bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial‐temporal subtypes of amyloid deposition show distinct baseline and longitudinal cognitive profiles
Authors: Mastenbroek Sophie E , Salvadó Gemma , Alves Isadora Lopes , Wottschel Viktor , den Braber Anouk , Visser Pieter Jelle , Gispert Juan Domingo , Hansson Oskar , Barkhof Frederik , Ossenkoppele Rik , Collij Lyduine E.
Published: December 2022

Background

We recently identified three distinct spatial‐temporal trajectories of amyloid deposition through the application of a machine‐learning model (i.e., Subtype and Stage Inference [SuStaIn]) to amyloid positron emission tomography (PET) data. These included Frontal, Parietal, and Occipital subtypes, defined by the earliest regions to show abnormality. The current study aimed to determine whether these subtypes of amyloid accumulation hold value in predicting baseline and longitudinal cognitive functioning in addition to a validated measure of global amyloid burden, i.e. Centiloid (CL) units.

Method

The Frontal, Parietal, and Occipital subtypes were applied to the amyloid‐PET standard uptake value ratios (SUVr) of 2,510 subjects from 3 cohorts (ADNI, EMIF‐AD, OASIS‐3). Of these, 570 subjects with a high subtype probability assignment (>50%), assigned stage ≥ 1, and available cognition were included in the analyses. Subtypes were compared on global cognition and several cognitive domains including memory, attention, executive functioning, language, and visuospatial functioning. To assess whether subtype assignment added to baseline CL in predicting baseline and longitudinal cognition (range follow‐up=0.4‐11 years), linear models (predictors: subtype and CL) and linear mixed models (predictors: subtype*time and CL*time) were performed, respectively. All models were adjusted for baseline age, sex, education, and baseline cognitive stage.

Result

Participant characteristics are shown in Table‐1. The majority was assigned to the Frontal subtype (57%), followed by Occipital (22%) and Parietal (20%). After adjusting for baseline CL, the Occipital subtype showed lower baseline language scores than the Parietal subtype (β=‐0.34, p=.046) (Fig‐1A) and lower baseline attention scores than both Frontal (β=‐0.39, p=.047) and Parietal (β=‐0.73, p=.002) subtypes (Fig‐1B, Table‐2). In addition, the Occipital subtype declined faster over time on global cognition (Fig‐2A) and language (Fig‐2B) as compared to the Frontal (βglobal cognition=‐0.35, pglobal cognition=.007; βlanguage=‐0.10, planguage=.015) and Parietal (βglobal cognition=‐0.50, pglobal cognition=.002; βlanguage=‐0.13, planguage=.015) subtypes.

Conclusion

Our results show the added value of amyloid subtype assignment on top of CL measures on baseline and longitudinal cognition. Specifically, the Occipital subtype was associated with lower baseline performance and showed faster rates of cognitive decline. These findings suggest that subtype assignment based on amyloid PET might improve prognosis and patient stratification in clinical trials.
The CUL3 adaptor protein SPOP plays a role in tauopathy mechanisms
Authors: Eck Randall , Kraemer Brian C
Published: December 2022

Background

The pathological accumulation of the microtubule binding protein tau drives age‐related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer’s disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain unknown and no effective disease modifying pharmacological interventions for tauopathy currently exist.

Methods

We employed classical forward genetic approaches and identified multiple loss of function alleles in the C. elegans spop‐1 gene that ameliorate tauopathy, suggesting SPOP is required for tau mediated neurodegeneration. CRISPR based genome editing methodology enabled the generation of customized SPOP‐1 loss of function and null alleles. Molecular genetics, behavioral, neuronal reporter assays, and biochemical analyses were also employed to characterize the consequences of spop‐1 loss of function on tauopathy related phenotypes in model systems.

Results

Knockout of SPOP‐1 rescues tau mediated behavioral deficits caused by neuronal dysfunction in tau transgenic C. elegans. Biochemical analysis revealed that SPOP‐1 loss of function promotes clearance of phosphorylated and total tau species from C. elegans neurons, but no change in tau transgene mRNA levels. Tau transgenic animals exhibit obvious neurodegeneration of GABAergic neurons, but loss of spop‐1 rescues neurodegeneration. While SPOP functions as an CUL3 E3 ligase adaptor protein, CUL3 function is not required for SPOP loss of function rescue of tauopathy. Genetic epistasis analysis suggests the nuclear speckle resident poly(A) RNA binding protein sut‐2 and spop‐1 function in a parallel molecular pathway.

