bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid induced neuronal hyperexcitability triggers progressive epilepsy
Authors: Tanila Heikki
Published: December 2022

Background

Unprovoked seizures are more common in Alzheimer (AD) patients than in general population and subclinical epileptiform activity has been reported in 20‐40% of early‐stage AD patients. Similarly, spontaneous seizures and epileptiform spiking have been reported in all commonly used amyloid plaque producing APP transgenic mouse lines. Furthermore, epileptiform spiking in both AD patients and APP transgenic mice occurs almost exclusive during sleep. These observations speak for common underlying mechanism across species.

Method

With the help of in vivo multichannel and multi‐site local field potential recordings and post‐mortem immunohistochemistry in APP/PS1 mice we have aimed to find answers to three keys questions about AD‐related epilepsy. (1) Is there a focal onset of epileptiform activity in the brain? (2) How does the hyperexcitability relate to amyloid plaque formation? (3) Is the problem primarily of enhanced excitation or attenuate inhibition?

Result

In most cases we have identified hippocampus (both CA1 and dentate gyrus) as the focus for epileptiform activity, although some spikes have cortical origin. Neuronal hyperactivity and epilepsy related sudden deaths tend to peak around the time when first amyloid plaques are formed. On the other hand, intracellular accumulation of full‐length APP or its C‐terminal fragment does not seem to correlate with increased excitability. In line with reported increased glutamate release in the hippocampus of APP/PS1 mice, we found increased vGlut immunopositive terminal around amyloid plaques. Studies on paralbumin‐positive interneurons are ongoing.

Conclusion

Amyloid plaque formation in the hippocampus is at least one of the triggers for AD‐related epileptiform activity.
Sensory stimulation improves daily functions in Alzheimer’s disease
Authors: Cimenser Aylin , Hempel Evan , Konisky Alexandra , Vaughan Brent , Megerian Jonathan Thomas , Malchano Zach , Hajos Mihaly
Published: December 2022

Background

Abnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to the pathogenesis of the disease has been recently proposed. It has been demonstrated that induction of synchronized gamma oscillation of neuronal networks by sensory stimulation reverses AD‐related pathological markers in transgenic mice carrying AD‐related human pathological genes. The current study evaluated whether non‐invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for patients in AD spectrum.

Method

The data studied here is from Overture clinical trial (NCT03556280). The study included a treatment group, where participants received daily, 1‐hour, 40Hz gamma visual and auditory stimulation for 6‐months at home, and a placebo group. To assess the treatment efficacy on daily functional abilities, the Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale was used. Assessments were made at baseline and every four weeks throughout the study. ADCS‐ADL consists of 23‐items where each item aims to assess different functional abilities. The change in ADCS‐ADL as well as change in each individual item’s score between the treatment group (n = 33) and the placebo group (n‐ = 19) were compared using a mixed model for repeated measures (MMRM).

Result

We observed that treatment group participants were able to maintain their functional abilities while placebo group participants showed a decline as assessed by ADCS‐ADL, p<0.001. Within the instrumental ADCS‐ADL individual items, the most significant differences between the two groups, all favoring treatment group, were observed in: (1) Attentive participation in conversations, p<0.001, and (2) Finding personal belongings, p<0.043.

Conclusion

Our results suggest that daily, 1‐hour 40Hz gamma sensory stimulation may help prevent functional decline in patients with AD spectrum disorder. Preventing functional loss would help both patients and caregivers. Furthermore, it may reduce the need for institutionalization and reduce healthcare costs. Larger studies are planned to confirm these initial findings on the benefits of gamma sensory stimulation on function.
Digital Pathology Investigation of SERPINA5‐Tau Protein Interaction in Alzheimer’s Disease and Primary Tauopathies
Authors: Sirmans Tiffany N. Hicks , Kouri Naomi , Tamvaka Nicole , Labuzan Sydney A , Matchett Billie J , Lincoln Sarah J. , Hinkle Kelly M , Moloney Christina M. , Peng Zhongwei , Carter Rickey E , Ross Owen A. , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Murray Melissa E.
Published: December 2022

Background

We recently discovered a novel tau binding partner, SERPINA5, to be upregulated in Alzheimer’s disease (AD) and co‐localize with corticolimbic tau distribution. As tau pathology is also observed in primary tauopathies, we hypothesized that SERPINA5 burden would mirror tau burden in these diseases. Thus, we sought to define the relationship between SERPINA5 and tau in primary tauopathies and compare this relationship to AD.

Method

Immunohistochemistry was performed on the hippocampus or cingulate in 4 groups (n=6 per disease group): 1) AD, 2) 3R+4R primary age‐related tauopathy, 3) 4R tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grains disease), and 4) 3R tauopathy (Pick’s disease). Burden analyses for SERPINA5 and a phospho‐tau marker (AT8) were performed on digitized whole slide images.

Result

Visual interpretation of SERPINA5 immunostaining identified both neuronal and glial inclusions that are commonly AT8‐positive in primary tauopathies. There were exceptions to this pattern such as SERPINA5‐positive Pick bodies being rarely observed. However, some pathologic structures, like ballooned neurons, were preferentially stained by SERPINA5. Quantitative analyses confirmed this observation with AT8 and SERPINA5 burden correlating in both the cingulate (R2=0.47, p<0.0001, Figure 1a) and hippocampus (R2=0.74, p<0.0001, Figure 1d). Nonparametric rank sum tests revealed majority of the primary tauopathies had less AT8 and SERPINA5 burden compared to AD in both the cingulate and hippocampus (Figure1b‐c, e‐f; Table 1).

