bluuebunny/crossref_metadata_2025 huggingface dataset:
Facilitating clinical use of the Amsterdam instrumental activities of daily living questionnaire: Dutch normative data and clinical cutoff values
Authors: Postema Merel C. , Dubbelman Mark A. , Verrijp Merike , Visser Pieter Jelle , Zwan Marissa D. , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: June 2023

Background

The Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) is a proxy‐based instrument aimed at measuring difficulties in daily functioning due to cognitive decline in the context of dementia. To facilitate its interpretation and clinical implementation, normative data from the general population are necessary. Here, we aimed to compose normative scores for the A‐IADL‐Q and provide clinical cutoff values for mild cognitive impairment (MCI) and dementia.

Method

Cross‐sectional data from three Dutch cohorts (i.e., Dutch Brain Research Registry, European Medial Information Framework‐Alzheimer’s Disease (EMIF‐AD) 90+, and Amsterdam Dementia Cohort (ADC)) were used, including 1127 cognitively healthy individuals and 380 individuals with MCI and/or dementia. Regression‐based norms were constructed in the healthy sample, using linear models including age, sex, education(high/low) and their interactions, and the optimal model was selected using backward elimination. Individual differences between observed and expected IADL t‐scores were divided by the residual standard error of the model. Optimal normative score cutoffs to distinguish healthy from MCI and/or dementia were based on bootstrap average estimates(500 repeats) of the Youden Index. Diagnostic accuracy was evaluated using receiver operating curves (ROC), area under the curve (AUC), sensitivity and specificity.

Result

Normative data (mean age = 64±13year, 68.6%female, 67.8% highly educated) and memory clinic data (mean age = 66±8year, 43.9%female, 38.9% highly educated) were used (Table1). The best normative model (i.e., with the lowest Akaike information criterion) included age‐squared, sex, education and the interaction between age and education. The optimal normative score cutoffs to distinguish healthy from dementia and MCI/dementia were, respectively, 1.78SD and 1.79SD below the mean, with high AUCs of 0.96 [95%CI 0.95‐0.98] and 0.94 [95%CI 0.92,0.95]. The optimal cutoff to distinguish healthy from MCI was higher; 1.01SD below the mean, also with a high AUC‐score of 0.86 [95%C 0.81‐0.9])(Table2, Figure1).

Conclusion

We composed normative scores with clinical cutoff values that can aid in the distinction between cognitively healthy from MCI and/or dementia with high diagnostic accuracy. These normative scores are accessible via an online tool to further facilitate and implement clinical use of the A‐IADL‐Q. Future studies should include participants from different countries, cultures and different socio‐economic background to facilitate world‐wide use.
Associations of cortisol with neuroinflammation biomarkers in a memory clinic cohort
Authors: Daniilidou Makrina , Hagman Göran , Holleman Jasper , Sindi Shireen , Solomon Alina , Sandebring‐Matton Anna , Kivipelto Miia
Published: June 2023

Background

Cortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer’s disease (AD) patients and correlates with disease severity. Stress response and inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort.

Method

A total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups.

Result

Awakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD.

Conclusion

We provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state.
A systematic review on the effects of tACS on cognitive function within older adults
Authors: Kraft Jacob D , Hampstead Benjamin M.
Published: June 2023

Background

Novel interventions that delay the onset or delay the progression of cognitive decline in older adults are extremely important, especially as the proportion of older adults steadily grows. Data on transcranial Alternating Current Stimulation (tACS) suggests it may have the potential for improving cognitive function; however, the direct implication for older adults, including those with cognitive impairment is far less understood. It is imperative to better understand the effects of tACS on cognitive function within older adults, along with treatment parameters if the therapeutic utility of tACS is to be realized.

Method

For this reason, we performed a systematic review of the literature to evaluate the effectiveness of tACS on cognitive functions within older adults. Databases were reviewed up to February 2022, which initially produced 347 unique projects. Thirty‐seven articles passed initial screening eligibility and the full texts were reviewed. Eligibility criteria included single and multiple session frequency‐specific tACS applied with the purpose of modulating cognitive performance in one or multiple cognitive domains in older adults. A total of 14 reports met the eligibility criteria and were included in the review, consisting of 294 older adults receiving tACS.

Result

The systematic review revealed that tACS show improvement in cognitive function for cognitively intact older adults (n = 5), those with mild cognitive impairment (n = 3), multi‐etiological dementia (n = 3), and Parkinson’s (n = 2), whereas 2 Alzheimer’s reports and 1 healthy aging report found no improvements. Gamma (n = 7) and Theta (n = 6) frequencies were largely targeted and showed modulations in memory, executive functioning, working memory, and gross cognitive screening measures.