Conclusions

SPOP is a novel modifier of tauopathy phenotypes. Combined with previous findings investigating ALYREF, PARN/TOE1, SUT‐1 and SUT‐2/MSUT2, this work suggests phase‐separated nuclear speckles are an important cellular site controlling susceptibility to pathological tau. Recent work showing SPOP modification of PR dipeptides derived from C9orf72 expansion suggests common pathways may be at work in the neurodegenerative molecular mechanisms of tauopathy and repeat dipeptides.
Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD
Authors: Kamal Farooq , Morrison Cassandra , Zeighami Yashar , Maranzano Josefina , Dadar Mahsa
Published: December 2022

Background

White matter hyperintensities (WMHs) are pathological changes that develop with increased age and are associated with cognitive decline. Most research on WMHs has neglected to examine regional differences and instead focuses on using a whole‐brain approach. This study examined regional WMH differences and their association with different cognition domains in normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimer’s disease (AD).

Methods

We included participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Few studies using ADNI data have examined the most recent cohort, ADNI‐3. Our study included datapoints from this recently released cohort. Participants were selected from ADNI and were included if they had at least one WMH measurement and cognitive scores examining global cognition (Alzheimer’s Disease Assessment Scale‐13), executive functioning (Trail Making Test‐Part B, and memory (Rey Auditory Verbal Learning Test). MCI and AD participants were included only if they were amyloid positive. A total of 1573 participants with 7381 follow‐ups met inclusion criteria. Linear mixed‐effects models were completed to examine group differences in WMH burden and the association between WMH burden and cognition in aging, MCI, and AD.

Results

People with MCI and AD had increased total and regional WMH burden compared to cognitively healthy older adults. An association between WMH and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions of interest. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region.

Conclusion

Including ADNI‐3 data in this study is a novel strength to this study. These results suggest WMH burden increases from aging to AD. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between and WMH and global cognition. These findings indicate that WMH burden is associated with changes in cognition in healthy aging and prodromal AD but not AD.
Loss‐of‐set and strategy application on the Menu Task: An exploratory study.
Authors: Giles Gordon Muir , Marks Timothy S , Edwards Dorothy Farrar
Published: December 2022

Background

Performance‐based tests of functional cognition (FC) use simulated instrumental activities of daily living (IADL) performed under rule constraint to evaluate ability to perform actual IADL. Because the test characteristics and the test‐takers daily activities are similar, the test‐takers need to avoid becoming “derailed” by habits or personal preferences that are not relevant to the test, a phenomenon referred to as loss of set (Burgess, 2005; Schneider, 1984). The Menu Task, a sensitive FC screening test, was designed to provoke loss of set by having the format of a food selection activity, in which test‐takers own food preferences may disrupt actual task requirements. However, there has until now been no examination of whether test‐takers approach and strategies to maintain set are associated with cognitive abilities and FC abilities.

Method

A convenience sample of 93 adults living independently in the community were administered a battery of cognitive screening measures, a self‐report IADL measure, and assessments of FC including the Menu Task, and the After Menu Task Interview. Responses to the After Menu Task Interviews were qualitatively categorized according to 1. loss of set 2. calorie counting as a strategy, or 3. self‐reported planning. Independent t‐tests were used to compare the categorized group performance on cognitive, FC, and IADL measures.

Result

Individuals who lost set on the Menu Task performed significantly poorer on the MoCA (p = .012), the ADCS‐MCI (p < .001), and FC assessments (p < .01) than those who did not lose set. Those who reported counting calories as a strategy scored significantly better on the MoCA (p = .012), TMT A (p = .023), TMT B (p = .012), the ADCS‐MCI (p = .044), and FC assessments (p < .05). No significant group differences were observed for those who reported planning compared to those who did not report planning.

Conclusion

Clinicians using the Menu Task may wish to incorporate an After Task Interview focusing on the client’s reported way of approaching the Menu Task. Individuals who focus on their own food preferences or show other indications of loss of set while completing the Menu Task may benefit from further cognitive or FC assessment.
Change in cardiorespiratory fitness, hippocampal subfields and virtual navigation in older adults: a randomized controlled trial
Authors: Alotaibi Razan , Schon Karin
Published: December 2022

Background

Hippocampal neuroplasticity is oppositely affected by aging and exercise. Rodent models have demonstrated a specific exercise‐induced neuroplasticity enhancement in the dentate gyrus (DG) subfield of the hippocampus associated with improved spatial memory. In humans, exercise‐induced enhancement in cardiorespiratory fitness (CRF) has been shown to increase the left anterior DG volume among young adults. Cross‐sectional studies in older adults showed that higher CRF is associated with greater subiculum volume in women and attenuated age‐related decline in performance of hippocampus‐dependent spatial navigation tasks. However, it is unknown whether these relationships hold for exercise‐induced enhancement in CRF among older adults.