Conclusion

SERPINA5 immunostaining patterns in primary tauopathies reflect tau immunostaining patterns. Our data suggests the SERPINA5‐tau interaction may not be specific for AD, which may implicate the role of SERPINA5 more broadly across tauopathies.
Anterior chamber enhancement – a window into the orbital glymphatic system and beyond?
Authors: Deike‐Hoffmann Katerina , von Lampe Paula , Eerikaeinen Maija , Ting Saskia , Schlüter Sabrina , Schlemmer Heinz‐Peter , Bechrakis Nikolaos , Forsting Michael , Radbruch Alexander
Published: December 2022

Background

Recently, an orbital glymphatic system (GS) was described, that serves retinal homeostasis and clearance. In accordance to the brain GS, the orbital GS is supposed to be altered in a variety of disease, first and foremost Alzheimer's Disease (AD). Disturbances of the orbtial GS where suggested to serve as early (imaging) biomarker. Therefore it is highly desirable to visualize orbital GS function in vivo. This study investigated intravenously injected Gadolinium‐based contrast agent (GBCA) to visualize the orbital GS. We used a retrospective patient cohort of children suffering from retinoblastoma (RB) who are supposed to show altered orbital GS function to test the validity of this method.

Method

This IRB approved retrospective single‐center study encompassed 539 orbital MRIs performed with an orbital coil and with the children in a state of general anesthesia.

Differences of signal intensity ratios of the AC to the lens (∆SIRs) were determined between native and GBCA‐enhanced T1‐weighted images. Subsequently, ∆SIRs were correlated with histopathologic tumor features such as infiltration of the ON, choroid, ciliary body, sclera and AC.

Result

∆SIR of the RB eye was an independent, significant predictor for ON infiltration in multivariate analysis with adjustment for tumor size (p < 0.05) and increased with infiltration level (compare fig. 1A+B). ∆SIR was not predictive for any other assessed histopathologic tumor feature.

Conclusion

GBCA enhancement of the AC predicts ON infiltration by RB. This might be caused by impairment of the orbital GS, which is supposed to clear toxic metabolites from the retina to the postlaminar ON (compare fig. 2). In RB with ON infiltration, this efflux path might be inhibited, which is supposed to result in disturbed retinal homeostasis, release of vascular endothelial growth factor and iris neovascularization with increased penetration of GBCA into the AC (compare fig. 3). We conclude, that GBCA‐enhanced MRI might enable visualization of (orbital) GS function in vivo and suggest assessment of this imaging approach in patients with neurodegenerative diseases.
Change in Plasma ATN Biomarkers Over a 12‐Week Physical Activity Intervention Among Older African Americans: Program for African American Cognition and Exercise (PAACE)
Authors: Carmichael Owen T. , Gwizdala Kathryn L. , Brouillette Robert , Beyl Robbie , Johnson William , Hebert Callie , Carter Leah , Harris Melissa , Newton Robert L
Published: December 2022

Background

Plasma markers of amyloid, tau, and neurodegeneration (ATN) are promising as correlates of AD biological and clinical features, but data from older African Americans, and data on change during non‐pharmacological interventions, is limited.

Method

The Program for African American Cognition and Exercise (PAACE) randomized older cognitively normal African American adults into a 12‐week successful aging group (SAG) to attend educational sessions or a 12‐week physical activity group (PAG) to complete supervised and in‐home physical activity. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and cardiometabolic risks were assessed pre‐ and post‐intervention. The Quanterix Simoa® Neuro 4‐Plex E and pTau‐181 Advantage Kits were used to measure plasma concentrations of amyloid beta (ABeta) 1‐40 and 1‐42, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau protein phosphorylated at threonine 181 (pTau‐181). Linear mixed effects regression models assessed modifiers of change in plasma and RBANS measures.

Result

A set of 54 PAACE completers aged 69.3 +/‐ 3.4 years (40 female, 14 male) provided non‐outlier measurements. ABeta 1‐40 decreased (p=.027), and RBANS global cognition, visuospatial, and delayed memory scores increased, over the intervention (maximum p value: .040). Plasma ATN biomarkers did not differ between SAG and PAG at baseline, but SAG did have greater declines in pTau‐181 than PAG did (p=.003, Figures 1‐2), and women had greater declines in pTau‐181 than men did (p= .045, Figure 3). Greater age was associated with greater ABeta 1‐40, ABeta 1‐42, GFAP, and NFL (maximum p= .008). Greater diastolic blood pressure was associated with lesser NFL (p= .021) and ABeta 1‐40 (p= .041). Greater GFAP, NfL, and pTau‐181, suggestive of greater burden of tau and neurodegeneration, were associated with lesser RBANS language score (maximum p= 0495). Greater pTau‐181 was associated with lesser RBANS immediate memory score (p= .035). Plasma ATN markers did not modify pre‐to‐post‐intervention change in any RBANS summary score (minimum p=.10).

