bluuebunny/crossref_metadata_2025 huggingface dataset:
DRhQ: a novel therapeutic that improves cognition and mitochondrial function and reduces neuroinflammation in beta‐amyloid overexpressing Mice
Authors: Gray Nora E , Lockwood Denesa R , Hack Wyatt E , Brandes Mikah S , Meza‐Romero Robert E , Neff Cody E , Gladen‐Kolarsky Noah E , Quinn Joseph F , Vandenbark Arthur A
Published: December 2023

Background

Neuroinflammation and mitochondrial dysfunction are central to the progression of Alzheimer’s disease (AD), provoking neuronal loss and cognitive decline. Identifying strategies for mitigating these responses could therefore be of significant therapeutic relevance. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T‐cell and macrophage activation and migration into the CNS, enhances anti‐inflammatory microglia cell numbers and reduces pro‐inflammatory gene expression. DRhQ treatment resulted in reduced neuroinflammation and disease severity in a mouse model of multiple sclerosis. Because neuroinflammation is a prominent in the AD brain as well we hypothesized that DRhQ could be a similarly effective neuroprotective agent in the context of AD. We evaluated this hypothesis using the 5xFAD mouse model of β‐amyloid (Aβ) accumulation.

Method

Six month old male and female 5xFAD mice and their wild‐type littermates will be treated with 0 or 100 ug of DRhQ subcutaneously for five days followed by a 3 day booster series weekly for the next 3 weeks. During the 4th week of treatment mice were evaluated cognitively using the novel object recognition test and brain tissue was harvested to evaluate mitochondrial function, Aβ pathology as well as markers of microglial activation and neuroinflammation.

Result

DRhQ improved cognition and reduced neuroinflammatory markers in both male and female 5xFAD mice. DRhQ also significantly attenuated deficits in cortical mitochondrial function in female 5xFAD mice and elicited a similar, though non‐significant, effect in male 5xFAD mice. Aβ plaque burden was likewise reduced in the hippocampus and cortex of female 5xFAD mice but not significantly reduced in male 5xFAD animals.

Conclusion

These results suggest that DRhQ attenuates Aβ pathology, mitochondrial dysfunction and neuroinflammation and improves cognitive function in 5xFAD mice. Future experiments will explore dose response effects and investigate the apparent sex differences in the magnitude of effect of DRhQ on specific endpoints in these mice as well as evaluate the effects of DRhQ in models of tauopathy.
circRNAs mediate the effect of chronic lysosomal dysfunction on Alzheimer’s disease pathology
Authors: Romero Skarleth Cardenas , Eteleeb Abdallah M , Nykanen Niko‐Petteri , O’Dell Kevin , Nunez Marie , Harari Oscar , Cirrito John R , Sands Mark , Benitez Bruno A.
Published: December 2023

Background

Circular RNAs (circRNAs) and microRNAs (miRNAs) are non‐coding RNAs. CircRNAs modulate miRNA levels by sequestration. MiRNAs regulate amyloidogenic pathways, disrupting transcripts including APP, BACE1, and ADAM10. CircRNAs regulate key endolysosomal transcripts. Chronic lysosomal dysfunction (CLD) is linked to Alzheimer’s Disease (AD). However, the role circRNAs downstream of CLD and AD is unclear. Here, we tested whether CLD affects the amyloidogenic pathway in 5xFAD mice through circRNAs.

Method

Cortical circRNA expression was obtained of 5xFAD, PPT1+/−, 5xFAD: PPT1+/− (P5X), Naglu+/−, 5xFAD: Naglu+/− (N5X) mice. TruSeq Stranded total RNA was extracted with Ribo‐Zero to deplete rRNA and generate stranded‐RNA‐seq. Libraries were sequenced on a NextSeq 500 platform of Illumina and analysis was done with the DESeq2 package with an FRD <0.05. In silico microRNA binging was done using circAtlas 2.0 browser. The insoluble Aβ‐40 and Aβ‐42 were quantified by ELISA in the hippocampal fraction. The Aβ plaque load was quantified in coronal brain sections using immunohistochemistry.