Conclusion

Discussion will focus on the impact of various stimulation parameters and experimental methods since significant heterogeneity in these factors indicates the need for greater standardization. In summary, tACS appears beneficial across the ADRD continuum but the intentional mapping of parameter space and standardized outcomes will be vital for future translational efforts.
Neuroprotective Effect of Perillyl alcohol in Experimental Sporadic Alzheimer’s disease
Authors: Sharma Rupali
Published: June 2023

Background

Alzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD whereas Perillyl alcohol (POH) shows ant oxidative & anti‐inflammatory properties.

Method

54 Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with three different doses of Perillyl alcohol (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis had done using OFT and MWM.

Result

Perillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.

Conclusion

Study outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypo function and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanisms.
The dynamic functional role of triggering receptor expressed on myeloid cells 2 (TREM2) assessed with cerebrospinal fluid and positron emission tomography measures
Authors: Crook Harry , Wahdan Malak , Edison Paul
Published: June 2023

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates several microglial activities and is essential for microglia to switch to an activated state. The role of TREM2 in the pathogenesis of Alzheimer’s disease (AD) is unclear, however. Following its role in microglial activity, the ectodomain of TREM2 is cleaved into the soluble proteolytic end product of TREM2 (sTREM2), which is released from the transmembrane domain into the cerebrospinal fluid (CSF) and, therefore, CSF sTREM2 is considered a biomarker of TREM2 activity.

Method

To examine the role of TREM2, we explored the relationships between CSF sTREM2, amyloid‐beta (Aβ42), phosphorylated tau‐181 (p‐tau‐181), and total‐tau (t‐tau) in a cohort of 495 participants (100 patients with AD, 257 patients with MCI, and 138 controls) whose data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Associations between CSF sTREM2 and 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET), 18F‐florbetapir (18F‐AV45) PET, and grey matter volume (GMV) were also investigated.

Result

CSF sTREM2 levels were stable across AD, MCI and cognitively normal subgroups. In the whole cohort, CSF sTREM2 positively correlated with age (r = 0.214,p<0.001), CSF Aβ42 (r = 0.118,p = 0.009), CSF t‐tau (r = 0.423,p<0.001), and CSF p‐tau‐181 (r = 0.396,p<0.001), and negatively correlated with MMSE score (r = ‐0.105,p = 0.019). CSF sTREM2, t‐tau and p‐tau‐181 could significantly predict CSF Aβ42 levels, while CSF sTREM2 and Aβ42 could significantly predict CSF p‐tau‐181 and t‐tau levels. Higher CSF sTREM2 was associated with greater amyloid load, decreased glucose metabolism, and reduced GMV in MCI, but not in AD, in certain brain regions.

Conclusion

CSF sTREM2 levels were comparable across clinical groups, and with CSF sTREM2 correlating with markers of AD and neuronal damage, we predict that changes in neuropathological processes occurring in relation to changes in CSF sTREM2 levels are a result of alterations in TREM2 function, rather than quantity. Taken together with the relationships between CSF sTREM2 and imaging findings, these results suggest that sTREM2 appears early on in the AD trajectory, probably in response to early microglial activation in MCI in response to evolving pathological processes.
Experiencing the digital working transition in participant and public involvement in dementia research during the COVID‐19 pandemic
Authors: Ulate Mauricio Molinari , Woodcock Rebeca , Smith Isabelle , van der Roest Henriëtte G. , Martin Manuel Angel Franco , Craven Michael P
Published: June 2023

Background

Involvement of patients and public in research have been disrupted by the consequences of the COVID‐19 pandemic, forcing a rapid transition from face‐to‐face meetings to digital working as an alternative to engage experts by experience. This project presents a co‐production experience of a Participant and Public Involvement (PPI) group implementing a framework in dementia research, during this transition period.

Method

A PPI activity was developed with the participation of the MindTech Involvement Team (PPI group) through the entire process. A group of experienced researchers, facilitators, and contributors in PPI in dementia research, and an active PPI group during the pandemic were targeted. Three online workshops were performed, and thematic analysis was chosen for the data analysis.

Result

Conflicting positions were identified regarding the transition from face‐to‐face meetings to digital working by using a refine version of the ‘E‐nabling Digital Co‐production' Framework as the coding structure. Regarding e‐PPI (digital PPI), the participating groups shared two perspectives associated to the non‐geographical constraints and the more business‐like sessions. For dementia research, e‐PPI was identified to decrease the supportive and respite environment associated to face‐to‐face meetings, however, it was considered to allow the participants to attend more meetings.

