized formulation had shown mean particle size (177.8 nm), zeta potential (+ 16.6 mV), drug payload (22.2 mg/100 mg of chitosan), process yield (91.96%) and mucoadhesive strength (9.26 g). In‐vitro release and ex‐vivo diffusion of drug from nanoparticles were found be > 90% and >70% in 24 hours, respectively. The delivery of drug to rat brain was found to be three times higher with nanoparticles vis‐à‐vis its solution. Further, confocal laser scanning microscopy confirmed the grater extent of localization by nanoparticles in the brain after nasal administration.

Conclusion

From the above results, it was concluded that the nose to brain delivery of donepezil hydrochloride using mucoadhesive nanoparticles has better potential as compared to conventional formulation approach for brain drug delivery.
Longitudinal lipidomic analyses in patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Minguet Carla , Ortiz Ana Maria , Gonzalo Ricardo , Horrillo Raquel , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Costa Montserrat
Published: December 2022

Background

Differences in ceramides, glycerides, phospholipids, cholesterol esters and fatty acids (FA) lipid subclasses have been reported between Alzheimer’s disease (AD) patients and healthy subjects (Liu et al. Transl Psychiatry 2021;11:344). The AMBAR phase 2b/3 trial is a therapeutic approach for mild‐moderate AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma exchange procedures with albumin replacement (PE‐Alb) to remove neurotoxic Aβ and other pathological substances from plasma, thus slowing AD progression (Boada et al. Alzheimers Dement 2020;16:1412). The aim of this study was to assess PE‐Alb effects on lipidomics across the AMBAR study.

Method

250 metabolomic biomarkers were quantified from serum samples of 309 individuals included in the AMBAR study using high‐throughput proton NMR (Nightingale Health Ltd, Helsinki, Finland). Up to 236 PE‐treated and 73 placebo [sham‐PE] patientsâ€™ samples, at 3 time points, were assessed. Raw metabolic levels were log2 normalized and scaled. Biomarkers were analyzed with a mixed model for repeated measures including fixed effects factors for month, treatment group and month*treatment group interaction, adjusted for baseline MMSE, age, sex, BMI, apoε4, lipid‐lowering medication, baseline biomarker levels and patient as a repeated factor. Differences from placebo as fold change (FC) were assessed through month*treatment group interaction term estimates.

Result

57 metabolomic biomarkers showed statistical significance (Adj.p‐value <0.05) of PE‐treated patients compared to placebo at the end of study (EOS, 14 months). All significant metabolites were up‐regulated in PE‐treated patients vs placebo. 45/57 significant metabolites belonged to lipidomic subclasses such as cholesterols (including cholesteryl esters), glycerophospholipids and fatty acids. Polyunsaturated FA (docosahexaenoic acid and linoleic acid), which may have a positive role against AD (Heath et al. Int J Mol Sci 2021;22:11826), were significantly increased at EOS (Adj.p‐value 0.038 and 0.020; linear‐FC=1.2 both), while saturated and monounsaturated FA were not (Adj.p‐value 0.19 and 0.735, respectively). Similarly, phosphatidylcholine levels, reported as altered in AD (Whiley et al. Neurobiol Aging 2014;35:271), were significantly upregulated (Adj.p‐value 0.049, linear‐FC=1.2) at EOS.

Conclusion

PE‐Alb procedures used in AMBAR induced changes in lipidomic profiles. This supports the multimechanism basis of AMBAR therapeutic approach that may contribute to slowing AD progression.
Genetically Proxied Angiotensin‐Converting‐Enzyme Inhibition is Potentially Causal for Alzheimer Disease: A Mendelian Randomization Study
Authors: Nassan Malik , Piras Ignazio , Rogalski Emily J. , Geula Changiz , Mesulam M.‐Marsel , Dashti Hassan , Saxena Richa , Huentelman Matthew J
Published: December 2022

Background

Angiotensin‐converting enzyme (ACE) has been implicated in the pathogenesis of Alzheimer disease (AD), in which ACE plays a role in metabolizing Amyloid Beta (AB). Genetic variants in the ACE locus have also been associated with AD. The effect of ACE inhibitors on AD risk remains unclear. We sought to investigate the potential causal relationship between ACE inhibition and AD and other neurodegenerative disorders using a mendelian randomization (MR) approach.