Result

The P5X and N5X mice exhibit increased amyloid plaque load, hippocampal Aβ‐40, and Aβ‐42 levels, and reduced lifespan compared to 5xFAD mice. We detected 1286 cicRNAs in all the groups. 38 from P5X and N5X groups, 37 from PPT1+/−, and 29 from Naglu+/− passed FRD correction compared with 5xFAD mice. Both linear and circRNAs of 4933406I18Rik, Zfp609, Zfp532, and Nnt changed between PPT1+/− and P5X compared to 5xFAD. The levels of circAdam10, circPan3, circMbtd1, circ4930402H24Rik, circSt6gal2, and circCdc14b were reduced, while circZranb1 and circMyo9a were increased in P5X and N5X compared with 5xFAD. CircNlgn1 levels changed only downstream of PPT1+/−. In silico analyses show amyloidogenic‐related microRNAs exhibit circRNAs binding sites. MiR‐361‐3p has binding sites for circZranb1 and circADAM10, as well as miR‐298‐3p, can bind circNlgn1. Both miR‐361‐3p and miR‐298‐3p trap and inhibit BACE1 function and Aβ production, interfering in the amyloidogenic pathway. CircPan3 regulates the autophagy‐related miR‐421. Experimental evidence shows that overexpression of circPan3 suppresses autophagy through a miR‐421/Pink1 pathway.

Conclusion

CLD (PPT1+/− and Naglu+/−) boosted AD pathology and induced differential changes in circRNAs levels affecting amyloidogenic and autophagy pathways. There is a positive feedback loop between CLD and circRNAs in AD mouse models.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells
Authors: Rogers Brianne B. , Anderson Ashlyn G , Lauzon Shelby N. , Davis M. Natalie , Hauser Rebecca M. , Roberts Sydney C. , Rodriguez‐Nunez Ivan , Trausch‐Lowther Katie , Roberts Brian S. , Barinaga Erin A. , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas
Published: December 2023

Background

Tau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.

Methods

Three‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.

Results

We identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.

Conclusions

Overall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
Targeting hyperactive antiviral response to treat tauopathy
Authors: Gan Li
Published: December 2023

Background

Cyclic GMP‐AMP synthase (cGAS, Cgas), the major antiviral DNA sensor, binds double‐stranded DNA (dsDNA) and catalyzes cyclic GMP‐AMP (cGAMP) formation, which activates stimulator of interferon genes (STING). Activation of cGAS‐STING has been implicated in several neurodegenerative conditions. The role of cGAS in tauopathy remains unknown.

Method

We investigated cGAS‐STING‐IFN activation in microglia of tauopathy mice and human AD brains. We crossed cGAS knockout mice with P301S tauopathy mice and performed behavioral, immunohistochemistry, electrophysiology and single‐nuclei (sn) RNA‐seq.

Result

we demonstrated potent protective effects of Cgas genetic deletion against synaptic and cognitive deficits associated with induction of transcriptional network of MEF2C, a gene implicated in cognitive resilience against amyloid and tau pathology. SnRNA‐seq analyses of human AD brains revealed dysregulation of microglial IFN‐I genes and neuronal MEF2C transcriptional network.

Conclusion

Our current study linked a hyperactive cGAS‐IFN antiviral response with diminished MEF2C‐associated cognitive resilience. In diseased conditions, cGAS hyperactivation promoted microglial IFN‐I response, reduced neuronal MEF2C transactivation, and rendered loss of cognitive resilience. cGAS ablation diminished microglial IFN‐I response and enhanced neuronal MEF2C transcription network and associated cognitive resilience against tau pathology. Pharmacological inhibition of cGAS with TDI‐6570 enhanced MEF2C target genes and restored synaptic integrity and memory, supporting the therapeutic potential of targeting cGAS‐MEF2C axis to improve resilience against AD and related neurological disorders.
Consequences of neuromelanin‐like pigmentation on locus coeruleus integrity and function in mice
Authors: Weinshenker David
Published: December 2023

Background

The locus coeruleus (LC) is the first region of the brain to accumulate tau pathology in Alzheimer’s disease (AD) and subsequently undergoes catastrophic degeneration as disease progresses. It has been proposed that neuromelanin (NM), a dark cytoplasmic pigment that is a byproduct of catecholamine metabolism, may contribute to the selective vulnerability of the LC. However, causal relationships between NM and LC degeneration have been difficult to establish because, unlike primates, rodents do not produce appreciable amounts of NM.

Method

We adapted a viral‐mediated approach for expression of human tyrosinase (hTyr), the enzyme responsible for peripheral melanin production, to promote pigmentation in rodent LC neurons. Cre‐dependent AAV‐hTyr virus was infused bilaterally into the LC of 2‐month old TH‐Cre mice, and the LC and behavior was examined 1‐10 weeks later.

Result

We found that viral vector‐mediated hTyr expression drove pigment expression in the LC that recapitulated key features of endogenous NM found in primates, including eumelanin and pheomelanin, lipid droplets, and a double‐membrane encasement. Pigment accumulation resulted in mild neurodegeneration, altered catecholamine levels, transcriptional changes, and novelty‐induced anxiety phenotypes as early as 1 week post‐injection. By 6‐10 weeks, severe LC neurodegeneration and a robust neuroinflammatory response were observed.

