bluuebunny/crossref_metadata_2025 huggingface dataset:
Motor cerebro‐cerebellar network breakdown among different subtypes of Parkinson’s disease
Authors: Basaia Silvia , Agosta Federica , Francia Alessandro , Cividini Camilla , Stojkovic Tanja , Stankovic Iva , De Micco Rosita , Albano Luigi , Sarasso Elisabetta , Gardoni Andrea , Piramide Noemi , Markovic Vladana , Stefanova Elka , Kostic Vladimir S. , Filippi Massimo
Published: February 2022

Background

To investigate functional alterations in the cerebro‐cerebellar system in two Parkinson’s disease (PD) clinical phenotypes (tremor‐dominant [TD] and postural instability and gait disorder [PIGD]using stepwise functional connectivity (SFC).

Method

58 PD patients performed clinical and cognitive evaluations and resting‐state functional MRI (fMRI). PD cohort was divided into two groups: 32 patients with TD (PD‐TD) and 26 with PIGD (PD‐PIGD). 60 age‐ and sex‐matched healthy controls were also enrolled. SFC analysis aims to characterize regions that connect to specific seed brain areas at different levels of link‐step distances. The cerebellar seed‐region was identified using motor task‐based fMRI in 23 controls. For each of the SFC maps, whole‐brain two‐sample t‐test comparisons between groups were performed.

Result

The performance of the motor task during fMRI was associated with activation of the lobule VI and vermis of the cerebellum. SFC analysis at one‐link step distance showed, in both PD subtypes, a decreased regional–local connectivity between seed region and thalamus and parietal lobe relative to controls; across intermediate link‐steps, a reduced connectivity was observed with frontal, parietal and occipital lobes. Only PD‐PIGD patients showed lower connectivity at intermediate link‐step distances between the seed‐cerebellar region and sensorimotor areas. In addition, SFC pattern identified different localization of functional over‐connectivity in frontal lobe in both PD groups: in inferior frontal gyrus and insula in PD‐PIGD, and in orbitofrontal gyrus in PD‐TD.

Conclusion

These findings highlight subtype‐specific PD changes in cerebellar functional connectivity, providing novel insights into the pathophysiological mechanism potentially underlying different motor phenotypes. Ministry of Education and Science Republic of Serbia (Grant #175090), Italian Ministry of Health (Grant #RF‐2018‐12366746).
Feasibility of the occupational therapy protocol TAP (Tailored Activity Program) for the management of behaviors in a dementia hospital unit: Preliminary results from a pilot study
Authors: Lanzoni Alessandro , Chiesa Roberto , Guerzoni Valentina , Romano Elisabetta , Tarozzi Adriano , Fabbo Andrea
Published: February 2022

Background

BPSD may have a significant impact on the quality of life of people with dementia (PWD), cause significant burden in their caregivers (CG) and rise probability of hospitalization .The Tailored Activity Program (TAP) is an evidence‐based OT program based on meaningful activities of PWD. The primary goal of the program is to prevent and reduce BPSD. The intervention is delivered also toward professional and non professional CG to help them with the implementation of the identified strategies, delivered as tailored non‐pharmacological “prescriptions". OBJECTIVE: verify the applicability in Italy of the TAP OT program.

Methods

The program was adapted for the Italian cultural context in agreement with the main author. It consisted of 6 sessions to be carried out at the SCU‐B after being selected by the Geriatrician. Inclusion criteria for PWDs: MMSE <24, CDR <5, absence of psychiatric comorbidities.In addition to the applicability of the program, other parameters were also detected, specifically BPSD (UCLA‐NPI), autonomy (Barthel), quality of life (QUALID), the use of psychotropic drugs, the confidence of the CG in use of strategies.

Results

A total of 10 patients (age 80.7 ± 5.12) and their primary caregivers were recruited. The TAP program proved to be feasible in all its parts as required by the protocol within a specialist hospital dementia unit. There was also a reduction in BPSDs at NPI (median IN = 42; OUT = 12.5), an improvement in autonomy (Barthel median IN = 52.5; OUT = 57.5) and quality of life (Median QUALID IN = 31; OUT = 26). Caregivers reported greater confidence in using activities (M ± SD IN = 2.60 ± 1.96; OUT = 6.75 ± 2.31), communication (M ± SD IN = 4.40 ± 2.64; OUT = 7.63 ± 1.06) and environmental strategies (M ± DS IN = 3.30 ± 2.836; OUT = 7.25 ± 1.69) for the management of BPSDs at the end of the program.

