bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional blood‐brain barrier breakdown and Alzheimer’s disease pathology in aging
Authors: Becerra Marisa N. , Baker Suzanne L. , Inglis Ben A , Jagust William J.
Published: December 2022

Background

Although blood‐brain barrier disruption (BBBd) is described in aging and AD, its regional characteristics and relationship with AD pathology have not been fully characterized. We aimed to determine whether there are age‐related regional differences in BBBd in cognitively normal adults and if regional BBBd is related to Aβ, tau, and neurodegeneration.

Method

BBBd was measured using DCE‐MRI in 9 older adults (OA; 78±6 years, 7M) and 10 young adults (YA; 24±2 years, 7M). The Patlak model was used to generate BBB permeability volume transfer constant (Ktrans) maps in FreeSurfer regions of interest (ROIs). In the OA, PiB‐PET was used to measure global amyloid burden, FTP‐PET to measure tau in medial temporal lobe (MTL) regions, and T1 MRI to measure cortical thickness. We conducted repeated measures ANOVA (group, region, and group x region) with post‐hoc tests to investigate regional differences in Ktrans values between OA/YA and Aβ+/Aβ‐. Linear regressions were used to evaluate the relationships of tau and thickness with Ktrans.

Results

There was a significant region by age interaction (p< 0.001). OA had greater Ktrans than YA in the entorhinal cortex, parahippocampus, cuneus, fusiform, inferior temporal gyrus (IT), and the lateral occipital cortex (independent sample t‐tests, ps < 0.05; Fig 1). YA had greater Ktrans in the superior and transverse temporal lobe (ps <0.05). In the OA, a trend‐level region by Aβ status interaction (p=0.09) was found for the same ROIs (Fig 2). There were no significant relationships between MTL tau and Ktrans. There was a significant negative relationship between thickness and Ktrans in an averaged ROI consisting of the six regions where OA showed greater Ktrans than YA (p=0.025; Fig 3).

Conclusion

These findings show that greater BBBd in OA is relatively specific to the MTL and IT, which are regions affected early in AD. They also suggest that increased BBBd in these regions may be related to amyloid accumulation and neurodegeneration. These findings require extension in larger samples, but implies BBBd as a potentially important event in aging and in the pathophysiology of AD.
Air pollution nanoparticle exposure reduces neurotrophin signaling and causes hippocampal neural stem cell quiescence in mouse brain
Authors: Zhang Hongqiao , Zhang Nathan , Li Andrew , Diaz Arnold , Shkirkova Kristina , Ge Brandon , Florentino Abigail , Sioutas Constantinos , Mack William J , Bonaguidi Michael Anthony , Finch Caleb E
Published: December 2022

Background

Exposure to urban air pollution particles is strongly associated with higher risks of accelerated cognitive decline, cerebral atrophy, and dementia in multiple population studies. Among possible mechanisms is the decrease of neurotrophins, shown for BDNF in human exposures, which have critical roles in regulating adult neurogenesis and synaptic plasticity.

Method

C57BL/6 mice were exposed to nano‐sized particulate matter (nPM, batch nPM2016a) from urban traffic air pollution for 8 weeks and the mRNAs of neurotrophins and receptors in mouse brain were measured by qPCR assay and neural stem cells measured by immunohistochemistry.

Result

nPM exposure altered mRNA levels of neurotrophin genes (Ngf, Bdnf, Ntf‐3 and Ntf‐4/5) with brain region‐specificity. In cerebral cortex (CX), Ngf and Ntf‐3 were decreased (17% and 29% respectively), Ntf‐4/5 increased (78%), and Bdnf unchanged. In hippocampus (HP), Bdnf and Ntf‐4/5 were decreased (40% and 38% respectively) while Ngf and NTF‐3 unchanged. In olfactory bulb (OB), only Bdnf was decreased (10%). The mRNAs of neurotrophin receptors (Trka, Trkb, Trkc and p75Ntr) in CX, HP and OB were less responsive to nPM exposure, and only shown by OB with 22% decrease of p75Ntr and 14% decrease of Vgr (VGF nerve growth factor inducible). Exposure to nPM increased the quiescence of neural stem cells in hippocampal SGZ by IHC assay (Control 69.3% VS nPM 76.6%, P = 0.02), but did not alter the total number of neural stem cells. .

Conclusion

Chronic air pollution exposure altered neurotrophin signaling with factor‐ and brain region‐specificity, and increased neural stem cell quiescence.
Transitioning to Elecsys automated immunoassay for fresh CSF biomarkers to support the diagnosis of Alzheimer’s disease in Australia
Authors: Li Qiao‐Xin
Published: December 2022

Background

Alzheimer’s disease (AD) biomarker proteins, amyloid β1‐42 (Aβ42) and Tau (Phospho‐tau 181 [pTau] or Total‐tau [tTau]), in the cerebrospinal fluid (CSF) are used to support the clinical diagnosis of AD, and for enrolment of patients into therapeutic trials. Currently Roche Elecsys Generation I (GI) for frozen CSF is used, which will be replaced by Generation II (GII) for routine diagnostics use. This study examined the correlation of the biomarkers obtained from the automated Elecsys GI vs the manual INNOTEST immunoassays and the concordance of diagnostics outcome between the two methods. In addition, we also examined performance of GII on fresh CSF.