Conclusion

Among cognitively normal older African Americans, change in plasma ATN biomarkers over the course of a nonpharmacological intervention differed by study group and gender. The markers differed by cardiometabolic risks and associated with cognitive function in an intuitive fashion.
Distinct signatures of white matter damage in cerebral small vessel disease and Alzheimer’s disease: a fixel‐based analysis study
Authors: Dewenter Anna , Gesierich Benno , Hager Paul , Biel Davina , Ewers Michael , Franzmeier Nicolai , Duering Marco
Published: December 2022

Background

Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) are the two main causes of age‐related cognitive decline and frequently co‐exist in memory clinic patients. White matter diffusion alterations have been described as key features of both diseases with different spatial patterns in AD and SVD. Biomarkers that capture and disentangle the effects of each disease on white matter integrity are of great need but are still lacking. Advanced diffusion MRI‐based techniques on the fixel level (fiber population within a voxel) yield promise, since one can derive measures of both fiber density and fiber bundle cross‐section (Dhollander et al., Neuroimage, 2021). In this multimodal imaging study, we assessed the ability of these fixel metrics to detect disease‐specific signatures of white matter fiber tract damage yielding the path towards personalized medicine.

Method

We included genetically defined SVD (n=73) and the full continuum of biomarker‐characterized AD from ADNI (n=34 Aβ–T–; n=19 Aβ+T–, n=18 Aβ+T+). Using multi‐shell diffusion MRI, we assessed the fiber density and fiber bundle cross‐section of six well‐established white matter fiber tracts previously shown to be damaged or related to cognitive decline in AD and SVD (see Figure 1). Using simple linear regression analyses and while controlling for intracranial volume, we determined associations between tract‐specific fixel metrics and imaging markers of SVD (white matter hyperintensity volume, lacune and microbleed count) and AD (global amyloid‐ and tau‐PET SUVR) as well as age and brain volume.

Result

Fiber density of all fiber tracts was strongly associated with white matter hyperintensity volume in SVD (e.g. inferior fronto‐occipital fasciculus, R2adj=73%). In contrast, fiber bundle cross‐section was highly associated with cerebral atrophy in the AD sample (e.g. corpus callosum, R2adj=36%). Of note, both fiber density and fiber bundle cross‐section were only weakly associated with amyloid‐ and tau‐PET (e.g. fiber density of uncinate fasciculus ∼ amyloid‐PET, R2adj=11%; fiber bundle cross‐section of inferior longitudinal fasciculus ∼ tau‐PET SUVR, R2adj =5%).

Conclusion

Fiber density captures the effects of SVD on white matter integrity whereas fiber bundle cross‐section indicates tract‐specific neurodegeneration in AD. Fixel‐based analysis allows to assess disease‐specific effects of SVD and AD on white matter fiber tracts.
Brain Derived Biologically Relevant Tau Oligomers
Authors: Kayed Rakez
Published: December 2022

Background

Neurodegenerative Tauopathies, including Alzheimer’s disease (AD), are characterized by the appearance of extracellular lesions composed of aggregated and post‐translationally modified tau proteins. The resulting tau pathology is an established marker for differential disease diagnosis and staging, a surrogate marker for neurodegeneration, a potential vector for disease propagation, and a source of toxicity in biological models. In comparison to the well‐established methods for isolation/preparation and biochemical and structural characterization of stable tau filaments from tauopathy brain, the characterization of smaller and much dynamic oligomeric tau aggregates has not been investigated to the same degree. As a result, tau oligomers that may associate most closely with disease propagation and toxicity as suggested by a large body of research, are not fully established.

Method

Herein, we leverage our well‐optimized brain‐derived tau oligomers (BDTOs) from well‐vetted human tauopathy cases of AD, progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB). In addition to our rigorous biochemical characterization of the BDTOs by immunological probing, and structural characterization by proteolysis and microscopic analyses, we have optimized Fluorescent Amyloid Multi Emission Spectra (FLAMES) microscopy for cataloging and comparing tau conformational variants across a wide range of samples, from brain tissue sections and BDTOs to in vitro aggregated tau assemblies. For selective immunodetection of the BDTOs, we have used our novel four fully sequenced and epitope mapped Tau Oligomer Monoclonal Antibodies (TOMAs), which recognize non‐continuous sequences on tau. Furthermore, the bioactivity of the BDTOs was assessed by evaluating their seeding propensity in biosensor cells and primary cortical neurons from tauopathy mice and their effects on synaptic function by electrophysiological studies.

Result

We observed that the BDTOs differed in their immunological properties, morphology, and sensibility/stability to proteolysis. The BDTOs were distinguished based on FLAMES spectral signature. Distinct seeding propensity and impairment of long‐term potentiation (LTP) indicated their differences in bioactivity as well.

Conclusion

Our thorough investigation/characterization of biologically active disease‐relevant tau oligomers will provide new opportunities to diagnose and evaluate therapeutics beyond the current capabilities for AD and related tauopathies by developing specific tau aggregation inhibitors and/or diagnostic probes for pathological tau protein.
The rationale behind the NIA‐AA research framework definition of Alzheimer's disease
Authors: Jack Clifford R.
Published: December 2022

Background

The NIA‐AA research framework group and the IWG both agree that abnormal AD biomarkers are necessary for the diagnosis of AD; however, the groups disagree on the appropriate definition of Alzheimer’s disease. The NIA‐AA framework argues that a CU A+T+ individual has AD pathology and therefore has the disease. The IWG argues that such an individual should be labeled “at risk for AD” because both abnormal biomarkers and clinically significant impairment are required for an AD diagnosis.

Method

The major IWG argument against a biological‐only definition of AD is that some CU A+T+ individuals will die of other causes without experiencing overt symptoms (MCI or dementia) in their lifetime. However, the same statement can be made about any other disease in medicine. The question therefore must be how often will CU A+T+ individuals die without experiencing dementia.