Conclusions

TAP was overall feasible and applicable in all its parts and has shown to be useful for both PWD and CG in different outcomes. It is necessary to enlarge the sample to confirm these preliminary positive results.
Inflammatory, degeneration and neuritic growth biomarkers predict cognitive decline and dementia in Parkinson’s disease
Authors: Hall Sara , Janelidze Shorena , Pereira Joana B. , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: February 2022

Background

Cognitive decline is common in Parkinson’s disease (PD) and has been associated with cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers such as Aβ1‐42, total tau and phosphorylated tau in addition to inflammatory proteins. VGF, a nerve growth factor, is a promising marker that has recently been implicated in cognitive decline in dementia with Lewy bodies and could potentially play a role in PD. The aim of this study is to assess a wide panel of CSF biomarkers reflecting different neuropathological processes to determine which best predict cognitive decline and conversion to dementia in PD.

Method

We included 174 PD patients from the Swedish BioFINDER study, who were followed for up to 10 years. At baseline, 47 CSF biomarkers were measured, including Aβ1‐42, Aβ42/40, total tau, phosphorylated tau, α‐synuclein as well as markers of neurodegeneration, vascular, inflammatory, synaptic and lysosomal dysfunction. Cox regression analyses were applied to identify biomarkers predicting dementia, adjusting for age, sex, education and disease duration. We then used linear mixed effects models to assess whether the significant biomarkers predicted longitudinal cognitive decline in MMSE, memory and semantic fluency, controlling for age, sex, education and disease duration.

Result

Of the PD patients, 29% converted to dementia during follow‐up (4.9 ± 2.2 years). At baseline, converters were older (p<0.001) and had worse memory and semantic fluency tests (<0.008) compared with non‐converters. Levels of CSF Aβ1‐42, Aβ42/40, tau, Neurofilament light, Serum Amyloid A (SAA), Interleukin 7, Interferon‐gamma‐inducible Protein‐10 (IP‐10) and VGF (p<0.037) significantly predicted conversion to dementia in univariate models. When these biomarkers were included in a multivariable regression model, only higher tau (p<0.001), lower VFG (p<0.001) and higher SAA (p=0.028) independently predicted dementia. Further, CSF tau predicted cognitive decline in MMSE and semantic fluency (p<0.005), lower VGF predicted decline in memory (0.012) and SAA predicted decline in MMSE (p=0.011).

Conclusion

These findings suggest that CSF tau, SAA and VGF are useful markers to predict conversion to dementia and cognitive decline in PD. VGF is emerging as an additional prognostic biomarker for cognitive decline in PD.
Longitudinal changes in the brain language system as amyloid accumulates
Authors: Reinartz Mariska , Gabel Silvy , Schaeverbeke Jolien , Luckett Emma Susanne , Van Laere Koen , Sunaert Stefan , Dupont Patrick , Vandenberghe Rik
Published: February 2022

Background

Language dysfunction is common in Alzheimer disease (AD). There is increasing interest in the preclinical phase of AD. Here we tested longitudinally how activity in the associative‐semantic language network, measured with task‐based fMRI, changes in relation to increases in amyloid load, measured with 18F‐flutemetamol and 11C‐PIB. The main hypothesis was that an increase in amyloid would be associated with changes in activity in left or right posterior superior temporal sulcus (STS) and/or medial temporal gyrus (GTm).

Method

A cohort of 35 cognitively intact older adults (mean age=65.4; range: 52‐78 years, 54.3% APOE‐ε4) participated who all received a task‐based fMRI and amyloid PET in 2009‐2011 and a repeat scan for both modalities in 2016‐2017. As primary analysis, we examined how longitudinal change in amyloid, measured using Centiloids (CL), relates to longitudinal activation change in the posterior temporal nodes of the associative‐semantic language network. The left and right posterior STS and GTm were defined as regions of prior interest using the Fan Brainnetome atlas, based on prior studies in amnestic mild cognitive impairment (MCI) and clinically probable AD using the same functional paradigm (Nelissen et al., 2007; Vandenbulcke et al., 2007; Adamczuk et al., 2016). Within this VOI, significance was determined based on SPM12 small volume correction. As a secondary analysis, we also performed a voxelwise whole‐brain analysis with a FWE whole‐brain corrected threshold <0.05. We also examined how the change in amyloid and the change in fMRI activation related to changes in offline language measures.