Method

Cerebrospinal fluid (CSF) samples were collected from local hospitals/clinics and from the study cohort of the Australian Imaging Biomarkers and Lifestyle study of Aging (AIBL). Aβ42, pTau and tTau were measured with both Elecsys and INNOTEST. Most recent collected CSF with a paired frozen and fresh CSF were assayed in parallel of both GI and GII.

Result

In the cohort of 34 collected frozen CSF from the AIBL cohort, the Spearman r correlations between INNOTEST and Elecsys methods were 0.91, 0.98, and 0.97 for Aβ42, pTau181, tTau, respectively. From 166 clinical diagnostic CSF samples (from local hospitals and clinics), the correlation was 0.89, 0.93, 0.88, respectively. Using the Aβ42 and pTau as primary parameters, the diagnostic outcome is highly concordant between the two methods in these two groups. Initial data from the paired frozen and fresh CSF showed GI and GII correlated well (r = 0.9643). Assessments on the GII cohort are ongoing.

Conclusion

The automated Elecsys is highly correlated with the INNOTEST and offers high throughput and excellent precision with lower interassay/interlaboratory variation. This supports the use of Elecsys for CSF AD diagnostics in routine practice. The availability of fresh CSF analysis on GII will make the test more easily accepted into routine pathology setting.
Chronic conditions, multimorbidity, and its trajectory in relation to incident dementia: a prospective study
Authors: Chen Hui , Zhou Yaguan , Zuo Guangmin , Xu Xiaolin , Yuan Changzheng
Published: December 2022

Background

Many single chronic conditions and multimorbidity have been related to dementia in previous studies. However, the long‐term relation of multimorbidity and its developmental trajectory with dementia remains unclear.

Method

The study included 5,998 dementia‐free participants (58.9% female, mean [standard deviation] age = 73.5 [6.8] years) from the Health and Retirement Study. Data on the health status, including self‐reported diagnosis of eight chronic conditions (high blood pressure, diabetes, cancer, lung diseases, heart diseases, stroke, psychological disorders, and arthritis) were collected from 1994 to 2008. Trajectories of multimorbidity development (including “no new condition, 31.2%”, “slow growth, 25.1%”, “steady growth, 32.2%”, and “rapid growth, 11.4%”) were identified using group‐based trajectory modeling methods. Incident dementia were detected during 2008 to 2018. Cox proportional hazard models were used to assess the relations of number of chronic diseases and its developmental trajectory to dementia.

Result

During the study follow‐up (median [IQR] = 8 [6‐10]), a total of 741 (12.3%) participants developed dementia. Number of chronic conditions was associated with risk of subsequent dementia (hazard ratio [HR] for per condition increment = 1.14; 95% confidence interval [CI] = 1.08 to 1.20). The associations were consistently observed across major study subgroups. Psychological disorders (HR = 1.72, 1.42 to 2.08) and stroke (HR = 1.64, 1.32 to 2.02) demonstrated the strongest relations, followed by diabetes (HR = 1.23, 1.03 to 1.48) and heart diseases (HR = 1.21, 1.03 to 1.43). Moreover, participants with “rapid growth” trajectory of multimorbidity development were observed to have the highest dementia risk (HR = 1.38, 1.09 to 1.76), compared to the “no new condition” group.

Conclusion

Our study provided evidence that the number of coexisting conditions and the faster development of multimorbidity were both associated with higher risk of subsequent dementia. Further investigations are warranted to understand the underlying mechanisms.
Crop Filling: artefact removal for real‐world clinical neuroimaging data
Authors: LaPoint Molly R. , Whitfield Tim , Walker Zuzana , Oxtoby Neil P
Published: December 2022

Background

The use of standard clinical neuroimaging data for quantitative research is often precluded by imaging artefacts caused by real‐world limitations. For example, partial coverage (cropping) of T1‐weighted MRI scans can occur when a memory clinic prioritises visual ratings on T2‐weighted MRI, and so the T1 scan field‐of‐view is reduced to minimise the overall acquisition time. This study investigated cropping‐induced biases in T1‐MRI volumetric measurements and proposed and validated a solution.

Method

This study involved 1.5T T1‐weighted and T2‐weighted MRI data from 577 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI): 173 cognitively normal (CN); 262 mild cognitive impairment (MCI); 114 probable Alzheimer’s disease dementia (AD). The ADNI data was preprocessed to resemble clinical data seen in the CODEC dataset from the Essex Memory Clinic in the UK. The T1w scans were artificially cropped to a field of view of 120mm laterally. The T2w scans were down‐sampled to have axial slice thickness of 5mm. FreeSurfer’s synthSR tool was used to synthesize a super‐resolved T1wSR from the down‐sampled T2w. The T1wSR image was registered to the cropped T1w using mri_robust_registration, with the data from the T1wSR used to fill the missing voxels in the cropped image. FreeSurfer’s recon‐all tool was used to estimate regional brain volumes in cropped , crop‐filled and original T1w images, with results compared using Bland‐Altman analysis, R2 correlation metric, and T‐test between original and cropped/crop‐filled values.

Result

Figure 1 shows an example T1w from ADNI (coronal/axial view, AD patient): original (top); artificially cropped (centre); crop‐filled (bottom). Table 1 shows groupwise demographics of the ADNI participants and overall experimental results. Figure 2‐5 shows Bland‐Altman plots and R2 correlation metric for the volumes of three AD‐relevant brain regions: hippocampus, middle temporal gyrus, and ventricles. Results suggest that the proposed crop‐filling solution works well: low percentage bias (<1% crop‐filled; ∼2% cropped), high correlation (R2∼0.9 crop‐filled; ∼0.85 cropped).