Result

Many studies have examined rates of cognitive decline in CU A+ relative to CU A‐ (fewer studies in CU A+T+ vs CU A‐T‐). Studies have examined the risk of incident MCI/dementia in CU A+ relative to CU A‐ (fewer in CU A+T+ vs CU A‐T‐). Relative risk indicates likelihood of an outcome in a particular risk group relative to a reference group; it does not indicate the likelihood in percentage terms that an individual will experience an outcome in their lifetime. It is lifetime risk (i.e., absolute risk) that is needed to address the current controversy and to our knowledge only 2 published studies have estimated lifetime risk associated with AD biomarkers. A recent Mayo Clinic Study of Aging analysis examined lifetime risk of dementia associated with varying levels of amyloid PET, APOE and sex. Among APOE ε4 carriers with high amyloid PET SUVR, remaining lifetime risk of dementia at age 75 years was 76% for women and 64% for men. Lifetime risk of CU A+T+ remains to be determined, however.

Conclusion

The major discordance between the NIA‐AA framework and the IWG (the definition of AD) points to the question, how risky is the CU A+T+ state? Accurate estimates of lifetime risk from population‐based studies are needed to address this question.
Guidance on the use of therapeutic lying among caregivers of people with dementia by Speech and Language Pathologists
Authors: Alves Emily Viega , Lopes Isabella Amaral , Beber Bárbara Costa
Published: December 2022

Background

Therapeutic lying (TL) is often used in people with dementia (PWD) who present challenging behaviors. In 2006, the creation of a guideline protocol about how to use TL, demonstrates that it requires trained professionals. Considering TL as a communication strategy, speech and language pathologists (SLPs) can play a fundamental role in guiding caregivers regarding its use. This study aims at verifying if SLPs guide caregivers of PWD to use TL to manage difficult situations and its association with their knowledge and training on the technique.

Method

Data collection took place through an online questionnaire that obtained sociodemographic information from Brazilian SLPs and asked them to answer the following questions: Have you ever heard about TL? Were you taught about TL in your academic education? Have you ever guided family members or caregivers of PWD to use TL? The results were presented descriptively and the association between the frequency with which the participants have guided caregivers to use TL and their knowledge about the subject was verified through Chi‐square Test with a significance level of 5%.

Result

The final sample consisted of 72 individuals. There was a predominance of female (100%), specialization (48.6%) as the highest educational level and the southern region of Brazil (45.8%). SLPs who claimed to have heard about TL comprised 23.6% of the sample, only 8.3% said they had been taught about TL during academic education and almost half of the professionals (48.6%) reported having already guided caregivers of PWD on the use of TL. There was no statistically significant association between the frequency with which the participants have guided caregivers to use TL and the fact they have already heard about the concept of TL (p = 0.07) or have already received training on it (p = 0.36).

Conclusion

The study showed that many professionals guide caregivers of PWD about the use of LT, however it happens without technical knowledge to do it properly. The work highlights the importance of including this subject in the academic education of these professionals.
Efficacy and safety of Kami‐guibi‐tang for mild cognitive impairment: a pilot, randomized, double‐blind, placebo‐controlled trial
Authors: Park Jung‐Mi , Shin Hee‐Yeon , Kim Ha‐Ri , Yim Tae‐Bin , Jeon Gyu‐Ri , Jahng Geon‐Ho , Cho Seung‐Yeon , Park Seong‐Uk , Ko Chang‐Nam
Published: December 2022

Background

Mild cognitive impairment (MCI) is considered an intermediate phase between normal aging and dementia. As the majority of cases of amnestic MCI (aMCI) progress to Alzheimer’s disease (AD), it is considered the prodromal stage of AD, and a treatment target for prevention of further cognitive decline. However, no medications have been shown to have symptomatic or preventive benefits in MCI. Kami‐guibi‐tang (KGT) is a traditional herbal formula used in Korean medicine to treat amnesia, which is reported to increase acetylcholine levels via activation of choline acetyltransferase. The objective of this study was to evaluate the efficacy and safety of KGT in patients with aMCI.

Method

This study was designed as a single‐center, randomized, double‐blind, placebo‐controlled pilot study. Participants diagnosed with aMCI were randomized to receive either KGT or placebo granules for 24 weeks. The efficacy measure was a change in the Seoul Neuropsychological Screening Battery (SNSB) score. The safety measures included the occurrence of adverse events and abnormalities in vital signs and blood chemistry, electrocardiogram (ECG), and brain magnetic resonance imaging (MRI) findings.

Result

A total of 16 patients in the KGT group and 14 patients in the placebo group were investigated in the study. The mean score of Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) significantly improved from 1.53 (0.64) points to 1.13 (0.62) points in the KGT group (p = 0.010), whereas it worsened from 1.61 (0.88) points to 1.75 (0.94) points in the placebo group. There was a significant difference in the CDR‐SB scores between the two groups after the intervention (p = 0.045). The total SNSB‐D scores and the scores in the memory domain after the treatment were significantly higher than the baseline values in the KGT group, but not in the placebo group. The frequency of adverse events was not significantly different between the two groups, and there were no abnormalities in vital signs or blood test, ECG, and brain MRI findings after the intervention.

Conclusion

KGT may provide a safe and effective treatment option for patients with aMCI. Further studies with a larger sample size are needed to validate the findings.
Modeling functional and structural brain‐predicted age in relation to Alzheimer disease and cognition
Authors: Millar Peter R , Luckett Patrick H , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Hassenstab Jason J. , Schindler Suzanne E. , Morris John C. , Ances Beau M
Published: December 2022

Background

Estimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior studies have typically modeled brain‐predicted age with volumetric magnetic resonance imaging (MRI), but other modalities, including resting‐state functional connectivity (FC) and multimodal MRI, have more recently been explored. In the present study, we tested the sensitivity of brain‐age predictions derived from volumetric, FC, and multimodal MRI to group differences in AD status and individual differences in cognition.