Method

In this study, 32 older adults who completed one of two randomized controlled trials (RCT; ClinicalTrials.gov; NCT02057354; NCT02775760) participated in a 12‐week moderate‐intensity, trainer‐supervised exercise training program. Participants were randomized into two groups, active control (resistance training; RT) and endurance training (ET). The aim of this RCT was to examine the effects of exercise training and training‐induced increases in CRF on hippocampal subfield volumes and activation during virtual navigation in cognitively‐healthy sedentary older adults (55‐85 years old) using structural MRI and fMRI. FreeSurfer 7.1 was used to automatically segment hippocampal subfields using T1 and high‐resolution T2‐weighted images. AFNI 19.0 was used for fMRI preprocessing and analyses.

Result

Our structural MRI results demonstrated that after the 12‐week period, the RT but not the ET group showed a marginally significant volume decrease in the right anterior DG. Additionally, CRF increase was significantly associated with volume increase in the left anterior subiculum among women. Our fMRI results showed that CRF increase predicted a marginally significant lower fMRI activation in the left subiculum. Finally, an exploratory whole‐brain fMRI analysis showed that CRF increase significantly predicted lower activation in the cuneus and right inferior frontal gyrus

Conclusion

Our results extend findings from animal models on DG neuroplasticity to older adult humans and to brain areas associated with spatial navigation. Furthermore, our results suggest that exercise and CRF may attenuate aging‐related decline in the structural and functional integrity of hippocampal subfields among older adults, especially among women, and possibly by targeting the subiculum.
Ex vivo quantitative amyloid and perivascular space measurements in white and gray matter on immunohistological microscopy in AD, MCI, and cognitively intact individuals
Authors: Schwartz Daniel L , Roese Natalie E , Hurworth Justin , Lahna David , Krajbich Victoria , Kaye Jeffrey A , Dodge Hiroko H , Woltjer Randy , Silbert Lisa C
Published: December 2022

Background

Amyloid (Aβ) clearance is disturbed in late‐onset Alzheimer’s disease (AD), and a local relationship between Aβ clearance and gray (GM) and white matter (WM) perivascular spaces (PVS) is presumed. Most in vivo primate work has focused on MRI‐visible PVS in WM, described as pathological and enlarged, while nearly all in vivo mechanistic work in animals interrogates “normal” GM PVS. This disparity describes a critical knowledge gap in the morphology, location and relevance of PVS to Aβ clearance.

Method: Ex vivo samples from four locations in 22 NIA‐Layton Oregon Alzheimer’s Disease Research Center participants (mean age at death=92y). Pre mortem diagnoses were cognitively intact (“C”, N=9), mild cognitive impairment (“MCI”, N=5), and AD (N=8, confirmed post mortem). Samples were sliced, stained and digitized (3.52µm/pixel). GM masks and morphometrics of vessels>6200µm2 in WM (n=1403) and GM (n=237) were derived from trichrome stain (Fig. 2H,C, and D). Aβ coverage (% positive 4G8 pixels in GM pixels within 1.76mm of the nearest GM pixel to the vessel center‐of‐mass) and normalized PVS size were used as dependent variables (Fig. 2D&F).

Result

There were significant main effects of group for Aβ burden in GM nearest to WM vessels (C<MCIAD>MCI) (Fig. 3D). There were significant main effects of group for PVS size in GM (AD>MCI and C) but not WM (Fig. 3C). There were no vessel‐by‐vessel associations between PVSnorm and nearby cortical amyloid within group. (Fig. 3E)

Conclusion

In MCI, relatively smaller PVS and high cortical Aβ near GM vessels may reflect a functional waste clearance system in those for whom Aβ burden is not yet advanced. In AD, large GM PVS and an absence of a relationship with cortical Aβ may describe a clearance system overwhelmed by Aβ deposition. Absence of group‐wise differences of relative PVS size in WM vessels, along with no vessel‐by‐vessel association of PVS size with nearby GM Aβ suggests that WM PVS size may not be relevant to Aβ clearance at this scale in individuals of advanced age.
18F‐fluorodeoxyglucose‐positron emission tomography Findings in Patients with Genetic Frontotemporal Dementia
Authors: Yadollahikhales Golnaz , Mundada Nidhi S. , Chapleau Marianne , Rosen Howard J. , Boxer Adam L. , Yokoyama Jennifer S. , Miller Bruce L. , Gorno‐Tempini Marilu , Lee Suzee E. , Seeley William W. , Hall Matthew , La Joie Renaud , Rabinovici Gil D.
Published: December 2022

Background

Mutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls.

Methods

(18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient’s FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference.

Result

On review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1).

On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2).

Conclusion

Hypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes.
Public and Patient involvement and engagement in research design. Co‐create a toolkit that enables quality time together across the Dementia journey.
Authors: Commane Brendan G , Chen henglien Lisa , Oquosa Odi , Research Participatory
Published: December 2022

Title: Public and Patient involvement and engagement in research design: Co‐create a toolkit that enables quality time together for Dementia.

There is a growing consensus in the U.K. that public and patient involvement and engagement (PPIE) – e.g. people living with dementia (PLWD), their families, carers, professionals and community – in dementia research is instrumental in improving the quality of research projects and strengthening its relevance and impact. However, publications on PPIE during dementia design research is lacking knowledge and learning exchange within research communities.