Conclusion

The new crop‐filling methodology was effective at removing this specific artefact seen in clinical neuroimaging data. This is an important step towards making real‐world neuroimaging data amenable to quantitative analyses.
Sex differences on a digitally‐administered cognitive assessment battery in adults at‐risk for development of Alzheimer’s disease.
Authors: Bryk Kelsey Nicole , Myers Jennifer Rae , Madero Erica N. , Campitelli Anthony , Gills Joshua L. , Jones Megan , Paulson Sally , Gray Michelle , Glenn Jordan M.
Published: December 2022

Background

Sex differences in cognition have been well‐established among both healthy individuals and various clinical populations, including patients diagnosed with Alzheimer’s disease (AD). Specifically, females with AD experience greater cognitive impairment than men. However, cognitive sex differences among a population at‐risk for AD have not been elucidated. Therefore, the purpose of this study was to examine sex differences among at‐risk individuals using a digital cognitive assessment battery.

Method

Data collected are part of the ongoing Digital Cognitive Multi‐domain Alzheimer’s Risk Velocity Study investigating the effects of a 2‐year digital lifestyle intervention on individuals at‐risk for developing AD. Risk factors were determined via the Australian National University‐Alzheimer’s Disease Risk Index (ANU‐ADRI); two positive risk factors for AD (e.g.: history of diabetes, smoking, and/or traumatic brain injury) and no more than one protective factor (e.g.: high level of physical activity) were required for participation. Participants (age 45–75) completed six digital assessments measuring executive function, inhibition, processing speed, attention, associative learning, and associative memory. Independent sample t‐tests were used to analyze group differences (female vs male) in cognitive performance.

Result

A significant difference between sexes exists for associative memory. Specifically, females had greater accuracy in recognizing previously presented images as compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). While males and females did not differ in their time spent gazing at the novel image, females demonstrated a significantly better accuracy at identifying which image pairs they had seen previously compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). No other differences in cognitive performance were observed.

Conclusion

This study demonstrates that at‐risk women demonstrate a more accurate behavioral response during an associative memory task than their male counterparts. These results are counter to evidence suggesting females with AD experience greater cognitive impairment, indicating that other factors should be considered to understand the process of dementia‐related cognitive decline and cognitive impairment differences between sexes among patients with AD.
Cerebral perfusion and glucose metabolism profiling reveal special phenotypes in the hAPOE3, hAPOE4, Trem2 risk, and doubled risks mice
Authors: Lin Peter Bor‐Chian , Persohn Scott C , Bedwell Amanda A , Jiang Lei , Eldridge Kierra , Speedy Rachael , Kotredes Kevin P , Pandey Ravi S , Williams Harriet M , Oblak Adrian L , Sasner Michael , Howell Gareth R , Carter Gregory W , Lamb Bruce T , Territo Paul R
Published: December 2022

Background

Alzheimer’s disease (AD) is the most common cause of dementia in the United States. Approximately 95% of patients have sporadic Late‐Onset AD (LOAD) which lacks an inheritance pattern. Therefore, identifying phenotypic patterns is critical for understanding disease progression.

Among all the genetic markers which being identified as AD risks, and APOE4 confers the strongest one. The GWAS analysis also revealed a LOAD‐associated locus on the gene of TREM2. As the microglial receptor of APOE, the R47H variant on TREM2 increases the AD risk. In this study, how these risk alleles affect the brain phenotypes were assessed by MODEL‐AD.

Method

We established an analytical scheme which elucidates the cerebral perfusion and metabolism profiles across 27 brain regions by using 64Cu‐PTSM and 18F‐FDG PET imaging platform in the mice with wild‐type, humanized APOE3 (hAPOε3/ ε3), humanized APOE4 (hAPOε4/ ε4), TREM2 risk (Trem2R47H/R47H), and doubled risks (hAPOε4/ ε4:Trem2R47H/R47H) alleles.

Also, RNA‐seq results from the hemisphere samples were used to conduct the correlation between PET measurements and the gene expression changes from each animal cohort.

Result

Longitudinal analysis (4mo animals as reference) revealed aging effects in each cohort. The male hAPOE4 mice and both sexes of Trem2 risk animals had hypo‐perfusion and metabolism, while female hAPOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype. In the doubled risks mice, perfusion and metabolism showed a mixed regional‐dependent phenotype.

Cross‐sectional analysis (wildtype mice as reference) showed the effects of humanized genes. A reduction in glucose metabolism was discovered. Intriguingly, male risks mice also showed reduced in perfusion, while the female mice showed a metabolic uncoupling profile.

Cross‐sectional analysis (hAPOE3 mice as reference) showed the effects of risk alleles. An overall reduction in both perfusion and metabolism was discovered in all animal cohorts.

To confirm these findings, RNAseq showed the genes involved in cerebral perfusion, glucose transportation, and metabolism regulation were altered, which are consistent with the findings.

Conclusion

These data suggest that the new perfusion‐metabolism strategy may help to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants. Finally, additional studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.
Tau heterogeneity in Aβ positive patients
Authors: Landau Susan M. , Lee Jia Qie , Murphy Alice , Ward Tyler J. , Harrison Theresa M. , Baker Suzanne L. , Jagust William J.
Published: December 2022

Background

A substantial proportion of individuals on the AD continuum have tau PET burden that is not elevated, suggesting that they may be in an earlier stage on the AD continuum and/or have other copathologies that account for their impairment. To examine these possibilities, we compared Aβ+, cognitively impaired individuals with lower tau burden to theirAβ+ high tau counterparts across a variety of biomarker and clinical measurements.