Method

We trained three Gaussian process regression models to predict age from (1) FC, (2) regional brain volumes, and (3) multimodal MRI (FC+volumetric) in 493 control participants (cognitively normal, amyloid‐negative [A‐], 18‐89 years old). We applied the trained models to independent samples staged by the presence or absence of amyloid (A+/A‐) and tau (T+/T‐) using PET (Centiloid) and CSF (amyloid β‐42/40 ratio, phosphorylated tau 181): 122 A‐T‐, 62 A+T‐, 62 A+T+, as well as 154 symptomatic AD participants. Global cognition was assessed using an established composite of cognitive tests across multiple domains.

Result

All models successfully predicted age in the control training set, with the multimodal model (mean absolute error [MAE]=5.3 years) outperforming the unimodal volumetric (MAE=6.0 years) and FC models (MAE=8.3 years) (Figure 1). In all three models, the brain age gap (BAG) was significantly elevated in symptomatic AD compared to cognitively normal controls. In the FC and multimodal models, the BAG was significantly reduced in A+T+ participants compared to T‐ controls (Figure 2). In symptomatic AD, lower global cognitive composite scores were associated with elevated volumetric and multimodal BAGs (Figure 3).

Conclusion

Both FC and volumetric estimates of brain age are sensitive to symptomatic AD, consistent with previous reports. Additionally, FC‐based brain age may exhibit a biphasic response to preclinical AD pathology while volumetric brain age may be sensitive to cognitive decline in the symptomatic stage. Multimodal estimates of brain age capture each of these modality‐specific relationships, and further, improve sensitivity to healthy age differences. Hence, multimodal neuroimaging models may be useful in staging early symptomatic and preclinical AD.
β‐Lactolin Improves Mitochondrial Dysfunction in Aβ‐treated Mouse Hippocampal Neuronal Cells and a Human iPSC‐Derived Neuronal Cell Model of Alzheimer’s Disease
Authors: Ayabe Tatsuhiro , Takahashi Chika , Ohya Rena , Ano Yasuhisa
Published: December 2022

Background

Mitochondrial dysfunctions are a key hallmark of Alzheimer’s disease (AD). β‐Lactolin, a whey‐derived glycine–threonine–tryptophan–tyrosine tetrapeptide, has been previously reported to prevent AD‐like pathologies in an 5×FAD mouse model via regulation of microglial functions. However, the direct effect of β‐lactolin on neuronal cells and neuronal mitochondrial functions remains unknown. Here, we investigated the effects of β‐lactolin on mitochondrial dysfunctions in amyloid β (Aβ)‐treated mouse hippocampal neuronal HT22 cells and human induced‐pluripotent cell (hiPSC)‐derived AD model neurons.

Method

Mouse hippocampal neuronal HT22 cell line, and hiPSC‐derived AD model neuron (PSEN1 P117L mutation) and its wild‐type control were used in this study. HT22 cells were treated with β‐lactolin (1–100 nM) for 1 hr, and Aβ42 (1–10 μM) was added for the next 23 hrs. Oxygen consumption rate was measured using extracellular flux analyzer. Intracellular ATP level was determined by luciferase activity. Cells were stained with MitoTracker, JC‐1, or MitoSOX fluorescent dye, and then mitochondrial morphologies, membrane potential, and oxidative stress, respectively, were examined by high content image analysis. Cell viability was measured by MTT assay. Gene expression levels were evaluated by RT‐PCR. hiPSC‐derived wild‐type and AD neurons were cultured for 14 days under β‐lactolin treatment, and mitochondrial morphologies and membrane potentials were analyzed.

Result

HT22 cells treated with both β‐lactolin and Aβ exhibited increased oxygen consumption rate and cellular ATP concentrations compared to cells treated with Aβ alone, suggesting that β‐lactolin improves mitochondrial respiration and energy production. In high content image analysis, β‐lactolin attenuated Aβ‐induced mitochondrial fragmentation, membrane potential decrease, and excess oxidative stress, eventually preventing neuronal cell death. Treatments with β‐lactolin increased gene expression of mitofusin‐2, which contribute to mitochondrial fusion events. Finally, β‐lactolin attenuated impairment in both mitochondrial morphologies and membrane potentials in hiPSC‐derived AD model neurons, suggesting β‐lactolin shows a suppressing effect on human AD pathologies.

Conclusion

β‐lactolin improved AD‐related neuronal mitochondrial dysfunctions and suppressed neuronal cell death in both mouse and human AD model neuronal cells. The dual function of β‐lactolin on both neuron and microglia marks an advantage in AD prevention.
Hearing loss was associated with cognitive impairment evaluated by Bangla Adaptation of Mini‐mental State Examination in a rural Bangladeshi elderly population
Authors: Suzuki Harumitsu , Siddiquee Ali Tanweer , Sobhan Sheikh Mohammad Mahbubus , Kadota Aya , Miura Katsuyuki , Fujiyoshi Akira , Choudhury Sohel Reza
Published: December 2022

Background

The Mini Mental State Examination (MMSE) is the most commonly used, first line screening tool for dementia and cognitive decline in adults. The Bangla Adaptation of Mini‐mental State Examination (BAMSE) has been tested as a reliable instrument to assess cognitive function of the normal elderly Bangladeshi population with regards to the socio‐cultural context and low literacy rate of the country. However, there is lack of evidence regarding lifestyle and socioeconomic determinants of cognitive performance in Bangladeshi elderly population. The purpose of this study is to investigate the relationships between lifestyle and socioeconomic determinants and cognitive impairment by BAMSE among elderly Bangladeshi.