Conclusion

The project gives feedback on the digital working in PPI by identifying concerns and fortes of this transition, both for general PPI and in the field of dementia research. It contributes further co‐production initiatives by introducing the ‘E‐nabling Digital Co‐production' Framework as a tool to reflect on future public involvement.
Co‐designing a virtual reality social connecting space for older adults living with dementia
Authors: Flynn Aisling , Reilly Gearoid , Barry Margeurite , Brennan Attracta , Redfern Sam , Casey Dympna
Published: June 2023

Background

Older adults living with dementia often experience reduced social connectedness and must be supported to enhance or maintain their social connections. Digital technology is increasingly being used to address this area. In particular, virtual reality (VR) has shown promising benefits for sociability despite not being designed for this purpose. Research has highlighted the need to design social VR spaces which can enable multi‐user experiences to foster social connectedness. Such a design process needs to meaningfully involve older adults living with dementia and their support persons from the outset.

Methods

Action research was used to co‐design a VR social connecting space for older adults living with dementia. The research aimed to explore one’s experience and perception of social connectedness and how VR may be used to help older adults living with dementia stay socially connected. Using participatory methods of data collection, older adults living with dementia and their support person had the opportunity to use a VR technology probe and participate in a series of semi‐structured interviews, group meetings and design workshops. Reflexive thematic analysis was used to analyze transcripts alongside observational field notes taken by the researcher. The findings from each phase of data collection were used to inform subsequent research activities.

Results

The meaning and importance of social connectedness is dynamic and transient. Older adults living with dementia experience several barriers and facilitators to social connectedness and their support person often plays an important role in maintaining existing connections. VR was considered a novel and enticing technology to enhance and maintain one’s connections. Older adults living with dementia and their support person expressed preferences for shared experiences and these were translated into the virtual environment (VE). Design preferences to facilitate co‐location and co‐presence in the VE were also integrated into the social connecting space.

Conclusion

VR was considered an enticing technology to enhance or maintain the social connectedness of older adults living with dementia. Older adults living with dementia and their support person contributed to the design decisions which shaped the development of the social connecting space.
The rate of use of actylcholinesterase inhibitors and/or the NMDA antagonist memantine in long term care dementia patients at risk for BPSD
Authors: Posar Steven Laurence , Heiser Daniel , Reid Anita
Published: June 2023

Background

According to the CDC, 47.8% of long‐term care residents have dementia and 98% of these residents are at risk for Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase Inhibitors (AChEIs) and the NMDA blocker memantine separately provide improvements in cognition, function, and BPSD associated with dementia. Data indicates that treatment with an AChEI and memantine in combination would be more beneficial for cognition, function, and BPSD than either drug separately. GuideStar Eldercare (GSE), a Neuropsychiatric Behavioral service agrees that this medication combination mitigates the development and severity of BPSD. We sought baseline data on long term care residents with dementia that are on either an AChEI, memantine, or both, to establish baseline information for clinical protocol development. We conducted this study to measure the levels of compliance with the standard of care that AChEI’s and/or memantine be provided for the majority of dementia patients.

Method

GSE selected four buildings that were new to our services. An audit of all residents to whom we had chart access was completed. Criteria included established dementia and AChEI and/or memantine use prior to initiation of our services. A ratio of those residents with a qualifying dementia diagnosis compared to those with AchEI and/or memantine use was calculated.

Results

Data review demonstrated: Building A, Michigan‐35 residents with dementia, 8 (23%) residents on medications, and 27 (77%) not on medications. Building B, Ohio‐41 residents with dementia, 8 (20%) residents on medications, and 33 (80%) not on any medications. Building C, Indiana‐26 residents with dementia, 3 (12%) residents on medications, and 23 (88%) not on medications. Building D, Michigan‐20 residents with dementia, 8 (40%) on medications, and 12 (60%) not on medications.

Conclusion

Of 122 total patients, 27 were on medications (22%) and 95 were not on any medications (78%). We believe this presents opportunity to initiate AChEI and memantine as the standard of care for almost all dementia residents yielding significant improvement in their BPSD clinical status.
Why should we discuss gender inequalities in Latin America and their effects in later life?
Authors: Ribeiro Fabiana , Leist Anja K.
Published: June 2023

Background

High inequalities in Latin America (LA) affect social groups differently, with women being disadvantaged in many domains. Further, dementia prevalence is higher and with earlier onset in LA, especially among women, after accounting for women’s longer life expectancy. This narrative review discusses the modifiable risk factors of dementia established by previous studies and postulates further harmful, often hidden, factors experienced by women that might influence gender‐specific time of onset and general prevalence of dementia.