Method

We identified Aβ+, impaired (MCI or AD) patients from ADNI with high and low tau burden using contemporaneous amyloid PET (florbetapir or florbetaben) and tau PET (flortaucipir) scans. The high/low tau threshold was the 90th percentile SUVr of Aβ‐ cognitively normal individuals for a composite flortaucipir region of interest spanning most of the medial/lateral temporal lobes and extratemporal neocortex relative to inferior cerebellar grey matter (Figure 1). We compared Aβ+ high vs low tau groups on AD/cerebrovascular biomarkers, and demographic, cognitive, risk factor, and clinical measurements.

Result

Of 218 Aβ+ impaired ADNI patients, 91 (42%) had cortical tau in the normal range. Compared to their high tau counterparts, low tau individuals were more likely to be male, older, have more years of education, and lower Aβ (within the elevated/abnormal range), but did not differ on proportion of ApoE4 carriers. Low tau individuals were also more likely to have cardiovascular risk factors and cerebrovascular pathology, but had less severe hippocampal atrophy and temporoparietal hypometabolism and better cognitive performance than high tau individuals. Examination of baseline tau (Figure 2A) and longitudinal tau (Figure 2B) rankings across 70 FreeSurfer‐defined regions revealed a highly overlapping set of medial/lateral temporal regions common to both high/low groups.

Conclusion

For impaired individuals on the AD pathway, low tau PET burden is associated with heterogeneous group characteristics that support a role for copathologies in accounting for cognitive symptoms, but also point to the less advanced stage of cognitive and biomarker progression in this group. Despite these striking group differences, the set of regions in which tau was highest in the brain was strikingly consistent between groups, suggesting a common spatial accumulation pattern regardless of the degree of tau burden.
The contribution of hyperhomocysteinemia and hypoperfusion to amyloid‐beta induced cerebral endothelial cell dysfunction
Authors: Carey Ashley M , Parodi‐Rullan Rebecca M , Fossati Silvia
Published: December 2022

Background

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer’s Disease (AD) pathology, with particularly endothelial cell (EC) stress promoting the focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Recent evidence has emerged suggesting a link between cardiovascular (CV) diseases and AD pathology, particularly showing that CV/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy) and hypoperfusion (oxygen and glucose deprivation (OGD)), contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for this interaction remain unclear. Previously our lab has demonstrated that amyloid beta (Aβ), particularly Aβ40‐Q22 (the vasculotropic Dutch mutant), promotes TRAIL death receptor (DR)‐mediated apoptosis, barrier permeability, and angiogenic impairment within human cerebral ECs. We tested the hypothesis that Hhcy and hypoperfusion exacerbate Aβ‐induced cerebral EC TRAIL DR‐mediated apoptosis, barrier dysfunction, and angiogenesis defects.

Method

Human cerebral microvascular ECs were challenged with AβQ22 and/or homocysteine (Hcy) in the presence/absence of hypoperfusion. Apoptotic mediator expression, caspase activation, and DNA fragmentation were measured to assess apoptosis. BBB protein expression and trans‐endothelial‐electrical‐resistance (TEER) were measured to assess EC barrier integrity. Angiogenesis inhibition and activation assays were utilized to measure EC angiogenic capability.

Result

AβQ22 and Hcy challenge independently upregulated EC expression of TRAIL DR‐related apoptotic mediators and caspase activity, and, at certain time‐points, resulted in an additive upregulation of apoptotic mediators and caspase activity. AβQ22, Hcy, and hypoperfusion individually increased DNA fragmentation within cerebral ECs. Combination treatments of AβQ22 and Hcy created an additive effect on DNA fragmentation. Hypoperfusion and AβQ22 independently decreased BBB protein expression and TEER, while an additive decrease was observed with the combined challenges. AβQ22 and Hcy independently decreased angiogenesis progression, with some timepoints revealing an additive decrease with the combination treatment.

Conclusion

The presence of CV risk factors seems to exacerbate Aβ induced‐EC apoptosis, barrier dysfunction, and angiogenic impairment, revealing several of the specific molecular mechanism through which amyloidosis and CV risk factors may additively act to produce EC dysfunction and death in AD pathology.
MR spectroscopic neurometabolite profile in aged rodents: a study in Sprague‐Dawley and Wistar rats, and C57bl/6J mice
Authors: Lehtimäki Kimmo , Dudek Mateusz , Oksman Juho , Puoliväli Jukka , Thompson Paul , Pearce Andy , Almond Sarah , Miszczuk Diana
Published: December 2022

Background

Cognitive decline and Alzheimer’s disease (AD) are closely related to aging in human population and the need for translational biomarkers is of crucial importance. Several approaches have been proposed to study Alzheimer’s disease in rodent models, including transgenic mice and rats to model either amyloid‐ or tau‐pathologies. We have shown age‐related 1H‐MRS phenotype in female Fisher rats (22‐24 months, Bolognin et al. 2014 Neurobiol Aging:2134‐46) with reduced N‐acetyl aspartate (NAA), GABA and glutamate, and increased myo‐inositol together with other AD‐like biomarkers (increased CSF levels of AbPP and Tau, defect in Morris Water Maze, Khatoon et al 2015 J Alzheimer’s Disease: 557‐564). The aim of this study was to explore if similar 1H‐MRS phenotype is present in other strains of aged rats and mice to allow easier access to cohorts of aged rodents and enable utilization of different strains to model pathology.