Method

Data was collected from an on‐going surveillance site at Tarail subdistrict in Kishorgonj district.Among the total of 410 study participants aged ≥65 years, after excluding history of stroke and Parkinson’s disease, finally 314 participants were included in this analysis. Trained interviewers assessed cognitive function using the BAMSE questionnaires and self‐reported lifestyle factors (smoking: never, past, current; hearing: normal, poor, smelling: normal, poor, lost), socioeconomic factors (marital status: married, widowed/divorced; working status: farmer, other workers, non‐workers), medication use (hypertension and diabetes) by a questionnaire, and physical measurements (weight, height and blood pressure). Hypertension was defined as either anti‐hypertensive medication use or systolic/diastolic blood pressure ≥140/90 mmHg. Literacy was defined as participants who had 1 year or more education. Cognitive impairment was defined by BAMSE score < 21. A multivariable logistic regression analysis was performed to assess the independent relationships between lifestyle and socioeconomic factors and cognitive impairment. Sex, age, hypertension, diabetes, smoking, hearing, smelling, marital and working status, and literacy were used as explanatory variables.

Result

Mean age (standard deviation) was 72.5(years and literacy rate was 23.6% in men and 5.9% in women. People who have hearing loss was 1.94 higher odds ratio (95% confidence interval:1.08‐3.47) for cognitive impairment compared to normal hearing in the multivariable analysis. Each 5‐year age increments was also significantly associated with cognitive impairment in the same model.

Conclusion

Hearing loss and older age were associated with cognitive impairment in elderly Bangladeshi in this study.
The impact of Virtual Individual Cognitive Stimulation Therapy (V‐iCST) on cognition, quality of life, mood, and communication in dementia: a feasibility randomized controlled trial
Authors: Hui Esther K , Tischler Victoria , Wong Gloria HY , Gibbor Luke , Spector Aimee E
Published: December 2022

Background

The COVID‐19 pandemic has led to the suspension of community‐based dementia services worldwide, where evidence‐based interventions for dementia, like Cognitive Stimulation Therapy (CST), were delivered. Treatment access is paramount during the pandemic and beyond for people with dementia to maintain functioning and well‐being. This study aimed to evaluate the feasibility and acceptability of a virtual, 14‐session program of Individual Cognitive Stimulation Therapy (V‐iCST) in the UK.

Method

A single‐blind feasibility randomized controlled trial (RCT) was conducted in the UK. Thirty‐four people with mild to moderate dementia were recruited from dementia organizations and networks. Seventeen were randomly assigned to receive V‐iCST (14, 45‐min sessions) and 17 to treatment as usual (TAU) over seven weeks. Feasibility and acceptability data, for example, recruitment, attrition, attendance, adverse effects, and fidelity, were collected. Outcome measures on cognitive function, quality of life (QoL), mood, and communication were collected pre and post‐test. Analysis of covariance was used to compare changes in V‐iCST and TAU.

Result

We have successfully completed recruitment. Results on feasibility, acceptability, and preliminary efficacy will be available at the conference.

Conclusion

We hypothesize that V‐iCST is feasible and acceptable and will have positive effects on cognitive, QoL, mood, and communication. Findings will be available at the conference.
Innovative Framework to Assess the Costs of Untreated Agitation in Alzheimer’s Disease (AAD)
Authors: Michael Mary
Published: December 2022

Background

In the past decade, researchers and advocates have taken steps towards quantifying the full costs of Alzheimer’s disease and related dementias. However, our current understanding of these costs does not fully consider the behavioral symptoms of dementia, notably agitation. Agitation in Alzheimer’s disease contributes to negative social and financial outcomes for people with the condition, their care partners, and health systems. When left untreated, the negative impact of these outcomes is exacerbated, yet the scale of this impact is unknown. A review of the literature shows that there are no frameworks to help assess the true costs of agitation calling for a need for further research and assessment.

Method

We created a Markov model that investigates each stage of Alzheimer’s disease with agitation. The model utilizes five transition states with six‐month cycles. This framework assesses direct and indirect costs of disease. Direct costs include professional caregiving, non‐pharmacological intervention, nursing home costs, healthcare professional consultations, and hospitalizations. Indirect costs of disease evaluated include loss of income and value of unpaid caregiving. To establish the difference in cost to understand true costs of untreated disease, this model will allow us to compare outcomes associated with intervention with that of no intervention, from which one can derive an Incremental Cost‐Effectiveness Ratio (ICER). Additionally, we used quality‐adjusted life years to measure disease burden and health outcomes. Finally, we utilized a deterministic and probabilistic sensitivity analysis to assess the robustness of this model.