Method

We searched databases for qualitative and quantitative articles systematising dementia‐associated factors between genders/sexes in LA.

Result

We review hidden modifiable risk factors for late‐life cognitive impairment that should be integrated into future research. In doing this, we point out pervasive gender roles around education, labour market participation, but also the distribution of resources within families and across generations. Gender roles affect family structure living conditions during childhood and extend their influence over the life course. Other stressors strongly correlated with established modifiable risk factors or intrinsically relevant to dementia risk seem to be commonplace in women’s lives in LA, such as food insecurity, overweight/obesity, violence, and limited career opportunities.

Conclusion

Based on the evidence of gender inequalities in many domains to the disadvantage of women in LA, there is a need to consider unexplored risk factors since they could perpetuate burden of dementia among women disproportionately. Moreover, bringing hidden risk factors to open discussion can encourage and promote public policies to decrease gender inequalities and protect women’s health and well‐being.
Sex‐specific DNA methylation differences associated with Alzheimer’s disease
Authors: Wang Lily , Silva Tiago C , Young Juan J , Zhang Lanyu , Gomez Lissette , Schmidt Michael A. , Varma Achintya , Martin Eden R.
Published: June 2023

Background

Sex has increasingly been recognized as an important factor contributing to the heterogeneity in Alzheimer’s disease (AD).

Method

We performed a sex‐specific meta‐analysis of two large epigenome‐wide association studies (ADNI, AIBL) in the blood, with a total of 633 and 651 samples in females and males, respecitively. For each dataset, we adjusted covariate variables age, sex, batch, and immune cell‐type proportions. The Inverse‐variance fixed‐effects meta‐analysis model was then used to prioritize the most consistent DNAm differences across datasets.

Result

In female samples, 2 CpGs, mapped to the PRRC2A and RPS8 genes, reached the 5% false discovery rate (FDR). No CpGs reached 5% FDR in male samples analysis. At a more relaxed significance threshold of P < 1×10−5, an additional 22 CpGs and 5 CpGs were identified in female samples and male samples, respectively. For these 29 AD‐associated CpGs, the odds ratios ranged from 0.843 to 1.335 in females and 0.993 to 1.058 in males. The majority of these CpGs were hypermethylated in AD subjects (23 CpGs), located outside CpG islands or shores (27 CpGs), or in distal regions located greater than 2k bp from the TSS (27 CpGs). Only 2 of these 29 CpGs were located in gene promoters at SLC5A8 and C16orf89.

At 5% Sidak corrected P‐value, our DMR analysis using comb‐p software identified 49 distinct differentially methylated regions (DMRs) in female and male samples each. The median numbers of CpGs in these DMRs are 5 CpGs in females and 4 CpGs in males. Among the top 10 most significant DMRs, about half of them (6 in females, 5 in males) were hypermethylated in AD. In females, 5 out of the 10 DMRs were mapped to promoter regions of the NNAT, CCDC169‐SOHLH2, ARHGEF15, LPAR5, and ZNF595 genes. In males, 4 out of the 10 DMRs were mapped to promoter regions of the MCCC1, PM20D1, PRR19, TTC23, and LRRC28 genes.

Conclusion

As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding AD pathophysiology. They also provide a valuable resource for sex‐specific biomarkers and drug targets in AD.
Repetitive mild traumatic brain injury induces hippocampal neural immune signaling linked to astrocyte reactivity
Authors: Pybus Alyssa F , Bitarafan Sara , Brothers Rowan , Rohrer Lilly , Udeshi Kareena , Davies Brae , Khaitan Arushi , Li Chenxing , Buckley Erin , Wood Levi B
Published: June 2023

Background

Repeated mild traumatic brain injuries (mTBIs) sustained within a “window of vulnerability” can lead to a cumulative severity of outcomes such as memory impairment, depression, and long‐term development of amyloid beta (Aβ) pathology and neurofibrillary tangles. We previously reported that acute increases in neural immune signaling within the MAPK pathway and expression of pro‐inflammatory cytokines were associated with low cerebral blood flow (CBF) and worse long‐term spatial learning and memory in a weight‐drop mouse model of repetitive mTBI. We hypothesized that an increasing number of injuries would lead to an increase in neural immune signaling, pathological markers, and glial activation in the hippocampus.