Method

Eighteen male Sprague‐Dawley rats (n=10/8, 4/24 months), 24 male Wistar rats (n=12/12, 3.25 /21.75 months) and 23 male C57Bl/6J mice (n=12/11, 4.75/23 months) were used. Hippocampal MRS was performed at 11.7T magnet using PRESS sequence and metabolites analyzed using LCModel.

Result

Although the evaluation was done at slightly different ages, all three models shared a similar phenotype in hippocampal metabolites, i.e. decreased GABA and glutamate, and increased glutamine and myo‐inositol. NAA was significantly reduced in aged Wistar rats and C57Bl/6J mice whereas the SD rats showed only non‐significant trend of decrease.

Conclusion

Based on the current data, the MRS phenotype is remarkably repeatable in aged rats (SD, Wistar) and in aged C57Bl/6J mice. Furthermore, the pattern of increased myo‐inositol with decreased levels of glutamate and NAA is descriptive of human AD. Aged rodents can therefore model biochemical changes potentially related to natural aging/AD.
Cross‐country Effects of the Tailored Activity Program to Reduce Neuropsychiatric Symptoms and Other Dementia‐related Symptoms: Results from Randomized Trials
Authors: Gitlin Laura N. , Aravena Jose , Koeuth Sokha , Gajardo Jean
Published: December 2022

Background

The Tailored Activity Program (TAP) is a nonpharmacological approach shown to reduce neuropsychiatric symptoms and other dementia‐related clinical symptoms in people living with dementia and family caregivers.

Method

TAP has been tested in 8 different randomized trials (stage 3 efficacy) in four different countries and is currently used in over 9 countries with varying results.

Result

Across 8 trials, TAP was found to have a wide range of benefits including reducing functional dependence and neuropsychiatric symptoms, improving quality of life of both people living with dementia and their caregivers, and enhancing caregiver well‐being. Findings from trials also demonstrate differences in outcomes among samples. For example in a USA trial involving 250 families, TAP compared to attention control resulted in differential effects for Black and White families. Statistically and clinically significant reductions in agitation and aggression (frequency and severity scores) were found for Black families in TAP compared to White families in TAP and those in the control group. In contrast, White caregivers receiving TAP reported less depressive symptoms than other groups.

Conclusion

Comparing outcomes across trials highlights the role of contextual factors and how country specific needs for dementia care may impact outcomes from nonpharmacological interventions. The comparison also reveals multiple challenges concerning dissemination and implementation of TAP (stage 4 and 5) such as lack of workforce preparation, payment mechanisms, and knowledge and acceptability of nonpharmacological approaches.
Integrated [Primary +] Memory Care Clinic
Authors: Clevenger Carolyn K
Published: December 2022

Background

The Integrated Memory Care Clinic (IMCC) is a model of care for people living with dementia directed by advanced practice registered nurses. The post‐diagnosis model incorporates the expertise of nursing, social work and nurse practitioners certified in gerontology, palliative care and/or geriatric psychiatry.

Method

The Clinic nurse practitioners provide comprehensive and coordinated primary care for dementia and other stable chronic conditions and episodic care for minor acute illnesses. Care delivery is structured to maximize ongoing dialogue with patients and their caregivers during office visits and by phone and patient portal access. The Clinic provides a number of services to care partners, including an after‐hours line, stage‐based educational groups, and a monthly support group. The IMCC aims to reduce the overall burden of dementia by partnering with affected individuals and their caregivers in the co‐production of care.

Result

Now at full capacity, the IMCC serves 525 active patients and their care partners with 1.3 FTE primary care nurse practitioners. The mean age is 78.6 years; most are female (63%); and 42% identify as a racial minority. The majority of patients are moderate (27% early‐moderate; 36% late‐moderate) stage of dementia clinical syndrome. The mean monthly rate of hospital admissions for ambulatory care sensitive conditions in 2022 is 1.42%. The published rate for this population is 13‐15%. Finally, the model is financially neutral in a fee‐for‐service environment.

Conclusion

Open in 2015, the IMCC has combined primary care and dementia care in one clinical practice. The IMCC developed strong rapport and trust with patients and families to achieve outstanding health outcomes. The model is an American Academy of Nursing Emerging Edge Runner, recognized by NCQA as a Patient Centered Medical Home, recognized as a Level 2 Age‐Friendly Health System participant, and a Best Practice Exemplar by the Institute for Patient‐ and Family‐Centered Care.
Blood‐brain barrier permeability is increased in early Alzheimer’s disease and correlates with brain microstructure
Authors: Reas Emilie T. , Tsiknia Amaryllis A. , Banks Sarah J. , Rostowsky Kenneth A , Andrews Murray , Brewer James B. , Bolar Divya S
Published: December 2022

Background

Vascular dysfunction frequently accompanies Alzheimer’s disease (AD), and its suspected contributions to AD pathogenesis may be partly mediated by disrupted blood‐brain barrier (BBB) function. Despite consistent evidence for increased BBB permeability in AD, it remains unclear whether BBB damage occurs in preclinical stages, when therapeutic interventions may be most effective. Furthermore, the relationship between BBB breakdown and microstructural neurodegenerative changes have not been well characterized.