Result

Results will describe a finalized Markov model with which one can assess the costs of untreated agitation in Alzheimer’s. This discussion will include perspectives and feedback from key opinion leaders in Alzheimer’s research, care, and economics from across the world

Conclusion

Agitation has severe consequences on individuals, families, and health systems. Oftentimes one of the first symptoms of Alzheimer’s or dementia, agitation can increase the caregiving responsibilities, trigger placement into nursing homes, and cause severe emotional and physical toll on care partners. We cannot understand the full costs of dementia or AD until we account for untreated agitation vis‐à‐vis a multi‐symptom assessment. This framework is the first step in evaluating the costs of agitation.
Shedding light on innate immune dysfunction in a mouse model of Alzheimer’s disease using a novel myeloid cell‐targeted PET imaging strategy
Authors: Chaney Aisling M , Jain Poorva , Nagy Sydney C , Cropper Haley , Reyes Samantha T. , Wu Sophia , Dwivedi Shriya , Azevedo Carmen , Jackson Isaac M , Carlson Mackenzie L , James Michelle L.
Published: December 2022

Background

Non‐invasive assessment of maladaptive innate immune responses in the brains of Alzheimer’s disease (AD) patients is a critical unmet need; such techniques have the potential to not only improve diagnosis and disease monitoring, but also serve as endpoints in clinical trials of novel therapeutics. Positron emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO) is a widely used experimental approach for assessing inflammation in vivo but is limited by its lack of cell specificity and inability to discriminate between beneficial and adverse immune responses. We developed the first PET probe targeting triggering receptor expressed on myeloid cells 1 (TREM1) and demonstrated its ability to specifically detect CNS‐infiltrating pathogenic peripheral myeloid cells (e.g., macrophages, monocytes, neutrophils) in the context of neurological disease. Herein, we assess the utility of TREM1‐PET compared to TSPO‐PET for detecting innate immune responses in the 5XFAD mouse model of AD.

Method

5XFAD and wild‐type (WT) 6–7‐month‐old mice underwent 10 min static TREM1‐ and TSPO‐PET/CT imaging. TSPO‐PET was performed 50–60 minutes post‐intravenous injection of [18F]GE‐180 (175.1±13.8 μCi). TREM1‐PET was performed 20 hours following intravenous injection of [64Cu]TREM1‐mAb (94.75±4.96 μCi). Tracer binding was quantified in the cortex, hippocampus, thalamus, and whole brain using a semi‐automated brain atlas‐based approach. CD68 immunostaining of brain tissue was performed to assess microglia/macrophage activation.

Result

TREM1‐PET quantification revealed significantly increased [64Cu]TREM1‐mAb binding in the hippocampus (1.37‐vs‐1.14 %ID/g, p=0.02) and thalamus (1.00‐vs‐0.76 %ID/g, p=0.04) of 6–7‐month‐old 5XFAD compared to WT mice (Fig 1A). Elevated TREM1‐PET binding was observed in the cortex (1.77‐vs‐1.62 %ID/g, p=0.14) and whole brain (1.64‐vs‐1.46 %ID/g, p=0.08) but did not reach significance. TSPO‐PET imaging demonstrated significantly increased [18F]GE‐180 binding in all regions (cortex: 2.36‐vs‐1.48 %ID/g; p=0.0003, hippocampus: 2.59‐vs‐1.52 %ID/g, p<0.0001, thalamus: 2.18‐vs‐1.20 %ID/g, p<0.0001, whole brain: 2.55‐vs‐1.66 %ID/g, p=0.0003, Fig. 1B). CD68 staining confirmed increased microglia/macrophage activation in cortical, hippocampal, and thalamic regions (Fig 2).

Conclusion

Differential regional binding patterns were observed with TREM1‐ and TSPO‐PET imaging. Notably, increased TREM1‐PET signal in 5XFAD animals suggests a role for peripheral myeloid cells in AD. Longitudinal whole‐body TREM1‐ and TSPO‐PET imaging in this model is currently underway.
Novel hydroxyl dendrimer‐based PET tracer [18F]OP‐801 detects early‐stage neuroinflammation in 5XFAD mouse model with higher sensitivity than TSPO‐PET
Authors: Carlson Mackenzie L , Reyes Samantha T. , Jackson Isaac M , Azevedo Carmen , Alam Israt S , Nagy Sydney C , Brewer Matthew , Cleland Jeffrey , Shen Bin , James Michelle L.
Published: December 2022

Background

Chronic activation of macrophages/microglia plays a critical role in the onset and progression of neurological diseases, including Alzheimer’s. While PET imaging could enable non‐invasive visualization and quantification of activated macrophages/microglia in vivo, most available PET tracers are nonspecific for macrophages/microglia (Lambert, 2009). To address this need, we developed [18F]OP‐801, a synthetic hydroxyl dendrimer‐based PET tracer that is selectively (>95%) taken up by reactive macrophages/microglia across the blood‐brain barrier (Alnasser, 2018). Here, we evaluated the ability of [18F]OP‐801 to detect activated macrophages/microglia in the 5XFAD murine model of Alzheimer’s compared to an established neuroinflammation imaging approach (translocator protein 18 kDa [TSPO]‐PET, using [18F]GE180).

Method

[18F]OP‐801 (150‐250 μCi) was injected intravenously into female 5XFAD (TG) mice (n=12) and age/sex‐matched wild types (WT, n=7) at 3.75 and 5 months old. Sensitivity of [18F]OP‐801 was compared to [18F]GE180 by assessing brain signal‐to‐background ratios. [18F]GE180 (150‐250 μCi) was administered to a subset of TG (n=5) and WT (n=4) 3.75‐months‐old mice. Static 10‐minute PET/CT images were acquired at 50‐60 minutes post‐injection for both tracers. VivoQuant brain atlas was fit to CT images and fused to PET to quantify uptake in specific brain regions.