Conclusion

These results suggest that NM may contribute to the selective vulnerability of LC neurons in AD. The phenotypes of NM‐expressing mice were reminiscent of LC dysfunction and degeneration in AD, validating the utility of this model for studying the consequences of pigment accumulation in the LC as it relates to neurodegenerative disease.
Psychometric Validation and Prognostic Performance of the Bedford Alzheimer Nursing‐Severity Scale in community‐dwelling persons with severe dementia (PWSD)
Authors: Cheong Chin Yee , Yap Philip Lin Kiat , Malhotra Chetna
Published: December 2023

Background

Assessment of disease severity and prognostication are germane to dementia care yet extant instruments are limited by floor effects and inadequate mortality prognostic performance. To date, the Advanced Dementia Prognostic Tool‐ADEPT(AUC = 0.68) is the best available but was validated in only nursing home residents. We aimed to investigate the psychometric properties of the 7‐item Bedford Alzheimer Nursing‐Severity Scale(BANS) in community‐dwelling people with severe dementia (PWSDs) and explore its prognostic utility.

Method

Panel study Investigating Status of Cognitively impaired Elderly in Singapore is a multi‐centre prospective longitudinal study which recruited 215 PWSD, mean age 83.6±8.2 and median follow‐up 25 months. We evaluated the internal consistency reliability, factor, construct and predictive validity of BANS compared to FAST, a well‐established dementia severity tool. A 1‐year mortality prognostic index was derived from the adapted BANS and significant clinical variables.

Result

Factor analysis revealed a two‐factor solution(variance 58.4%) with item‐2(sleep‐wake cycle) not loading onto any factor. Dropping item‐2(BANS‐6) revealed a single‐factor solution (variance 40.2%) and Cronbach’s α improved from 0.701(BANS) to 0.782(BANS‐6). FAST did not correlate with agitation(CMAI) and poor quality of life(QUALID), but BANS and BANS‐6 did. After adjusting for age, sex and comorbidities, BANS‐6 but not FAST was significantly associated with complications of severe dementia. A new index(comprising BANS‐6, malnourishment, age) was derived with superior mortality predictive performance (AUC = 0.68,95%CI = 0.60‐0.75) compared to BANS(AUC = 0.64,95%CI = 0.56‐0.71) and FAST(AUC = 0.52,95%CI = 0.44‐0.59).

Conclusion

The 6‐item BANS(BANS‐6) outperformed FAST in predictive utility and was comparable to ADEPT’s previous mortality predictive performance (AUC = 0.68). BANS‐6 is psychometrically reliable and valid for assessing disease severity in community‐dwelling PWSD.
Implementation and dissemination of home and community‐based interventions for informal caregivers of people living with dementia: A systematic scoping review
Authors: Zhu Eden Meng , Buljac‐Samardžić Martina , Ahaus Kees , Sevdalis Nick , Huijsman Robbert
Published: December 2023

Background

Informal caregivers of people with dementia (PwD) living at home are often the primary source of care, and, in their role, they often experience loss of quality of life. Implementation science knowledge is needed to optimize the real‐world outcomes of evidence‐based interventions (EBIs) for informal caregivers. This scoping review aims to systematically synthesize the literature that reports implementation strategies employed to deliver home‐ and community‐based EBIs for informal caregivers of PwD, implementation outcomes, and the barriers and facilitators to implementation of these EBIs.

Methods

Embase, MEDLINE, Web of Science and Cochrane Library were searched from inception to March 2021; included studies focused on “implementation science”, “home‐ and community‐based interventions” and “informal caregivers of people with dementia”. Titles and abstracts were screened using ASReview (an innovative AI‐based tool for evidence reviews) and data extraction was guided by the ERIC taxonomy, the Implementation Outcome Framework, and the Consolidated Framework for Implementation Science Research; each framework was used to examine a unique element of implementation.

Results

67 studies were included in the review. Multi‐component (26.9%) and eHealth (22.3%) interventions were most commonly reported, and 31.3% of included studies were guided by an implementation science framework. Training and education‐related strategies and provision of interactive assistance were the implementation strategy clusters of the ERIC taxonomy where most implementation strategies were reported across the reviewed studies. Acceptability (82.1%), penetration (77.6%) and appropriateness (73.1%) were the most frequently reported implementation outcomes. Design quality and packaging (intervention component suitability) and cosmopolitanism (partnerships) constructs, and patient’s needs and resources and available resources (infrastructure) constructs as per the CFIR framework, reflected the most frequently reported barriers and facilitators to implementation.