Method

Female 3xTg mice at 3‐4mo of age were subjected to 1x, 3x, or 5x weight‐drop closed head injuries (CHI) spaced once‐daily. Animals were sacrificed and brains harvested at 30min, 4h, 24h, or 1‐month after the final CHI (n = 7‐10/time point/injury group). 32 cytokines, 10 MAPK phospho‐proteins, Aβ42, Aβ40, phospho‐tau (pThr181), and total tau were measured by Luminex in hippocampal tissues. GFAP was measured by ELISA. CBF was non‐invasively measured immediately prior to sacrifice.

Result

We observed a steady increase in both total tau and phospho‐tau and a trend of increased GFAP in the hippocampus after repeated injuries. We then identified groups of cytokines and MAPK phospho‐proteins which co‐vary with either GFAP or phospho‐tau. GFAP‐associated cytokines showed a rapid acute increase after injury then a return to basal levels by 24h, while GFAP‐associated MAPK dynamics changed with repeated injury. Cytokines and MAPK phospho‐proteins showed a notably high degree of cross‐correlation 4h after repeated injury, when GFAP levels were at their highest. Multivariate analysis revealed that high levels of GFAP were associated with low CBF while increased phospho‐tau in the frontal cortex was associated with high CBF.

Conclusion

Together, our data indicate an increase in hippocampal neural immune signaling and astrocyte reactivity after repetitive brain injury. Immune signaling changes may be causally linked to spatial learning and memory deficits after repetitive mTBI.
Computational CRISPR deep learning simulation of the likelihood of Alzheimer’s disease using chromosome 19 GWAS
Authors: Bae Jinhyeong , Acri Dominic J , Nho Kwangsik , Saykin Andrew J. , Penchev Valentin , Apostolova Liana G.
Published: June 2023

Background

Several genetic variants in chromosome 19 have been determined as independent Alzheimer’s disease (AD) risk factors. It is presumed that different combinations amongst them would further impact AD risk and progression at the individual level. In order to advance AD precision medicine, it is critical to understand the underlying complex genetic mechanisms. Deep learning technology is capable of not only identifying such variants but also defining complicated interactions that could further influence disease progression.

Method

We applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. By using occlusion mapping we identified the SNPs that contributed to predictive accuracy of AD vs. CU and sequentially replaced each of them with all other biologically plausible alleles to most precisely measure the impact of the variability at the SNP level. Next, we examined the possible epistatic interactions on the SNP level on AD likelihood by co‐occlusion of pairs of SNPs and investigating the additional changes on predictive accuracy.

Result

Rs56131196 (APOC1) emerged as the most powerful chromosome 19 AD SNP. 79.69% (51/64) of the predicted AD patients were heterozygous, i.e., AG, at this locus. In contrast, 88.89% (80/90) of the predicted CU patients had GG genotype at rs56131196. Substituting AG for GG in predicted AD participants resulted in changing the diagnostic prediction to CU in 36% of the cases. Substituting GG for AA in predicted CU participants resulted in changing the diagnostic prediction to AD in 6% of the cases. The model further identified that AG→GG replacement further affects the likelihood of AD by interactions with SNPs in other genes including APOC1/APOC1P1, TOMM40, and ERCC1/CD3EAP.

Conclusion

We tested the APOC1 rs56131196 genotype risk for AD by creating a simulator analogous to CRISPR. This innovative approach could provide a potential in silico CRISPR predictive modeling and help advance personalized preventive gene therapy for AD.
The association of amyloid‐beta, tau, and cerebrovascular biomarkers with neurodegeneration in dementia with Lewy bodies
Authors: Ferreira Daniel , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Diaz‐Galvan Patricia , Graff‐Radford Jonathan , Senjem Matthew L. , Fields Julie A. , Savica Rodolfo , Ferman Tanis J , Graff‐Radford Neill R , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Westman Eric , Boeve Brad F. , Kantarci Kejal
Published: June 2023

Background

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). While alpha‐synuclein pathology is the hallmark of DLB, AD and cerebrovascular pathologies are common in DLB patients. However, the contribution of these pathologies towards neurodegeneration in DLB is largely unknown. We investigated associations of amyloid‐beta, tau, and cerebrovascular biomarkers with regional gray matter (GM) volume in DLB patients and cognitively unimpaired (CU) controls.

Method

We included 30 DLB patients (69.3±10.2 years old, 87% men) and 100 CU individuals balanced on age and sex (Table 1). We used 11C‐Pittsburgh Compound‐B (PiB) and 18F‐Flortaucipir positron emission tomography (PET) to assess amyloid‐beta and tau in‐vivo. We used structural MRI to assess white matter hyperintensity (WMH) volume, a marker of cerebrovascular lesion load, and regional GM volume (a marker of neurodegeneration). We used correlations and ANCOVA in the whole dataset and structural equation modelling in the DLB patients to investigate associations of WMH volume and regional amyloid‐beta and tau PET standardized uptake value ratios (SUVRs) with regional GM volume.