This project fills in this knowledge gap by involving and engaging 12 family caregivers, care workers and professionals who care for PLWD aged 65 and above at any stage (mild, moderate, and severe) as well as relevant stakeholders. The participants contributed in the research design to co‐create an easy access, supportive toolkit that could be used by both PLWD as well as their in/formal carers to promote person centredness care in dementia. This was achieved through participatory approaches with dementia carer focus group workshops and a stakeholder engagement workshop to: (a) generate the ideas and research questions by spending meaningful/quality time together face‐to‐face and digitally across the dementia journey, (b) using an experience‐based co‐design approach to design the research methodology for co‐creation workshops, (c) co‐produce a research funding proposal which has strong PPIE in all stages. d) feedback on the experience with the design research.

We argued a participatory approach to PPIE during design research can be time consuming and costly though critical. Firstly, the primary strength of participatory approach was the target population trying our initial research design, then design the research collaboratively. Secondly, it developed a sense of ownership and ongoing commitment among the PPIE groups. Thirdly, it helped us to ensure culturally and logistically appropriate design research. Fourthly, it helped participants to be more meaningfully engaged in research, which in turn concluded with a co‐created research design that could have greater potential to produce relevant, meaningful research findings translated to care practice and policy.
Impact of a web‐based psychoeducational intervention on carer mental health quality of life: Results from a pragmatic randomized control trial
Authors: O'Rourke Hannah M , Swindle Jennifer , Ghosh Sunita , Chacinski Dorothy , Baxter Pamela , Peacock Shelley , Thompson Genevieve N , Dubé Véronique , Holroyd‐Leduc Jayna , Nekolaichuk Cheryl , McAiney Carrie A , Duggleby Wendy
Published: December 2022

Background

Carers of a person who is living with dementia in long‐term care experience transitions which can challenge their mental health. My Tools for Care‐In Care (MT4C‐In Care) is an online psychoeducational intervention that aims to offer informational, appraisal, and emotional support to assist carers to adapt to the transitions they experience. This presentation will report on the impact of using MT4C‐In Care on carer outcomes including mental health quality of life (primary outcome), and secondary outcomes of social support, hope, self‐efficacy, grief and loneliness.

Method

In a single blinded pragmatic randomized control trial, 234 Canadians participated from Alberta, Saskatchewan, Manitoba, and Ontario between February 2020 and October 2021. Carers were eligible if they were ≥18 years of age, had an email address and internet access, and provided physical, emotional or financial care to an adult ≥65 years of age who was living with dementia in a long‐term care home. The intervention group received access to MT4C‐In Care for 2 months; the educational control group received an Alzheimer Society information booklet. Outcomes were assessed using valid and reliable scales at baseline, 2 months and 4 months in telephone interviews. Generalized estimating equations were used to compare changes in the outcomes over time in the treatment and control groups, adjusting for clinically important covariates of gender, age, heart disease, caregiver relationship (spouse vs. non‐spouse) and outcome variables measured at baseline.

Result

The primary outcome, mental health quality of life (p = 0.035), improved in both groups over time, along with hope (p = 0.041) and grief (physical distress, p = 0.068). Comparing change in the intervention to the control group, treatment benefit was observed for secondary outcomes of grief (existential concerns; p = 0.095) and social support (total score p = 0.049 and family subscale p = 0.065), but not for the primary outcome of mental health quality of life (p = 0.93).

Conclusion

MT4C‐In Care demonstrates benefits for carers in terms of both the primary outcome (mental health quality of life), and secondary outcomes. In comparison to an active educational control group, MT4C‐In Care lessens grief and promotes social support, helping to explain how this intervention promotes carers’ mental health.
Hippocampal mossy cells exhibit some of the earliest signs of increased excitability in the Tg2576 model of Alzheimer’s disease neuropathology
Authors: Alcantara‐Gonzalez David , Criscuolo Chiara , Botterill Justin J , Lisgaras Christos , Kennedy Meghan , Scharfman Helen E
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative illness characterized by progressive accumulation of amyloid beta (Aβ) and neurofibrillary tangles, with cognitive impairment and altered neural activity. Hyperexcitability in the early stages of AD contribute to Aβ accumulation and cognitive impairment, aggravating the progression of AD. However, the hyperexcitability origin is not clear. This study aimed to test whether mossy cells (MCs), an excitatory cell of the hippocampal dentate gyrus, show increased excitability at early stages of AD and contribute to the increased network excitability generation. Indeed, alterations of MCs contribute to hyperexcitability and cognitive impairment in epilepsy. However, the role of MCs in AD has not been substantially explored.