Conclusion

Current studies focused largely on intervention outcomes rather than implementation outcomes and lacked detailed insights on inner and outer setting determinants of implementation success or failure. Future dementia studies must prioritize implementation science for more contextually relevant findings and structurally examine the mechanisms through which implementation partners can strategically leverage existing resources and regional networks to streamline local implementation. Mapping local evidence ecosystems will facilitate structured implementation planning and support implementation‐focused theory‐building.
Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease
Authors: Fu Siu Ting , Cai Yuan , Huang Junzhe , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong
Published: December 2023

Background

Although positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.

Method

We recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aβ deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aβ40, Aβ42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.

Result

Among 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aβ42 were associated with A+T+ after adjusting for age, gender, and education (p<0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aβ42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).

Conclusion

A panel of AD‐RAI, plasma p‐tau, and plasma Aβ42 might help with screening and diagnosis of Alzheimer’s disease.
Cerebrospinal fluid synaptic biomarkers in AT(N)‐based subgroups of Lewy body disease
Authors: Barba Lorenzo , Rumeileh Samir Abu , Halbgebauer Steffen , Bellomo Giovanni , Paoletti Federico Paolini , Gaetani Lorenzo , Oeckl Patrick , Massa Federico , Steinacker Petra , Parnetti Lucilla , Otto Markus
Published: December 2023

Background

Patients with Lewy body disease (LBD) often show a co‐occurring Alzheimer’s disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detection in vivo of AD‐related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro‐axonal damage are correlated with the presence of AD co‐pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles.

Method

We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p‐tau, t‐tau) and of synaptic (β‐synuclein, α‐synuclein, SNAP‐25, neurogranin) and neuro‐axonal proteins (NfL) in 28 cognitively unimpaired participants with non‐degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD‐MCI, and dementia stages, AD‐dem). We compared CSF biomarker levels in clinical and AT(N)‐based subgroups.

Result

CSF β‐synuclein, α‐synuclein, SNAP‐25, neurogranin and NfL levels did not differ between LBD (n = 101, age: 67.2 ± 7.8 years, 27.7% females) and controls (age: 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD‐MCI n = 30, AD‐dem n = 30, age: 72.3 ± 6.0 years, 63.3% females) compared to both groups (p<0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro‐axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A‐T‐ profiles (LBD/A‐T‐) (p<0.01 for all), and β‐synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI: 0.884‐0.991). CSF β‐synuclein (p = 0.0021), α‐synuclein (p = 0.0099) and SNAP‐25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T‐ cases, which had synaptic biomarkers levels within the normal range. CSF α‐synuclein was significantly decreased only in LBD patients with T‐ profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level.

Conclusion

LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro‐axonal biomarkers compared to LBD/A‐T‐ and control subjects. LBD patients with AD co‐pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases.
Dual decline in gait and cognition as a risk factor for dementia. The role of sex
Authors: Montero‐Odasso Manuel
Published: December 2023

Background

Motor (slowing of gait) and cognitive declines are common in older adults. We reported that older adults with both motor and cognitive decline (dual‐decliners) had a higher risk of progressing to dementia than individuals with either decline alone. Our aim in this study is to examine the role of sex in these cognitive and motor trajectories before dementia.

Methods

Data was used from the Gait and Brain Study, a prospective cohort study in community‐dwelling older adults free of dementia at baseline. Participant’s motor and cognitive trajectories were assessed twice a year for 5 years, using gait speed and the MoCA test, respectively. We ascertained incident dementia using DSM‐IV‐RT criteria. The risk to progress to dementia was evaluated with Cox regression models, stratifying by sex and adjusting by age and comorbidities.

Results

From 207 older adults, 37 individuals (18%) progressed to dementia, from which 43% were males and 57% were females. Among dual‐decliners, males had a higher risk for progressing to dementia when compared with females (Males HR: 3.90, 95%CI: 1.02‐14.87, p = 0.046; Females: HR: 2.41, 95%CI: 0.72‐ 8.12, p = 0.155). In addition, in males, the association becomes stronger after adjusting for comorbidities (HR: 4.36, 95%CI: 1.08‐17.66, p = 0.039), whereas in females, the risk for progressing to dementia lowers when adjusting for comorbidities (HR: 1.44, 95%CI: 0.38‐ 5.41, p = 0.590), suggesting that number of comorbidities might be driving the association with dementia in females. Male dual‐decliners showed a stronger association with progression to dementia (HR = 4) when compared with females (HR = 1) in both adjusted and unadjusted models.