Result

DLB patients showed lower GM volume across all cortical and subcortical regions except for cuneus, putamen, and pallidum (Fig.1). Greater WMH volume was associated with lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in DLB patients (Fig.2). Greater PiB SUVR was associated with lower volume in the inferior temporal cortex, while Flortaucipir SUVR did not correlate with GM volume (Fig.2). Structural equation modelling showed that higher age and positivity for the APOE e4 genotype were significant predictors of greater WMH, and WMH in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex (Fig.3). In contrast, we observed two distinct paths for the fusiform cortex, with age having an effect through PiB and Flortaucipir SUVRs on the one path, and through WMH on the other path (Fig.3).

Conclusion

DLB patients have widespread cortical atrophy, most of which likely is influenced by alpha‐synuclein pathology. Although amyloid‐beta, tau, and cerebrovascular pathologies often coexist in DLB, their contributions to neurodegeneration seem to be region specific.
Increased Expression of Kif11/Kinesin‐5 mRNA Offsets Cognitive Deficits In An Alzheimer’s Mouse Model, Blocks Aβ‐Mediated Decreases in Long‐Term Potentiation and Spine Density, and is Associated With Better Cognitive Performance in Alzheimer’s Patients
Authors: Lucero Esteban M , Freund Ron , Smith Alexandra N. , Johnson Noah R , Dooling Breanna , Sullivan Emily , Prikhodko Olga , Ahmed Md. Mahiuddin , Bennett David A , Hohman Timothy J. , DellAcqua Mark , Chial Heidi J , Potter Huntington
Published: June 2023

Background

Interactions between the Aβ with intra‐ and extra‐cellular molecules disrupt neuronal structures and functions, leading to cognitive dysfunction in Alzheimer’s disease (AD). We previously have shown that Aβ competitively inhibits the microtubule motor protein KIF11 (Kinesin‐5/Eg5), which regulates microtubule dynamics, cellular trafficking, neuronal migration, and neuronal structures important for learning and memory. In vitro cell culture and ex vivo electrophysiology experiments later revealed that the inhibition of KIF11 by Aβ underlies multiple phenotypes associated with AD, including decreases in LTP, breakdown of the microtubule network, and deficits in neurotransmitter receptor localization and function. Here we aimed to determine whether increased Kif11 expression overrides phenotypes associated with AD.

Methods

Kif11 overexpressing mice were crossed with the 5xFAD mouse model of AD to generate 5xFAD mice that overexposes Kif11. Learning and memory of these mice was measured through the performance of 6‐8 month old mice in the radial‐arm water maze and LTP was measured by the fEPSP response to high‐frequency stimulation of the CA1 region in hippocampal slices of our transgenic mice. Primary rat neurons were transiently transfected to express human APP harboring the Swedish mutation (APPswe) with or without Kif11 overexpression to determine whether increased Kif11 expression affects Aβ‐mediated decreases in dendritic spine, We then evaluated cognitive function in amyloid positive individuals in the ROS/MAP study with their KIF11 mRNA expression in 4 brain regions, the DLPFC (N = 939), PCC (N = 527), and the CN (N = 715).

Results

KIF11 overexpression overrides Aβ toxicity and rescues Aβ‐mediated decreases in LTP in hippocampal slices and dendritic spine density in cultured neurons. Furthermore, we found that spatial and working memory deficits were prevented in a 5xFAD Alzheimer’s mouse model that overexpresses Kif11. Analyses of RNAseq data from human participants in the Religious Order Study and Memory and Aging (ROS/MAP) revealed that higher KIF11 expression in AD patients correlated with better cognitive performance.

Conclusion

KIF11 is essential for maintaining synaptic structures and functions critical for learning and memory in AD, and preventing or overriding the inhibitory interaction of Aβ with Kif11 could be a promising therapeutic target for multiple AD phenotypes.
Neuropsychiatric symptom progression in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Mackenzie Ian R , Lapid Maria I. , Huey Edward D. , Wittenberg Dana , Rosen Howard J. , Boeve Brad F. , Boxer Adam L , Rankin Katherine P , Hsiung Ging‐Yuek Robin ,   the ALLFTD Consortium
Published: June 2023

Background

Neuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.

Method

Participants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.

Result

We analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.