Methods

Intrinsic and synaptic properties of MCs and granule cells (GCs) from WT and Tg2576 mice at early ages (1‐2 m.o.) were characterized by whole‐cell patch‐clamp recordings. Synaptic properties included the frequency and amplitude of spontaneous excitatory postsynaptic potentials (EPSPs) and excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs). Deterioration in MCs morphology was evaluated using Nissl staining and GluR2/3 labeling by light‐ and confocal microscopy. Aβ deposition was evaluated using the McSA1 antibody.

Results

Tg2576 GCs did not have any significant difference in their intrinsic properties, as we shown previously in mice ∼3 m.o. However, an enhanced excitatory and inhibitory input to GCs, depicted by augmented IPSC (7.16 vs 14.04 events/s) and NMDA‐mediated EPSC frequencies (0.81 vs 1.41 events/s) were found. Interestingly, Tg2576 MCs had an augmented EPSP frequency (5.75 vs 9.44 events/s), and their intrinsic properties showed a depolarized RMP (‐72.88 vs ‐58.36 mV), and reduced rheobase (145.56 vs 47.14 pA), AP amplitude (98.14 vs 76.66 mV), time‐to‐peak (552.75 vs 266.16 ms) and maximum rise (171.44 vs 88.68 mV/ms) and decay slopes (‐61.17 vs ‐42.38 mV/ms). The correlation between #APs and current injected showed Tg2576 MCs fired significantly more APs (SEZD = 0.34; z = 2.48). Tg2576 MCs showed robust intracellular Aβ aggregation without any significant morphological change.

Conclusions

MCs changes in excitability and early accumulation of Aβ suggest that MCs could be the cause of increased excitability occurring later in GCs. In this manner, MCs could be an important contributor to AD.
Everyday experiences of people living with MCI or dementia: a scoping review
Authors: Huizenga Jacoba , Scheffelaar Aukelien , Bleijenberg Nienke , Wilken Jean Pierre , Fruijtier Agnetha D. , Van Regenmortel Martine R.F.
Published: December 2022

Background

Increasing attention has been paid to the ‘voice’ of people living with MCI or dementia, but there is a lack of clarity about how everyday life is exercised, lived, and understood from this insider’s perspective. The current study aimed to explore and identify the everyday life experiences, challenges and facilitators, of home living individuals with MCI and dementia.

Method

Our study adopted a scoping review methodology, guided by the Joanna Briggs Institute Reviewers Manual. Eight databases were searched, resulting in 6345 records, of which 58 papers were included in the review. Only qualitative studies were included, published between 2011 and 2021. Analysis was done by descriptive content analysis.

Result

Included study characteristics are summarized in Table 1. Our findings were categorized into seven spheres of everyday life: experiences related to the condition, the self, relationships, activities, environment, health and social care, and public opinions [Figure 1, Table 2]. Results show the many disruptions and losses in everyday life and the ways people try to adapt to these changes. Highlighted in every area is the importance of reciprocal relationships and being engaged as citizens in the community in a meaningful way. Included studies showed no differences between groups in the impact on the experience of everyday life, such as between MCI and dementia.

Conclusion

This review shows that the change of focus from healthcare to all aspects of everyday life provides insight into the insider’s perspective of people living with dementia. The majority of included studies emphasize the social needs of people living with MCI or dementia. All areas of everyday life seem to be closely intertwined and reflect an socioecological model [1], [2], [3]. Furthermore, perhaps one of the defining aspects of MCI according to the current definition, that symptoms do not interfere with daily life, requires more nuance. More research is needed on factors that promote and impede the sense of reciprocity and belonging, as experienced by people living with MCI and dementia.
A Comparison of Heart Rate Variability Metrics Between Apolipoprotein E ε4 Carriers and Non‐Carriers in Cognitively Normal Middle‐Aged Adults
Authors: Anderson Travis , Slutsky‐Ganesh Alexis B , Wideman Laurie , Park Kyoung Shin , Labban Jeffrey D , Kibildis Samuel , Vance Jarod C , DuBois Samantha L , Holder Hadassah , Etnier Jennifer L
Published: December 2022

Background

The Apolipoprotein E (APOE) ε4 allele has been identified as a critical genetic risk factor for developing Alzheimer’s disease. Heart rate variability (HRV) metrics are non‐invasive indicators of autonomic nervous system function associated with cognitive performance in patients with dementia and mild cognitive impairment. Some evidence suggests reduced HRV complexity in elderly adults carrying the ε4 allele beyond the effects of aging. However, no study has evaluated whether cognitively normal middle‐aged adults differ in their HRV based on their APOE carrier status.