Result

In the right posterior STS, the change in response amplitude during the associative‐semantic versus the visuoperceptual task showed a positive correlation with the change in amyloid load (x=51 mm, y=‐31 mm, z=5 mm; Z=3.47, Pcorr=0.010; Fig. 1). The change in response amplitude also correlated with longer offline confrontation naming reaction times (RT; r=0.42, P=0.035; Fig. 2). In addition, in the whole‐brain analysis we observed a decrease in response in the right inferior frontal sulcus with increasing amyloid load (x=3 mm, y=20 mm, z=56 mm; Z=4.64, Pcorr=0.021).

Conclusion

This study confirms the central role of the posterior STS as area of predilection in the earliest stages of AD.
A hippocampal hyperactivity signature observed in cognitively normal APOE4 carriers using deep learning for functional enhancement of structural brain MRI scans
Authors: Nuriel Tal , Guo Jia
Published: February 2022

Background

Alzheimer’s disease (AD) affects millions of Americans and represents a significant and growing public health crisis. Despite this fact, there are currently no approved disease‐modifying therapies that are able to slow or prevent AD pathogenesis. One important reason for this is that most AD drug trials were performed on patients who had already begun to show significant cognitive decline, which is already well after the accumulation of AD pathology begins. For this reason, there is an urgent need to identify biomarkers that can help to identify which individuals will eventually develop AD, prior to the occurrence of irreversible pathological damage in the brain.

Method

In order to aid in these efforts, we have developed a novel deep‐learning method called DeepC, which is capable of extracting functional information from structural MRI scans. This functional extraction is performed with the help of prior training of the model with Gadolinium contrast‐enabled functional MRI scans, which allows DeepC to identify and amplify existing tissue/blood contrast information that is already embedded within T1w structural MRI scans, but which is otherwise imperceptible to the human eye. As an initial test of this DeepC method, we have analyzed the functional signals from publicly available T1w MRI scans in the ADNI database, focusing on APOE4 carriers and non‐carriers who were cognitively normal at the time of the scans.

Result

We observed increased "activity" in multiple brain regions of cognitively normal APOE4 carriers versus non‐carriers. Importantly, we observed a distinct "hyperactivity" signature in the hippocampus of the APOE4 carriers, which is consistent with previous studies. Furthermore, this hippocampal "hyperactivity" was also significantly correlated with the presence of other AD biomarkers present in these individuals.

Conclusion

We believe that this DeepC method may represent an important new biomarker tool that will allow clinicians and clinical trials to better identify at‐risk individuals long before the pathological effects of AD become irreversible. In addition, we believe that the functional data uncovered from these structural MRI scans can also be utilized to further inform us on the mechanisms responsible for AD pathogenesis, especially with regards to APOE4 carriers.
Psychosocial effects of Corona virus measures on (pre‐)dementia patients during 2nd lockdown
Authors: Bakker Els D , Van Maurik Ingrid S , Mank Arenda , Zwan Marissa D , van den Buuse Susanne , van den Broeke Jennifer R , Gillissen Freek , van de Beek Marleen , Lemstra Evelien , van den Bosch Karlijn A , van Leeuwenstijn Mardou , Bouwman Femke H , Scheltens Philip , van der Flier Wiesje M
Published: February 2022

Background

The COVID‐19 pandemic poses enormous social challenges, especially during lockdown. Recently, the second lockdown started in the Netherlands. We aimed to investigate and compare the psychosocial effects of corona measures during lockdown in memory clinic (pre‐)dementia patients and their caregivers.