Conclusion

Prior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.
Altered ubiquitination of phospholipase D3 contributes to lysosome dysfunction in Alzheimer’s Disease
Authors: Fernandez Wilber Romero , Antunes Lissa Ventura , Katdare Ketaki A. , Balotin Kylie M. , Prusky Alex , Solopova Elena , Shostak Alena , Wang Emmeline , Lippmann Ethan S , Schrag Matthew
Published: June 2023

Background

Proteinopathy is a common feature of multiple neurodegenerative diseases. Recent studies have demonstrated lysosomal dysfunction is closely linked to neurodegenerative proteinopathies. In the context of Alzheimer’s disease (AD), the lysosomal protein phospholipase D3 (PLD3) has been identified as a potential molecular player, but PLD3’s distinct role in lysosome function is not completely understood.

Method

We used immunohistochemistry, western blot, and proximity ligation assays to determine PLD3’s localization, expression level, post‐translational modification and protein‐protein interaction profile. Experiments were performed using iPSC‐neuron cultures and human brain tissue obtained from patients with AD and neurological controls through the Vanderbilt Brain and Biospecimen Bank.

Result

PLD3 is neuronal widely distributed throughout brain regions relevant to memory and cognition and PLD3 levels were significantly lower in AD brains compared to the controls. We discovered that PLD3 ubiquitination was significantly increased in AD brains relative to the controls, providing a possible explanation for the PLD3 reduction and localization into hallmark pathological structures of the AD brain. Furthermore, PLD3‐ubiquitin complexes were enriched in parenchymal β‐amyloid deposits and intraneuronal tau pathologies, both neuropil threads and neurofibrillary tangles.

We provide the first experimental evidence for the physical interaction between PLD3 and Cathepsin D (CTD), both in human brain tissue and iPSC neurons. The interaction between PLD3/CTD was promoted by exposure of iPSC‐neurons to human Aβ seeds isolated from post‐mortem brain, suggesting this protein‐protein interaction is relevant to Aβ pathology. We found this heterodimer was dramatically reduced in AD brain, especially in dystrophic neurites. The loss of this interaction in dystrophic neurites is notable because even though PLD3 levels are reduced in the AD brain, both PLD3 and CTD are present in abundance around β‐amyloid plaques. The loss of PLD3/CTD interaction observed in AD brain is only partly explained by reduced expression of both proteins, so it is likely that an alteration in lysosome function is impacting this protein‐protein interaction.

Conclusion

This study revealed an important role for both PLD3 ubiquitination and as an interaction partner for CTD within lysosomes. It will be interesting to further dissect the molecular mechanisms underlying the PLD3/CTD interaction.
Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment and Alzheimer Disease
Authors: Cieri Filippo , Yang Zhengshi , Cummings Jeffrey , Kinney Jefferson W , Cordes Dietmar , Caldwell Jessica ZK ,   ADNI study
Published: June 2023

Background

Age and sex are major risk factors for late onset Alzheimer’s disease (AD). Almost 70% of AD patients are women, but reasons for sex disparities are not well understood. One potential avenue of inquiry is investigation of default network (DN) functional connectivity (FC) differences between men and women.

Method

We studied amyloid positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), clinically diagnosed as healthy elderly controls (HCs), Mild Cognitive Impairment (MCI) and AD, with resting‐state functional Magnetic Resonance Imaging available at the diagnostic and cognitive testing visit (Table 1). We selected seven regions of interest (ROIs) in the DN (Figure 1), including bilateral angular gyrus (ANG), calcarine (CAL), precuneus (PCUN), medial orbital frontal gyrus (ORBmed) and bilateral middle occipital gyrus (MOG). Pearson’s correlation characterized FC between ROIs. Linear mixed effect models adjusted for covariates (education, handedness, presence of apolipoprotein [APOE] ε4 and intra‐subject effect), and analysis of variance (ANOVA) evaluated the effects of diagnosis, sex and their interaction, using Bonferroni correction.

Results

ANOVA showed significant differences between diagnostic groups in FC of left ANG – PCUN/CAL and bilateral MOG – CAL. Significant diagnosis by interaction effects were observed in FC especially at the level of posterior‐ventral DN. Specifically, between ANG‐CAL, and PCUN‐MOG (Table 2). Post‐hoc analysis demonstrated distinct effect sizes and/or opposite direction effects in women compared to men (Figure 2). Left ANG – CAL and left ANG – PCUN connectivity had medium effect (|d| >0.5) for men in the MCI versus HC comparison, although small effect (|d| <0.2) across sexes. The discrepancies between women and men were observed in the AD versus MCI comparison, such as the left ANG – left MOG and right ANG – CAL, where they show an opposite direction of FC.