Method

The present cross‐sectional analysis was based on the larger Physical Activity and Alzheimer’s Disease 2 clinical trial (NIH: R01AG058919). Eighty‐six cognitively normal middle‐aged adults (sex: 85.9% female; age: 57.5±5.9 years; height: 166.5±8.8 cm; mass: 78.3±18.8 kg) had height, mass, and resting blood pressure assessed and completed a series of surveys. Participants provided a saliva sample via passive drool to determine APOE ε4 carrier status and also completed a 5‐minute seated electrocardiogram assessment. R‐waves were identified, and the RR interval time series were filtered prior to HRV analysis. HRV metrics of the standard deviation of the normal‐to‐normal interval, root mean square of successive differences, high and low‐frequency power, and sample entropy were calculated. Differences in HRV metrics between ε4 carriers (n = 32) and non‐carriers (n = 54) were tested via general linear models. Differences were also tested after controlling for sex, age, education, ethnicity, body mass index, moderate to vigorous physical activity, and mean arterial pressure.

Result

No differences in any HRV metric were observed between APOE ε4 carriers and non‐carriers (all p’s > 0.05), including after controlling for all and sets of covariates.

Conclusion

The absence of significant associations between carrier status and HRV in cognitively normal adults suggests that HRV is not predictive of Alzheimer’s disease risk in the same manner as genetic factors. Rather, HRV may be concurrently altered with cognitive decline and thus serve as a non‐invasive biomarker that could be monitored to indicate when more intensive cognitive testing is required. Future research should test the similarity in HRV and cognition trajectories in APOE ε4 carriers and non‐carriers.
Neuropathological autopsy findings in an individual with Alzheimer’s disease who received long‐term treatment with lecanemab (BAN2401)
Authors: Honig Lawrence S , Sun Yu , Irizarry Michael C , Swanson Chad J , Dhadda Shobha , Charil Arnaud , Hart David E , Noble James M , Huey Edward D , Teich Andrew F
Published: December 2022

Background

Anti‐amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β‐amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80).

Method

Brain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double‐blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open‐label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death.

Result

Clinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR‐SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta‐amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near‐absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2).

Conclusion

In this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β‐amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β‐amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.
Comparison of the effect of computerized multidomain cognitive training and pen‐and‐paper educational program in older adults with mild cognitive impairment: a preliminary randomized controlled trial
Authors: Kang Jae Myeong , Yun Seonkyung , Seo Ha‐Eun , Kim Sangsoon , Cho Seong‐jin
Published: December 2022

Background

Cognitive intervention is accepted as a potential therapy to prevent the incident dementia. It was found that computerized cognitive training might be effective for older adults with mild cognitive impairment (MCI) in previous studies. We aimed to find the effect of multidomain cognitive training using tablet computer on the cognitive and psychological function in patients with MCI.

Method

Participants in training group (n = 15) conducted a multidomain cognitive training program using table computer and those in control group (n = 13) conducted an educational book reading twice a week for eight weeks. They were evaluated of their cognitive and psychiatric function before and after the program. The differences of the pre‐ and post‐ scores were compared between training and control groups.

Result

Participants in training group showed improvement in cognitive domains such as language (p = 0.012), memory (p = 0.050), and frontal executive function (p = 0.017), and psychiatric symptoms such as apathy (p = 0.001) and quality of life (p = 0.035) after the training. Control group participants showed improvements in frontal executive function (p = 0.013), positive affect (p = 0.019), apathy (p = 0.022) and mild behavioral impairment score (p = 0.049). Between group comparison of the pre‐ and post‐training difference showed significant improvement in training group compared to control group in memory (p = 0.020), frontal executive function (p = 0.024), positive affect (p = 0.037), apathy (p = 0.048), and quality of life (p = 0.047).

Conclusion

We found the effect of multidomain cognitive training using tablet computer in cognitive domain including memory and executive function, positive affect, apathy, and quality of life in MCI patients. Tablet computer cognitive training may be effective in multidomain cognitive training with transfer effect in the prodromal stage of dementia. Future trials with larger sample size and various devices would find the effect of the computerized cognitive training.
An epigenome wide association study of sub‐phenotypes in Parkinson’s disease.
Authors: Harvey Joshua , Smith Adam R. , Weymouth Luke Stephen , Smith Rebecca G. , Hubbard Leon , Bresner Kate , Pishva Ehsan , Williams Nigel , Lunnon Katie , Creese Byron
Published: December 2022

Background

Parkinson’s disease (PD) is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. Together the cumulative effects of these symptoms have huge impacts on individual quality of life. Here we aim to investigate genome wide DNA‐methylation in post‐mortem PD brain samples and test for region specific association with common secondary symptoms of sleep disorder, visual hallucinations and dementia.

Method

DNA methylation data was generated on the Illumina 450K microarray for a cohort of 142 individual post mortem brain samples from the Frontal Cortex (FC), Caudate Putamen (CP) and Substantia Nigra (SN). Data was quality controlled following standardized, previously published pipelines. Clinical records for each case were assessed for binary status of sleep disorder, visual hallucinations and dementia. Linear models were used to identify differentially methylated positions (DMPs) for each of these outcomes, controlling for age, sex, post‐mortem interval and inferred cell‐type proportions as covariates.