Conclusion

Older adults that present both motor and cognitive decline (dual‐decliners) have the highest risk to progress to dementia, particularly if they are men. Sex differences in motor and cognitive trajectories before dementia may increase accuracy of dementia risk prediction. Future studies are needed to understand mechanisms underlying our findings.
Apathy as a Predictor of Motoric Cognitive Risk Syndrome
Authors: Ceide Mirnova E
Published: December 2023

Background

Apathy is a psychological syndrome, characterized by lack of motivation and interest, flattening of affect, and social withdrawal; that predicts cognitive decline including dementia. Current literature highlights apathy as a separate entity from depression, which is uniquely correlated to cognitive and functional decline in neurologic diseases like stroke and Parkinson’s Disease as well as in community dwelling‐older adults. Further, apathy may mediate the previously described association between depression and cognitive/functional decline. Our objectives were to 1) investigate the association between apathy at baseline and incident predementia syndromes including mild cognitive impairment (MCI) and motoric cognitive risk syndrome (MCR) and 2) explore the direct and indirect relationships of apathy and motoric cognitive outcomes.

Method

We prospectively studied the association between apathy (3‐item subscale of the Geriatric Depression Scale) and incident predementia syndromes in 542 community‐dwelling older adults enrolled in the Central Control of Mobility in Aging study, using Cox proportional hazard models. Associations were reported as hazard ratio (HR) with 95% confidence intervals (CIs), adjusting for age, education, baseline cognitive performance, and dysphoria. In a subset of 347 participants, we examined the mediating role of cytokines on the association between apathy and gait velocity in linear regression models at cross section. We also looked at the mediating role of apathy on the association between dysphoria and multimorbidity and gait velocity.

Result

Apathy was associated with incident MCR (HR 2.39, 95% CI: 1.10‐5.20), but not MCI. Linear regression models showed that Interleukin‐6 (Il‐6), but not C‐Reactive Protein was significantly associated with apathy adjusted for age, gender, and years of education (B = 0.037, 95% CI: 0.002–0.072, p = 0.04). Apathy was associated with a slower gait velocity (B = 14.45, 95% CI: 24.89–4.01, p = 0.01), cross sectionally. Mediation analyses demonstrated that IL‐6 modestly mediates the relationship between apathy and gait velocity. Additionally, apathy mediated the relationships between dysphoria and multimorbidity and gait velocity.

Conclusion

Overall, our findings indicate that apathy may be an early predictor of motoric cognitive decline, which precedes predementia syndromes. Inflammation plays a modest role, but the underlying biology of apathy warrants further investigation.
Trajectories of Motoric Cognitive Risk and Incident Dementia in Scotland
Authors: Mullin Donncha S
Published: December 2023

Background

Motoric cognitive risk syndrome (MCR) ‐ objective slow gait and subjective cognitive complaints ‐ is quick and easy to measure, making it a potentially useful clinical tool for identifying those at high risk of developing dementia. This is the first exploration of MCR syndrome’s predictive ability for incident dementia in a Scottish cohort (Lothian Birth Cohort 1936) and the first examination of the various trajectories of MCR.

Method

We classified a total of 680 community‐dwelling participants (mean [SD] age 76.3 [0.8] years) free from dementia into non‐MCR or MCR groups. We used cox proportional hazard methods to evaluate the risk of developing all‐cause dementia in the years following MCR diagnosis. Our final model adjusted for age, sex, comorbidity index, apolipoprotein E status, physical activity level, and years of education. We analysed the trajectories for everyone with MCR by tracking their outcomes over 9 years. All analyses were performed in R version 4.0.2.

Result

The prevalence of MCR at baseline was 5.6% (n = 38/680). After 9 years of follow‐up, 11.6% (n = 79/680) of the total cohort developed dementia. The presence of MCR increased the risk of dementia (adjusted hazard ratio 2.37 [95%CI 1.06‐5.32; p = 0.0359]). The trajectories of those with MCR at baseline were: i) reverted to healthy (n = 6/38), ii) ongoing MCR (n = 13/38), iii) progressed to dementia (n = 9/38), or iv) died (n = 10/38).

Conclusion

MCR showed similar prognostic ability for dementia in a Scottish cohort as for other populations. MCR could identify a target group for early interventions of modifiable risk factors to prevent incident dementia. Individuals with MCR follow similar trajectories to the related predementia syndrome, Mild Cognitive Impairment.
A cross‐national comparison of the risk factors associated with the Motoric Cognitive Risk syndrome in high and middle‐income countries
Authors: Jayakody Oshadi , Verghese Joe , Blumen Helena M
Published: December 2023

Background

The Motoric Cognitive Risk (MCR) syndrome is associated with increased risk of Alzheimer’s disease and vascular dementia. MCR does not require cognitive or lab tests to diagnose, increasing its utility in resource‐poor settings. The specific risk factors associated with MCR in different high‐ and middle‐income countries are not established.