Conclusions

Our study found that the sex differences in DN FC did not remain consistent across the clinical AD spectrum. Instead, significant sex by diagnosis interaction effects suggest that treating sex as a covariate overlooks sex‐specific pathological changes in brain FC.
Deformation‐based morphometry analysis shows early degeneration in Nucleus basalis of Meynert in Subjective Cognitive Decline
Authors: Shafiee Neda , Morrison Cassandra , Dadar Mahsa , Fonov Vladimir S , Spreng R. Nathan , Collins D Louis
Published: June 2023

Background

People with subjective cognitive decline (SCD+) are thought to be at greater risk of Alzheimer’s disease (AD). The Nucleus basalis of Meynert (NbM) has been shown to change early in AD (Fernández‐Cabello et al., 2020), and it is the main source of cholinergic projection to entorhinal cortex (EC) (Mesulam et al., 2013). We thus investigated if there was evidence of degeneration in the NbM, or EC in SCD+ participants compared to those without (SCD‐), and if there was a relationship between changes in these regions and SCD status using deformation‐based morphometry (DBM).

Method

Data included baseline visit MRI scans of 232 cognitively healthy older adults (148 SCD‐; 84 SCD+) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (using only ADNI2). SCD status was extracted based on the cognitive change index (CCI) of the subjects reported in ADNIMERGE data (CCI ≥16). MRI resolution was increased to 0.5 mm isotropic voxel‐size before non‐linear registration to an ADNI‐based unbiased symmetric template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. NbM, and EC masks were mapped to our high‐resolution template and mean determinant values inside these masks were estimated, and sex‐ and age‐corrected z‐scores were calculated. Two‐sample t‐tests were then used to compare the SCD+:SCD‐ differences.

Result

Figure 1 shows the mean z‐score values for NbM and EC regions for both SCD+ and SCD‐ groups. Results for left NbM showed a significant difference between two groups (p = .007), but not for the right NbM (p = .12). However, z‐scored EC volumes did not show any statistically significant difference between groups for either left (p = .58) or right region (p = .41).

Conclusion

Our results suggest that in SCD+ subjects, while the EC is still intact, neurodegeneration in the NbM appears to have already begun. Quantifying degeneration in the NbM may allow for early diagnosis of AD. Further research is needed to evaluate if such differences can be computed on an individual subject basis for use as a biomarker.
Description of the ARMADA (assessing reliable measurement in Alzheimer’s disease) general population study cohorts
Authors: Karpouzian‐Rogers Tatiana , Ho Emily , Novack Miriam , Chinkers Miriam , Wortman Katy , Nowinski Cindy J. , Dodge Hiroko H , Giordani Bruno , Gershon Richard C. , Weintraub Sandra
Published: June 2023

Background

Given the growing population of aging adults, and subsequently individuals with dementia, there is a need for instruments that can detect cognitive impairment in early stages. The NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIHTB) is a computerized battery of assessments measuring multiple domains cognition, emotion, sensation, and motor abilities. The goal of the ARMADA study is to validate the NIHTB in individuals with mild cognitive impairment (MCI) and dementia of the Alzheimer type (DAT). Here, we describe the demographic and clinical characteristics of participants ages 65 to 85 from the general population sample.

Method

Normal control (NC), MCI, and DAT groups racially proportional to the US population were recruited from existing cohorts across nine Alzheimer’s Disease Research Centers and sites with cognitive aging studies. Diagnoses were based on the Uniform Data Set methodology, and included multiple clinical and cognitive assessments. Participants completed the NIH Toolbox at baseline, 12‐, and 24‐month visits.

Result

Groups were matched with respect to multiple demographic characteristics. There were some differences in age and sex, such that the NC group had more female participants and was the youngest. Dementia severity levels differed as expected, with the DAT group demonstrating greater cognitive and functional impairment compared to the MCI group, and the NC group demonstrating minimal cognitive or functional symptoms. Additionally, the DAT group reported more neuropsychiatric symptoms compared to the NC and MCI groups. There was no difference in reported family history of cognitive impairment across groups. Many participants across groups had at least one Alzheimer biomarker collected.

Conclusion

The study cohorts included in the ARMADA study accurately reflect their respective clinical syndromes for validating the NIHTB across the cognitive aging spectrum. The goals for the ARMADA study include comparing performance on all four modules of the NIHTB across groups, evaluating the relationship between Alzheimer biomarkers and NIHTB measures, and measuring changes in performance longitudinally. Special emphasis groups, including individuals over age 85, African American participants, and Spanish‐Speaking participants, were also recruited and are reported elsewhere.