Method

A genetic proxy for ACE inhibition (MR exposure) was generated using 17 single nucleotide polymorphisms (SNPs) in the ACE gene that were previously associated with lower ACE blood levels in a candidate gene study (n = 4,147; adjusted‐P < 0.05). Summary genome‐wide association study (GWAS) statistics for AD (111,326 cases, 677,663 controls), Frontotemporal dementia (FTD) (3526 cases, 9402 controls) and Lewy body dementia (LBD) (cases 2591, controls 4027) were used as proxies for the MR outcomes. Inverse weighted variance MR was performed to test the potentially causal relationship between the exposure and outcomes. Sensitivity analyses were completed to test the robustness of the results.

Result

ACE inhibition was significantly associated with increased risk of AD (OR = 1.07, P = 0.0000005); with robust and consistent effects in all sensitivity analyses. Using leave one out method; rs4343 (A allele) showed the strongest effect. rs4343 is in mild linkage disequilibrium with the SNP associated at genome wide significant level with AD rs4277405 (R2 0.35). Rerunning the MR analysis on the AD cohort after removing rs4343 continued to show significant results (OR = 1.04, P = 0.02). ACE inhibition was also associated with increased risk for FTD (OR = 1.16, P = 0.009), but the findings were not robust in some sensitivity analyses, possibly due to lower sample size of FTD cohort. ACE inhibition was not associated with LBD.

Conclusion

This is the first study to provide robust genetic evidence for the potentially causal relationship between ACE inhibition in the blood and the diagnosis of AD. These results should encourage further investigation of the potential neurodegenerative side effects of ACE inhibition; and further suggest ACE related pathways as pharmacological targets for treatment and/or prevention of AD.
Validation of a fully automated lab developed test for plasma phospho‐tau 181 levels for Alzheimer’s disease diagnosis
Authors: Malyavantham Kishore , Brock Mary , Brunelle Lynn A , Miller Mike , Marble Hetal , Wilson David , Teunissen Charlotte E. , Mattoon Dawn
Published: December 2022

Background

The potential usefulness of plasma phosphorylated tau (pTau) measurements for identifying individuals likely to be on the Alzheimer’s disease (AD) continuum is evident from recent literature. Here we report the validation of an immunoassay for measurement of pTau181 in human plasma that will aid in the evaluation of Alzheimer’s pathology in cases presenting with mild cognitive impairment.

Method

The Simoa pTau‐181 assay is a fully automated 2‐step digital sandwich immunoassay that utilizes paramagnetic beads with capture antibodies and biotinylated detector antibodies. Digital detection is achieved using Simoa discs via SβG (Streptavidin‐ß‐galactosidase) and RGP (Resorufin‐β‐D‐galactopyranoside) amplification of specific pTau181 immune complexes. Harmonization to the Simoa pTau‐181 method described by Karikari et al (Mol Psychiatry. 2021;26(2):429‐442) using 80 samples, establishes commutability with published results from ADNI cohorts. Analytical validation on HD‐X instrument followed CLSI guidelines. Thirty‐four AD cases from the Amsterdam Dementia Cohort (age 66 ± 8 years) diagnosed according to the NIA‐AA diagnostic AD criteria and had a CSF biomarker‐confirmed AD diagnosis, 36 age‐ and sex‐matched (age 66 ± 8 years) cognitively healthy controls from the Dutch Brain Research Registry were included for clinical validation of this LDT.

Result

The limits of detection (LoD) and quantification (LoQ) were 0.056 pg/mL and 0.276, respectively. Repeatability and reproducibility across 3 reagent lots using samples across the measuring range were 4.25% (95%CI:2.84‐5.65), 9.42% (95% CI: 4.46‐14.37) respectively. Linearity was demonstrated per CLSI EP06‐A, as ≤15% deviation at all dilutions. Cross reactivity against full length unphosphorylated‐Tau441 and synthetic peptides for pTau231 and pTau217 epitopes was below LoQ. ROC analysis resulted in a high AUC (area under the curve) of 0.897 (95% CI 0.825 to 0.969). Applying the cut‐offs described in Karikari1 (17.7 pg/mL) for this cohort resulted in a sensitivity of 94%, specificity of 72%.

Conclusion

This test demonstrated acceptable analytical performance for CLIA laboratory implementation. High AUC of 0.897 to discriminate AD from non‐AD cases helps both rule‐in or rule‐out scenarios, and further allows for setting of cut‐off values that not only take the pretest probability, impact on screening algorithm, treatment protocols into consideration but also the costs incurred by misdiagnosis.