Result

In this model, macrophage/microglial activation is associated with amyloid plaque formation and can be detected using immunohistochemistry between 2‐4 months. Image quantification revealed 3‐fold higher PET signal in 3.75‐months‐old TG compared to WT mice using [18F]OP‐801, whereas [18F]GE180 signal provided no significant difference in brain regions known to contain activated microglia: cortex and hippocampus (Figure 1, Table 1). Significant differences in [18F]OP‐801 uptake were observed between 5‐months‐old TG and WT mice in cortex (p=0.005) (TG: 0.26±0.095%ID/g, WT: 0.11±0.041%ID/g), hippocampus (p=0.017) (TG: 0.18±0.065%ID/g, WT: 0.10±0.026%ID/g) and whole brain (p=0.004) (TG: 0.20±0.082%ID/g, WT: 0.10±0.039%ID/g). TG had almost 5‐fold higher [18F]OP‐801 signal compared to WT mice (Table 2).

Conclusion

These results suggest that [18F]OP‐801 can detect early stage neuroinflammation with higher sensitivity than TSPO‐PET. We are currently replicating this study in a larger cohort of 5XFAD mice to correlate PET image findings with immunohistochemistry. [18F]OP‐801 is shows promise for visualizing the progression of neuroinflammation with high specificity and sensitivity, warranting further preclinical investigation.
Examining the diagnostic utility of the mnemonic discrimination task for classification of cognition and amyloid‐β burden
Authors: Kim Soyun , Chappel‐Farley Miranda G. , Keator David B. , Janecek John , Mikhail Abanoub , Hollearn Martina K , McMillan Liv , Yassa Michael A.
Published: December 2022

Background

Developing non‐invasive diagnostics that can effectively predict amyloid‐β (Aβ) burden is crucial, as this technology could help to identify individuals with increased risk for AD and provide a window for potential treatment or intervention. Mnemonic discrimination tasks (MDTs) are designed to assess the ability to discriminate highly similar episodic memory representations (e.g., objects or spatial locations). The relationship between the MDT performance and Aβ burden, however, has not yet been directly tested. In this study, we investigated whether MDT performance can successfully classify cognitive status or Aβ load in older adults.

Method

A sample of 85 older adults (60‐91 yrs old) with normal cognition and 9 older adults with a clinical diagnosis of Mild Cognitive Impairment (MCI) (62 ‐89 yrs old) underwent either cerebrospinal fluid (CSF) lumbar punctures or 18F‐florbetapir‐PET imaging. Cognitively normal individuals were stratified into Aβ+ and Aβ‐ subgroups based on quantitative thresholds for Aβ positivity (SUVR >1.11, CSF Ab1‐42/1‐40 < 0.062). Participants performed the object and spatial versions of the MDT. We used a random forest classification algorithm, including MDT performance metrics and demographic factors (age, gender, education) as features to classify cognitive status (normal vs. MCI) and Aβ status (positive vs. negative). We evaluated the area under the receiver operating characteristic curve (AUC) using the classifiers in a leave‐one‐out cross validation design.

Result

For classification of cognitive status, the best model performance was achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.80). For classification of Aβ status in cognitively normal participants, the best model performance was also achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.65).

Conclusion

Our findings suggest that MDT performance measures may have clinical utility as a diagnostic tool to predict cognitive status and in vivo Aβ burden in preclinical older adults.
Functional hyperconnectivity is associated with higher levels of sPDGFRβ, a marker of blood brain barrier breakdown, in older adults
Authors: Contreras Joey A , Fujisaki Kimiko , Ortega Nancy E , Barisano Giuseppe , Sagare Abhay P , Zlokovic Berislav V , Toga Arthur W. , Pa Judy
Published: December 2022

Background

Apolipoprotein E4 (APOE4) has toxic effects on the cerebrovascular system, neuronal function, and functional connectivity of brain networks (e.g., default‐mode, frontal‐attention, and salience networks). The thalamus, a vital structure that acts as a relay station between many networks, has become of interest in AD research with studies showing atrophy among those with early AD and diminished cortical‐thalamic connections among those with vascular impairment. Additionally, CSF soluble platelet‐derived growth factor receptor‐β (sPDGFRβ), a marker of blood‐brain barrier breakdown, has been associated with AD risk, especially in APOE4 carriers. The present study investigated the relationship between CSF sPDGFRβ and functional connectivity in APOE4 carriers and non‐carriers.

Method

One hundred sixty‐six older adults from the Los Angeles area were selected from a larger cohort (96 females, mean age+SD=67.4+10.7, 68 APOE4 carriers) based on availability of rsfMRI data. Image data was processed using CONN‐toolbox v19c. Grey matter was parcellated using Harvard/Oxford brain atlas, excluding cerebellum. ROI‐to‐ROI analyses were conducted selecting the thalamus as seed region averaging mean connectivity between the left and right structure of other parcellated brain regions. Linear regression models evaluated significant associations between blood oxygen level‐dependent (BOLD) and network connectivity among seed‐target regions and CSF sPDGFRβvalues, while covarying for age and sex. Comparison of averaged functional connectivity values between seed and all target regions among APOE4 carriers and non‐carriers was also examined.

Result

Higher functional connectivity between the thalamus and resting state network hub regions were associated with higher CSF sPDGFRβ (Fig 1A, 1C). Cortical regions within the networks included posterior cingulate gyrus, anterior cingulate gyrus, and frontal eye field. Averaged functional connectivity between these areas was significantly higher in APOE4 carriers compared to non‐carriers (Fig 1B).

Conclusion

The thalamus is a key subcortical structure for relaying signals across the brain for memory, attention and sleep/wakefulness cycles, and more recently with relevance to AD. These findings suggest a link between early BBB breakdown and elevated functional connectivity in brain regions known to have high synaptic activity and early pathology among non‐demented older adults at risk for AD.