Method

Dynamic contrast‐enhanced MRI and restriction spectrum imaging (RSI) were conducted to measure BBB permeability and brain microstructure, respectively, among 24 cognitively normal controls and eight individuals with mild cognitive impairment or mild AD (aged 77±5 years, 41% women). Participants were enriched for AD risk, with 72% amyloid‐positive as determined by cerebrospinal fluid amyloid‐B42/40 and 50% APOE4 carriers. The volume transfer coefficient Ktrans, an estimate of vascular permeability, and RSI measures of restricted, hindered, and free water diffusion, were computed in the hippocampus, entorhinal cortex, and across all white matter. Differences in Ktrans were examined between impaired and control subjects, and between APOE4 carriers and non‐carriers. Correlations between Ktrans and brain microstructure were computed to examine associations between BBB permeability and microstructure. Analyses adjusted for age, sex, and education. Subgroup analyses were conducted within cognitively normal controls.

Result

Entorhinal cortex Ktrans was higher for cognitively impaired subjects than controls. Higher Ktrans correlated with lower education, but was not associated with age, sex, amyloid‐B42/40, hypertension, or APOE genotype. Among controls, white matter Ktrans was higher for APOE4 carriers versus non‐carriers. Ktrans correlated with restricted, hindered, and free water diffusion in the hippocampus, entorhinal cortex, and white matter within controls in an APOE‐dependent manner. Results were essentially unchanged by adjustment for amyloid‐B42/40 or hypertension.

Conclusion

BBB permeability increases in individuals with mild cognitive impairment and in cognitively normal individuals at elevated genetic risk for AD, independent of amyloid pathology. BBB breakdown is associated with microstructural abnormalities that may reflect cell loss or dystrophy, or neuroinflammation, in an APOE‐dependent manner. Our findings suggest that BBB breakdown may occur in early AD and promote neurodegeneration via APOE‐dependent avenues, warranting further examination of the mechanisms underlying AD‐related BBB compromise.
Subcortical brain structure and APOE genotype: An analysis of 43,000 participants from the UK Biobank
Authors: Ching Christopher RK , Thomopoulos Sophia I , Santhalingam Vigneshwaran , Gleave Emma J , Zhu Alyssa H , Islam Tasfiya , Abaryan Zvart , Jahanshad Neda , Thompson Paul M
Published: December 2022

Background

Carriers of the ε4 allele of the apolipoprotein (APOE) gene are at higher risk for developing Alzheimer’s disease (AD). In individuals with mild cognitive impairment or AD, the ε4 allele is associated with lower hippocampal and amygdala volumes. How ε4 affects brain structure in healthy individuals before AD symptom onset is less clear. APOE ε2 allele carriers may show slower rates of hippocampal volume loss, suggesting protection against AD. In this large‐scale analysis, we plot normative regional brain volume trajectories in adults (45‐82 years) and map regional subcortical volume differences between APOE genotypes.

Method

We used FreeSurfer 7.1 to segment average left and right accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus and lateral ventricle volumes from T1‐weighted brain MRI (N=43,000). Comparisons between APOE genotypes (ε2ε2, n=257; ε2ε3, n=5,479; ε3ε3, n=26,016; ε3ε4, n=10,263; ε4ε4, n=985) were made using linear mixed effect models, correcting for population structure, age, sex, and intracranial volume (ICV) as fixed effects, and site as a random effect. Results were adjusted for multiple comparisons (FDR q<0.05). Nomograms were derived by adjusting subcortical volumes for population structure, ICV, and site then fitting normative quantile regression models based on the standardized residuals for each region stratified by genotype.

Result

Nomograms showed similar age‐related trajectories for all APOE genotypes, with smaller gray matter volume and larger ventricle volumes with increasing age. Significantly smaller amygdala and hippocampal volumes were found in ε4ε4 compared to ε3ε4, ε3ε3, and ε2ε3 carriers, and smaller amygdala volumes in ε2ε2 versus ε3ε3 carriers. Smaller accumbens volumes were found in ε4ε4 carriers versus ε2ε3 and ε3ε3, and in ε3ε4 versus ε3ε3 and ε2ε3. Smaller thalamus volumes were found in ε3ε4 versus ε2ε3 and ε3ε3, ε4ε4 carriers had smaller volumes versus ε2ε3 and ε3ε3, and ε2ε2 carriers had smaller volumes versus ε2ε3 and ε3ε3.

Conclusion

In this large sample of generally healthy individuals, APOE ε4 allele carriers exhibited lower subcortical volumes compared to those with more neutral AD genetic risk background (ε3ε3). Carriers of ε2ε2 had smaller thalamus and amygdala volumes compared to ε3ε3, suggesting differential effects of AD genetic risk across brain structures known to play a role in AD pathophysiology.
Analytical performance overview of the Lumipulse G pTau 181 Plasma RUO
Authors: Vandijck Manu , D'hont Jelle , Dekeyser Filip , Bastard Nathalie Le , Vandenbroucke Ina
Published: December 2022

Background

Studies have shown that changes in Alzheimer’s disease (AD) biomarker levels occur in blood at approximately the same time as in cerebrospinal fluid (CSF). Therefore, plasma‐based testing could be used as a simple, accessible, and scalable approach to help support the diagnosis of AD, avoiding the complexity of CSF sampling, and the high costs and limited availability of PET imaging. It was demonstrated that plasma pTau181 has the potential to be a good predictor of amyloid PET positivity, has proven to differentiate between AD and non‐AD neurodegenerative diseases, and is able to predict progression to AD. The aim of this study was to determine the preliminary analytical performance of the newly developed Lumipulse G pTau 181 Plasma RUO assay.