Methods

We examined the epidemiology of MCR in harmonized cross‐sectional data from 17,050 adults aged ≥ 65 years enrolled in the U.S. Health and Retirement Study (HRS; n = 3,748), English Longitudinal Study of Ageing (ELSA; n = 4,110), Mexican Health and Aging Study (MHAS; n = 738), the China Health and Retirement Study (CHARLES; n = 3,275), the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI‐DAD; n = 1,276) and the Survey of Health, Ageing and Retirement in Europe (SHARE; n = 3,973). MCR was defined as the presence of cognitive complaints and slow gait in the absence of mobility disability and dementia. Risk factors included demographics [age, sex, education], medical [hypertension, diabetes, Parkinson’s, heart disease, stroke, obesity], sensorimotor [grip strength, hearing], psychological [depression], behavioral factors [smoking, sedentariness, sleep quality] and falls (see Table 1 for definitions). Logistic regression was used to examine factors associated with prevalent MCR.

Results

Participants’ mean age in different cohorts ranged between 71.3 and 80.2 years. Proportion of females ranged between 45.3% and 60.9%. MCR prevalence was 3.6%, 2.1%, 8.9% 6.1%, 5.8% and 6.8% in HRS, ELSA, MHAS, CHARLES, LASI‐DAD and SHARE, respectively. Tables 2 and 3 show risk factors associated with each cohort in univariate and multivariable models. Despite some overlaps, specific risk factors were associated with each cohort with relative risk ratios ranging as follows: 0.4‐2.8 for education and multiple falls in HRS, 2.3‐7.1 for poor hearing and sedentariness in ELSA, 2.3‐2.6 for weak grip strength and diabetes in MHAS, 1.9‐2.2 for depression and sedentariness in CHARLES, 0.5‐5.3 for education and stroke in LASI‐DAD and 0.3‐2.4 for education and depression in SHARE.

Conclusion

In community‐dwelling older adults from twenty countries (high‐ and middle‐income), specific risk factors were associated with MCR in each cohort – laying the foundation for preventing MCR and subsequently dementia in ethnically, culturally, and socioeconomically diverse populations.
Predicting cognitive decline in short‐term as a viable method to improve recruitment in clinical trials of Alzheimer’s Disease
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Ezzati Ali
Published: December 2023

Background

Success of Alzheimer’s disease (AD) trials is partially dependent on enrollment of participants who show cognitive decline (CD) during treatment with placebo. We investigated whether trials could be enriched for CD using machine‐learning based predictive models.

Method

We used data from the placebo arm of trial of Solanezumab for mild dementia due to AD (EXPEDITION‐3 trial; N = 894) as well as individuals at the same stage of disease from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 86). Participants were classified as showing CD vs stable cognition (SC) based on their scores on the cognitive sub‐scale of the Alzheimer’s Disease Assessment Scale (ADAS‐Cog11; Range 0‐70). The CD group included individuals who showed a minimal clinically important difference (MCID of 3 or more points increase in their ADAS‐Cog11 scores from baseline to week 80) while the SC group had a change of less than 3 points. Participants were classified into CD and SC groups using different baseline feature‐sets including volumetric MRI and neuropsychological tests (Table 2). Models were trained using 70% of the EXPEDITION‐3 data and were validated using the remaining 30%. Models trained in EXPEDITION‐3 were then externally validated using the ADNI sample.

Result

Only 56% of EXPEDITION‐3 participants treated with placebo showed MCID at 80 weeks (Table 1). Performance of the different models is summarized in Table 2. Model 4 using the random forest algorithm, which included all features and data from 6‐month follow‐up, had the best overall performance in the internal validation sample (AUC: 0.75±0.03). Models 3 and 4 performed similarly when validated in the independent ADNI sample (AUCs: 0.70±0.05, 0.66±0.06, respectively). Both Models had positive predictive values approximately 15% higher than the base prevalence of cognitive decline in the ADNI subset (∼62%). The negative predictive value of Model 3 was 23% higher than the base prevalence of stable cognition in the participants, slightly higher than that of Model 4.