Result

Thus far, results been only been generated for the dementia phenotype, with one genome wide significant loci passing multiple testing correction in the frontal cortex (p = 5.25e‐8). This DMP, found in the gene FAM175A / ABRAXAS‐1 (cg14699004), is hypomethylated in PD patients with preserved cognition, with comparable higher measures in PD‐Dementia and control samples. This effect appeared to be FC specific, with no DMPs passing genome wide significance in other brain regions tested.

Conclusion

Preliminary evidence indicates potential sub‐phenotype associated DMPs, with methylation at one site specifically associated with dementia within the FC. Current analysis is focussing on generating reference results across each of the phenotypes and brain regions assessed. Future work will look at Weighted Gene Correlation Network Analysis to identify networks associated with these individual phenotypes.
Ex vivo target engagement of the Abeta oligomer disassembling compound RD2 in patient derived brain homogenates
Authors: Willbold Dieter , Kass Bettina , Bujnicki Tuyen , Pils Marlene , Zafiu Christian , Schemmert Sarah , Bannach Oliver , Kutzsche Janine
Published: December 2022

Background

Soluble Aβ oligomers are highly toxic and may be responsible for development and progression of Alzheimer’s disease (AD). Elimination of Aβ oligomers is therefore a promising therapeutic strategy. The compound RD2 was developed to stabilize Aβ monomers in their native conformation, which is very close to an intrinsically disordered protein (IDP). RD2 has demonstrated already to directly eliminate soluble Aβ oligomers in vitro and in vivo and to improve cognition or decelerate neurodegeneration in four different animal models in four different laboratories 1,2. Here, we wanted to test if RD2 is able to disassemble Aβ oligomers obtained from AD patient derived brain tissue.

Method

Aβ oligomers in AD patient derived brain tissue homogenates were incubated with different concentrations of RD2 and control compounds. Aβ oligomer concentrations were determined longitudinally by the sFIDA assay, a single‐particle sensitive method for quantitating protein oligomers and aggregates.

Result

RD2 concentration and incubation time‐dependent reduction of Aβ oligomers in brain homogenates was observed. Control compounds did not reduce Aβ oligomer concentrations.

Conclusion

The incubation time and RD2 concentration dependent disassembly of Aβ oligomers from human brain homogenate suggest a very efficient ability of RD2 to fulfill its mode of action, namely the direct disassembly of Aβ oligomers into their Aβ monomer building blocks. Kinetic analysis and the mode of action resemble very much that of catalytic chaperones.
Fast and accurate amyloid brain PET quantification without MRI using deep neural networks
Authors: Shin Seong A , Kang Seung Kwan , Kim Daewoon , Choi Youngeun , Choi Hongyoon , Lee Jae Sung
Published: December 2022

Background

We propose a novel method for automatic quantification of amyloid PET using a deep learning‐based spatial normalization (SN) of PET images, which does not require corresponding MRI or CT image of the same patient. In this study, the accuracy of the proposed method was evaluated for three different amyloid PET radiotracers by comparison with MRI parcellation‐based PET quantification using FreeSurfer, which is more accurate than SN‐based method but requires significantly longer computation time.

Method

Deep neural network model used for SN of amyloid PET images was trained using 994 multicenter amyloid PET images, as well as corresponding 3D MRIs of the patients with Alzheimer’s disease and mild cognitive impairments and cognitive normal subjects. The accuracy of SN and SUVR quantification accuracy relative to FreeSurfer‐based estimation was evaluated using other 148 PET images. Additional external validation was also performed using independent data set (30 18F‐Flutemetamol, 67 18F‐Florbetaben, and 39 18F‐Florbetapir). For the comparison, PET SN was also conducted using SPM12 program. Then, the quantification results using SN methods were compared with SUVR values obtained using on FreeSurfer in individual brain space. Reference region was cerebellar grey matter and AAL3 atlas was used to extract the regional SUVR values.

Results

The quantification results using the proposed method showed stronger correlations with FreeSurfer estimates than SPM SN using MRI did. For example, the slope, y‐intercept and R2 value between SPM and FreeSurfer for global cortex were 0.869, 0.113 and 0.946, respectively. On the other hand, those for proposed method were 1.019, ‐0.016 and 0.986. The external validation study also demonstrated the better performance of proposed method without MR images than SPM with MRI. In most brain regions, it outperformed the SPM SN in terms of the linear regression parameters and intraclass correlation coefficients.