Method

The LUMIPULSE G System is a chemiluminescent enzyme immunoassay platform that allows fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The assay uses AT270 for capturing and HT7/BT2‐conjugate for detection in a 2‐step set‐up. Parameters analysed were precision, sensitivity, linearity, and potential impact of interfering substances. The studies included a series of buffer– and K2EDTA plasma samples at different concentration levels, each tested in several replicates sized to the different parameters tested.

Result

The total within‐lab variability of the assay was found to be <5% CV for each of the samples tested, confirming the high precision of the LUMIPULSE G platform. Using low pTau181 concentrated plasma samples, the LoD was found to be <0.20 pg/mL, and the LoQ <0.50 pg/mL. The high sensitivity was confirmed by a formal concentration assignment to each tested samples of a cohort of healthy elderly subjects. Linearity was shown across the measurement range of the assay (0 – 60 pg/mL), and no significant impact of rheumatoid factor and human anti‐mouse antibodies was observed.

Conclusion

This preliminary verification of the analytical performance of the Lumipulse G pTau 181 Plasma RUO indicated promising results in terms of low variability, good dilutional linearity, and high sensitivity. The assay is now ready for full analytical verification and clinical validation towards the identified contexts of use.
White Matter Disease is Associated with Widespread Grey Matter Atrophy in APOE4 non‐carriers with Early‐Stage Dementia
Authors: Vipin Ashwati , Kumar Dilip , Soo See Ann , Zailan Fatin Zahra , Leow Yi Jin , Koh Chen Ling , Ng Adeline Su Lyn , Ng Kok Pin , Kandiah Nagaendran
Published: December 2022

Background

The APOE‐ε4 (APOE4) allele and cerebrovascular disease (CVD), represented by surrogate MRI measures involving white matter hyperintensities (WMH) are key dementia risk factors [Tosto et al.,2015; Mahley et al.,2006]. They relate to grey matter volume (GMV) and cognitive decline, and demonstrate increased occurrence with lowered age of dementia onset [Boyle et al.,2016; Brickman et al.,2014]. Whether APOE4 is a key effect modifier in the relationship between WMH and GMV needs further exploration. Therefore, we examined independent and interactive effects of WMH and APOE4 on GMV and cognition in cognitively unimpaired (CU) and early‐stage dementia (ESD) participants. We hypothesized that participants with higher WMH load would demonstrate worse GMV atrophy and greater cognitive impairment, especially among APOE4 carriers.

Method

We studied 259 CU and 192 ESD (mild cognitive impairment, mild dementia) from a Singapore research cohort with neuroimaging, APOE genotyping and neuropsychological assessment data (Table 1). We investigated independent and interactive effects of WMH and APOE4 on whole‐brain voxel‐wise GMV using voxel‐based morphometry (uncorrected p<0.001; minimum cluster size=100 voxels). Multiple linear regression models assessed APOE4 and WMH interactive effects on global cognition (mini‐mental state examination–MMSE), memory (Alzheimer’s disease assessment scale‐delayed word recall) and executive function (Color Trails 2) in ESD.

Result

Higher WMH load associated with widespread voxel‐wise grey matter atrophy across frontal, parietal, temporal and occipital lobes in CU and ESD (Fig.1). When stratified by APOE4 status, APOE4 carriers showed regions of GM atrophy in frontal, temporal and parietal regions. When examining the interaction between WMH and APOE4 on GMV, contrary to our hypothesis, APOE4 non‐carriers showed more extensive derogatory effects of WMH on GMV than APOE4 carriers (Fig.2). These effects extended into ESD cognitive performance with APOE4 non‐carriers displaying deteriorating global and executive function with increasing WMH load than APOE4 carriers (Fig.3).

Conclusion

We illustrate APOE4 status as likely a key moderator in the relationship between WMH and GMV in both preclinical CU and ESD stages. With differential effects of WMH on GMV and cognition between APOE4 carriers and non‐carriers, interventions targeting WMH may need a differential approach depending on the APOE4 status.
Impact of CSF pTau/Aβ42 ratio on brain structure and metabolism in middle‐aged cognitively unimpaired individuals
Authors: Cacciaglia Raffaele , Milà‐Alomà Marta , Shekari Mahnaz , Operto Grégory , Falcon Carles , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Quevenco Frances‐Catherine , Gispert Juan Domingo
Published: December 2022

Background

The cerebrospinal fluid (CSF) pTau/Aβ42 ratio has emerged as a promising biomarker to monitor the pathological progression of Alzheimer’s disease (AD), even at preclinical stages. To date, no studies have assessed the impact of this continuous biomarker on the brain structure and metabolism in cognitively unimpaired (CU) individuals.

Method

We included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI) and 18F‐Fluorodeoxyglucose (FDG) positron emission tomography (PET). CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). After image preprocessing, we applied a voxel‐wise linear regression to test the impact of CSF pTau/Aβ42 ratio, as well as its interaction with age, sex and APOE‐ε4, on both gray matter volume (GMv) and brain metabolism. The statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels.