Conclusion

Enrichment of trials through predictive models may increase the chance of success. Using 6‐month follow‐up data improves accuracy of decliner identification and may provide a basis for early exclusion of a subset unlikely to discriminate active treatment from placebo.
Investigating the synaptic mechanisms of the spread of wild type and P301S 1N4R human tau in in vitro and in vivo models
Authors: Panzi Chiara , Restani Laura , Novelli Elena , Guarascio Rosellina , Cheetham Michael , Wray Selina , Caleo Matteo , Schiavo Giampietro
Published: December 2023

Background

Tau aggregates propagate across functionally connected neuronal networks in tauopathies as Alzheimer’s disease. However, the mechanisms underlying this process are poorly understood. Different studies showed that tau release is dependent on neuronal activity and that pathological tau can be found in the extracellular space confined in extracellular vesicles or in a free form. We recently showed that metabotropic glutamate receptors and SNAP25 modulate the release of pathologic tau from human and mouse synaptosomes. Here, with the use of blocking agents such as botulinum neurotoxins (BoNTs), we plan to test the effect on the synaptic release of tau in vitro and in vivo. BoNTs enter synapses and cleave specific synaptic SNARE proteins, impairing synaptic vesicle fusion and release. We aim at demonstrating the potential of BoNTs as tools to study neurodegenerative diseases.

Methods

Primary mouse hippocampal neurons were cultured in microfluidic chambers, transduced with lentiviruses expressing human tau (hTau) isoforms, and treated with BoNTs and stimulators. ELISA was used to quantify hTau in the culture media. AAVs expressing hTau were injected in the vitreous of wild‐type mice, and BoNT type A (BoNT/A) was injected in the superior colliculus (SC). Retina, SC and lateral geniculate nucleus (LGN) were analysed through immunohistochemistry.

Results

Overexpression of hTau in primary neurons increases the expression of synaptic markers as compared to non‐transduced cells, while any difference is detected between wild‐type and P301S hTau. Neuronal stimulation significantly increases the release of P301S hTau, whereas BoNT/A blocks it. Preliminary in vivo data show no difference in the expression and transfer of wild type and P301S hTau in the SC and LGN. The ongoing analysis of BoNT/A injected mice will reveal any effect on tau spread in the brain.

Conclusions

The release of hTau is modulated by specific SNARE proteins and differs depending on the isoform in vitro. The use of BoNT/A in vivo will help us to clarify the mechanisms modulating tau release in a complex system. Moreover, with the use of other BoNTs, we will provide novel insights into the mechanisms of synaptic tau release and identify novel molecular targets for the development of therapeutic interventions to treat tauopathies.
The impact of inflammation on plasma biomarkers of Alzheimer’s Disease
Authors: Hall James , Petersen Melissa , O'Bryant Sid E.
Published: December 2023

Background

Plasma biomarkers of Alzheimer’s disease have been proposed as less expensive, less invasive and readily scalable biomarkers for use as diagnostic biomarkers, predictors of risk and progression and inclusion criteria for clinical trials. Our previous work has shown that medical comorbities such as dyslipidemia, diabetes, kidney disease and hypertension can impact the levels of these biomarkers and there are ethnic differences in this relationship. The current study extended this work by investigating the effect of inflammation on levels of plasma biomarkers of amyloid, tau and neurodegeneration in an ethnically diverse cohort.

Method

Data from 651 cognitively unimpaired non‐Hispanic White and 646 cognitively unimpaired Mexican American participants from the Health & Aging Brain Study‐ Health Disparities study were analyzed. Plasma markers of Aβ40, Aβ42, total tau and NfL were assayed using the ultrasensitive Simoa (single‐molecule array) technology. The relationship of peripheral inflammatory biomarkers (IL‐6, IL‐10, TNFα & CRP) to each of the AD plasma biomarkers was analyzed using partial correlation controlling for age, sex and APOE4 positivity.

Result

Higher levels of Aβ40, Aβ42, total tau and NfL were associated with elevated IL‐6, IL‐10 and TNFα for both ethnic groups. CRP was not significantly associated with any of the AD biomarkers for either group. Although the Mexican American participants had significantly lower Aβ40 (p = .000) and higher total tau (p = .000) than non‐Hispanic White participants, the two groups did not differ significantly on the level of any of the inflammatory markers.

Conclusion

The level of plasma AD biomarkers is influenced by the presence of peripheral inflammatory cytokines. CRP a non‐specific acute phase marker of inflammation is not related to plasma AD biomarkers in cognitively unimpaired older adults. Ethnicity in this bi‐ethnic study was not a factor in this relationship. Additional research investigating medical co‐morbidities as a factor in the inflammation‐AD plasma biomarker relationship is needed. As with medical co‐morbidities the level of inflammation may affect the interpretation and application of the plasma AD biomarkers in this study.
Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease
Authors: Quesnel Marc James , Labonté Anne , Picard Cynthia , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: December 2023

Background

Osteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD.

Method

The Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694.