Conclusion

In this study, we evaluated a novel deep learning‐based SN method, which allows quantitative analysis of amyloid brain PET images without structural MRI. The proposed quantification results showed strong correlation with MRI‐parcellation‐based amyloid PET quantification using FreeSurfer in all clinical amyloid radiotracers. Therefore, the proposed method will be useful for investigating Alzheimer’s disease and related brain disorders using amyloid PET scans.
How does alzheimer’s disease, atherosclerosis and comorbid alzheimer’s disease and atherosclerosis impact neurovascular function?
Authors: Eyre Beth , Shabir Osman , Lee Llewelyn , Francis Sheila , Howarth Clare , Berwick Jason
Published: December 2022

Background

The brain is an energy hungry organ, consuming approximately 20% of the body’s energy supply (Clark & Sokoloff 1999). Due to its high energy demands the brain has developed a critical mechanism termed neurovascular coupling (NVC). NVC is the relationship between neuronal activity and a subsequent increase in blood flow to the same brain region. This mechanism is suggested to be impaired in many disorders, including Alzheimer’s disease (AD) (Kisler et al., 2017). Additionally, approximately 90% of individuals living with dementia have a comorbidity (Browne et al., 2017), with some of the most common comorbidities being cardiovascular disease (Tini et al., 2020) and type 2 diabetes (Santiago et al., 2021). Therefore, we wanted to investigate neurovascular function in AD and comorbid mixed models of AD and atherosclerosis.

Method

Four separate groups of mice were used, aged 9‐12 months: AD (APP/PS1 (B6;C3 Tg(APPswe,PSEN1dE9)85Dbo/Mmjax)), WT (APP/PS1‐WT littermates) , atherosclerosis (WT + rAAV8‐mPCSK9‐D377Y + Western Diet) and Mixed AD and atherosclerosis (APP/PS1 + rAAV8‐mPCSK9‐D377Y + Western Diet). At 9m mice completed the novel object recognition test (NOR) to assess cognition. Following this, a thinned window surgery was completed. One‐week post‐surgery 2‐dimensional optical imaging spectroscopy (2D‐OIS) was utilised to investigate changes in cerebral haemodynamics, in response to a whisker stimulation in awake mice. A separate imaging session in anaesthetised mice was also completed, using 2D‐OIS concurrent with electrophysiology to assess neurovascular coupling. Immunohistochemistry was performed to assess amyloid plaque load within the brain.

Result

In the awake imaging session we found that neurovascular function was preserved in the AD group. However, mice in the atherosclerosis group showed a reduction in blood volume in response to a 2s‐whisker stimulation, compared to the WT group. We hypothesised that the mixed model would have the greatest impairment in the neurovascular response, however this was not observed and this group showed an evoked‐blood volume change in between levels of AD and atherosclerosis only groups.

Conclusion

Preliminary results suggest that neurovascular function is impaired in mouse models of atherosclerosis but not in the AD or mixed models. Analysis is ongoing to determine how neural activity and AD pathology are impacted by comorbidity.
Modulation of the spread of pathological tau in vitro and in vivo
Authors: Panzi Chiara , Restani Laura , Novelli Elena , Guarascio Rosellina , Cheetham Michael , Wray Selina , Caleo Matteo , Schiavo Giampietro
Published: December 2022

Background

In tauopathies such as Alzheimer’s disease, tau aggregates are known to propagate across functionally connected neuronal networks, but the mechanisms underlying this process are poorly understood. Several lines of evidence support the hypothesis that tau release is dependent on neuronal activity. Pathological tau can be found in the extracellular space, inside synaptic vesicles, and other synaptic compartments, or in a free form. We aim to test both in vitro and in vivo the effect of selected botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) on the release of tau from synaptic terminals. BoNTs and TeNT enter synapses and cleave different synaptic SNARE proteins, impairing synaptic vesicle fusion and release and they may affect tau spread.

Method

Primary neurons were cultured in MFCs and transduced with lentiviruses expressing human tau (hTau) isoforms. Cells were treated with BoNTs and stimulating agents. The content of hTau in the culture media was quantified with an enzyme‐linked immunosorbent assay (ELISA). Adeno‐associated viral vectors (AAVs) expressing hTau were injected in the vitreous, and the superior colliculus (SC) and lateral geniculate nucleus (LGN) areas were analysed through immunohistochemistry.

Result

The release of the 1N4R mutant hTau (P301S), but not the wild‐type form, is affected by botulinum neurotoxin type A (BoNT/A) and neuronal stimulation, which, respectively, significantly decreases and increases the release of P301S hTau. The AAV constructs are correctly expressed in both primary neurons and in retinal ganglion cells (RGCs), and brain sections of SC and LGN were analysed.

Conclusion

Clostridial neurotoxins represent a powerful tool for the study of neurons and synapses. Using BoNT/A, we showed that hTau release is modulated by specific SNARE complex components and differs depending on the isoform. The use of other BoNT types in both in vitro and in vivo models will help us to identify the SNARE proteins involved in tau release. This approach will provide novel insights on the mechanisms controlling tau release from synaptic terminals and identify novel molecular targets for the development of therapeutic interventions to treat tauopathies.