Result

There were no main effects of pTau/Aβ42 on either GMv or brain metabolism. However, a significant interaction with age indicated that for older individuals, a higher pTau/Aβ42 was associated with reduced GMv in the middle cingulum, the middle and superior frontal gyrus, and the angular gyrus (Fig. 1a). An interaction with sex indicated that for females, a higher pTau/Aβ42 was associated with reduced GMv in the precuneus, superior frontal and fusiform gyrus (Fig. 1b). For FDG, we found a significant interaction with sex indicating that females exhibited a metabolism reduction with increasing levels of pTau/Aβ42, in the hippocampus and anterior cingulum (Fig. 1c). Finally, an interaction with APOE‐ε4 indicated that ε4‐carriers showed lower metabolism in the bilateral striatum, as a function of increasing pTau/Aβ42 ratio (Fig.1 d).

Conclusion

In CU individuals, the impact of the progression of AD pathophysiology as indicated by a higher CSF pTau/Aβ42 ratio, on both brain structure and metabolism is modulated by AD risk factors. These data suggest that each of these risk factors confers a higher vulnerability to the progression of AD pathology in asymptomatic individuals, as manifested by an early impact on brain structure and metabolism in brain areas which are known to be affected in clinical AD stages.
Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation targeted to hippocampus in 3xTg‐AD/PVcre mice
Authors: Benthem Sarah Danielle , Moseley Shawn C , Dixon Jessica R , Silk Ashley L , Stimmell Alina C , Wilber Aaron A
Published: December 2022

Background

In preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired. We previously reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial reorientation task that requires learning to use landmarks for spatial orientation. Memory replay during sleep is critical for learning related plasticity, and hippocampal‐cortical dysfunction during sleep is a potential mechanism for memory impairments in AD. Consistent with this, we previously found that prior to emergence of significant pathology there were deficits in hippocampal‐parietal cortex (PC) coordination during sleep which predicted performance on the virtual spatial reorientation task. Gamma‐stimulation (40Hz) has been shown to clear AD pathology in mice, and improve functional connectivity in preclinical AD patients. Thus, we assessed hippocampal‐PC coordination in 6‐month female 3xTg‐AD/PVcre (4xTg) mice that were learning the same spatial reorientation task.

Method

We implanted a 16‐tetrode recording array targeting PC and hippocampus and an optical fiber aimed at hippocampus. Daily recording sessions of rest‐task‐rest commenced as mice learned to locate the unmarked reward zone. During the same surgery, cre‐dependent AAV was used to express channel rhodopsin 2 in hippocampal interneurons. This allowed for daily stimulation sessions after recording sessions, with either 40Hz or SHAM hippocampal stimulation. We assessed sleep quality metrics, and cortical spindles, and delta waves (DW) in PC during slow wave sleep. In hippocampus we assessed markers of memory replay (SWRs) during SWS.

Result

Animals with 40Hz entrainment showed increased REM sleep compared to SHAM animals. There was also a significant increase in SWR rate from pre‐ to post‐sleep, opposite a decrease in post‐sleep in SHAM mice; however, there was no difference in the absolute number or rate of DW or . Finally, in SHAM stimulated mice SWR‐DW temporal‐correlations were significantly reduced, similar to our previous findings in 3xTg‐AD mice; while in the 40Hz mice, this phase locking was rescued. .

Conclusion

Thus, 40Hz stimulation of hippocampus may rescue learning and memory related functional interactions in the hippocampal‐PC network during sleep and as a consequence at least partially rescue impairments in spatial navigation.
What is the practical utility of the MyCognitionPRO platform for monitoring and preventing cognitive decline in a real‐world context of people over 50years‐old experiencing cognitive ageing?
Authors: Sandford‐james Anna , Parkes Jacqueline , Campbell Jackie
Published: December 2022

Background

MyCognitionPRO is a CE‐marked digital health platform, offered as a subscription product by Beingwell Ltd; designed to help users self‐manage their cognitive health by combining cognitive assessment with personalised gamified training games. Reviews have highlighted computerised cognitive training as an effective non‐pharmacological intervention for enhancing cognitive functioning and quality of life of people with MCI or mild‐dementia (Hill et al., 2017; Bahar‐Fuchs et al., 2019). In a recent RCT, a now obsolete desktop version of MyCognitionPRO was used effectively by 21 Parkinson’s‐MCI patients (aged 40‐70 years) and caused a reversal in cognitive decline as compared to matched controls (van de Weijer et al., 2020). However, several real‐world trials investigating the effectiveness of the app‐based platform for people experiencing cognitive decline outside laboratory conditions indicate high rates of non‐adoption and non‐adherence in target users. The value of a digital health intervention is multi‐dimensional, relying on the willingness of end‐users, the capacity of features as well as its successful implementation in wider healthcare pathways (Kolasa & Kozinski, 2020).

Method

This mixed‐methods feasibility study explores the differing needs, opinions and variability of core stakeholders, representing multiple perspectives (people over 50 years‐old with early‐stage cognitive decline and their carers). Guided by digital‐health evaluation frameworks, quantitative data (app engagement and performance data) and qualitative data (e.g. observation of user‐experience and interviews) are analysed to assess feasibility.

Result

Analysis indicates key issues with acceptability, usability and accessibility of the MyCognition apps in this context, modelling factors that predict poor engagement as well as reporting the characteristics of subpopulations for which the MyCognitionPRO platform works best. Results are synthesised into a user‐centred product roadmap, providing recommendations for app developments, further user trials, coproduction and efficacy research.

Conclusion

A staged evidence‐generation strategy is necessary to ensure the effective launch of a usable, evidence‐based version of the platform that is tailored to user‐needs and implementation into relevant markets for the purpose of monitoring and preventing cognitive decline in people over 50years‐old.