Result

Aβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p < 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p < 0.001), SYT1 (p = 0.001), SNAP25 (p < 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374).

Conclusion

Our results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.
Unexpected and interesting distractors capture greater attentional gaze behavior in MCI in a naturalistic visual search task
Authors: Kleiman Michael J , Henriquez Adolfo M , Galvin James E
Published: December 2023

Background

Alzheimer’s disease can influence gaze behavior, even in prodromal stages such as mild cognitive impairment (MCI). Alzheimer’s pathology impacts exploratory eye movements, and can be detected with eye tracking applied to novelty preference tasks that leverage visual short‐term memory. MCI due to Alzheimer’s disease is often associated with attentional deficits, with distracting stimuli capturing a greater amount of attention than seen in healthy controls (HC). In this pilot study, we examine the effects of distractors, including categorical, background, and “unexpected” distractors, in a novel naturalistic visual search task.

Methods

Using a novel visual search task, 45 participants (35 HC, 10 MCI) were asked to count the number of animals (either flying or land animals) in a natural scene while their eye movements were recorded. Scenes contained either no distractors (11 scenes), “expected” distractors of the opposite animal type (8 scenes), or “unexpected” distractors that appeared unusual, such as fish on land (2 scenes). Four of the scenes (1 with distractors) contained a vibrant or interesting background.

Results

No difference was found between MCI and HC in gaze behavior towards expected distractors, however unexpected distractors captured significantly (p<.05) longer and more frequent visits in MCI participants (1.2 seconds and 7.0 visits) compared with HC participants (0.6 seconds and 4.5 visits). In contrast, duration and visits towards targets did not differ, however MCI participants took significantly longer to first attend targets (1.5 seconds) than HC participants (0.5 seconds) when unexpected distractors were present (p = .02). In MCI participants, interesting background stimuli captured significantly more gaze in the first 3 seconds of presentation (35.3% MCI vs 25.8% HC; p = .04).

Conclusions

In this preliminary study, we found that HC participants showed greater resilience to distractions compared to MCI participants, who showed less ability to maintain focus in the presence of unanticipated distractors. Attention was pulled from the counting task towards a distracting background as well as towards the unexpected distractors in MCI participants, but not when distractors appeared to fit naturally in the surrounding scene. Future research will examine effects of age‐related decline and biomarker status in unimpaired participants.
Anti‐inflammatory clearance of amyloid beta by a chimeric Gas6 fusion protein
Authors: Jung Hyuncheol , Lee Se Young , Kang Min Soo , Jung Hwa‐Jin , Shin Ah‐Young , Song Ji‐Yun , Chung Won‐Suk , Kim Chan Hyuk
Published: December 2023

Background

Aβ immunotherapy is the most promising approach in treating Alzheimer’s disease (AD). Although Aβ‐antibodies can substantially reduce Aβ burden in the brain, solutions for antibody‐induced inflammation and subsequent ARIA (Amyloid‐related imaging abnormalities) are still in demand. Here we developed a novel chimeric protein platform, GAIA (Gas6‐mediated anti‐inflammatory adaptor). GAIA platform utilizes TAM receptors, which are expressed on glial cells and mediate phagocytosis without associated inflammatory response.

Method

We developed a GAIA‐based novel chimeric protein (αAβ‐Gas6) which is composed of two distinct functional domains; a single‐chain variable fragment of Aducanumab, which selectively binds to Aβ, fused with Gas6, a TAM receptor‐binding domain. Aβ clearance and phagocytosis‐associated inflammatory responses of αAβ‐Gas6 were measured in comparison with Aducanumab.

Result

αAβ‐Gas6 showed selective uptake of Aβ through phagocytosis in vitro. While Aducanumab induced phagocytosis only in primary microglia, αAβ‐Gas6 significantly induced phagocytosis in both cultured microglia and astrocyte. In comparison with Aducanumab, αAβ‐Gas6 secreted significantly lower amount of pro‐inflammatory cytokines, such as TNF, IL‐6, and IL‐1β. In vivo application of αAβ‐Gas6 reduced Aβ burden in an extent significantly lower in mice treated with Aducanumab. Finally, αAβ‐Gas6 groups showed significantly reduced excessive synapse elimination levels comparable to non‐AD wild type groups.

Conclusion

We developed a novel chimeric fusion protein αAβ‐Gas6 by engineering TAM receptor‐binding domain Gas6. In comparison with antibody drug, αAβ‐Gas6 showed advanced amyloid clearance, significantly reduced neuroinflammation, and neurotoxicity. Thus, our results suggest a novel immunotherapeutic agent which can bifunctionally target Aβ and modulate gilal cells to reduce neuroinflammation.