Method

During second lockdown, n=137 symptomatic patients (age=67.7±6.54, 36.5%F, MMSE = 24.4±4.7; n=82 dementia, n=55 MCI), n=244 cognitively normal (age=63.6±7.56, 38.9%F, MMSE = 28.8±1.18; SCD) and n=198 caregivers of Alzheimer Center Amsterdam completed a survey on psychosocial effects of corona. Questions related to loneliness, worries for faster cognitive decline, psychological and behavioral problems. In a subset of patients (n=169) and caregivers (n=38) we were able to compare their answers to answers on a similar survey completed during first lockdown (May 2020).

Result

In total, n=17 (4.5%) patients [n=3 (2.2%) symptomatic, n=14 (5.7%) cognitively normal] and n=8 (4%) caregivers reported a positive test result for COVID‐19. Over one‐third of caregivers reported worries for faster cognitive decline [n=76 (38%)] and behavioral problems [n=70 (35%)] in patients. Feelings of loneliness were experienced by n=23 (17%) symptomatic patients, n=44 (18%) cognitively normal and n=50 (25%) caregivers. One quarter of patients [n=78 (25%)] reported more depressive feelings during lockdown [n=27 (20%) symptomatic, n=51 (21%) cognitively normal]. More feelings of fatigue were reported by n=23 (17%) symptomatic patients, n=46 (19%) cognitively normal, and n=67 (34%) caregivers. Comparing results to those obtained during the first lockdown, feelings of loneliness [Χ2=26.4, p<.001 in patients, Χ2=10.3, p<.001 in caregivers] and anxiety [Χ2=25.9, p<.001 in patients, Χ2=6.69, p=.010 in caregivers] increased. During second lockdown, less feelings of apathy [Χ2=13.0, p<.001], but more depressive feelings [Χ2=27.6, p<.001] were reported in patients compared to first lockdown. Caregivers were more worried for memory decline in patients during second lockdown [Χ2=4.09, p=.043].

Conclusion

Compared to first lockdown, feelings of loneliness, anxiety, worries for faster cognitive decline and depressive feelings increased in second lockdown. A noticeable part of (pre‐)dementia patients and caregivers report feelings of loneliness, worries for faster cognitive decline, psychological and behavioral problems in second lockdown. These psychosocial effects are more frequently reported by caregivers than patients.
Glucose metabolism changes in cerebellar tonsils as an early predictor of cognitive decline
Authors: Dartora Caroline Machado , Koole Michel , da Silva Ana Maria Marques
Published: February 2022

Background

Mild cognitive impairment (MCI) is associated with an increased risk of dementia, but imaging biomarkers are not clearly related to the likelihood of developing cognitive decline. This preliminary study aims to investigate the brain glucose metabolic PET imaging patterns in subjects that are cognitively unimpaired older adults (CUI) and those who convert to MCI within two years.

Method

CUI subjects with 18F‐FDG PET and MR images were selected from the ADNI study. Two groups were separated in our research: (i) 36 stable CUI subjects during a minimum of 5 years; (ii) 12 subjects initially cognitively unimpaired (preCONV) that convert to MCI within two years (posCONV). Static 18F‐FDG PET images were co‐registered with the correspondent MR image and normalized to MNI space with an 8 mm Gaussian filter. A normalized whole‐brain (WB) mask was determined. Each PET was normalized by its WB mean value. Image analysis was performed using SPM 12, with proportional scaling and age‐corrected. Groups have no difference in age (79.5±5)y and years of education (15.8±3)y. Brain glucose hyper‐ and hypometabolism were evaluated between groups (CUI versus preCONV, CUI versus posCONV) and longitudinally (preCONV versus posCONV).

Result

The cluster analysis (p(unc)≤0.001) of CUI subjects when compared to preCONV shows brain glucose hypometabolism in the cerebellar tonsil and putamen regions, and infero‐medial temporoparietal lobe, and hypermetabolism in the left parietal and right temporal and frontal lobes. CUI shows hypometabolism compared to posCONV in regions of the left and right cerebellar tonsil, culmen, frontal lobe, Brodmann Area (BA) 6 and midbrain, and hypermetabolism in the parietal lobe, including the precuneus and BA39. No differences are found between preCONV and posCONV.Just hypometabolism in cerebellar tonsil in CUI compared to preCONV and posCONV survived correction for multiple comparisons (cluster p(FWE)≤0.05), showing a possible involvement in the cognitive decline beginning. Recent evidence suggests the cerebellum's involvement in the regulation of cortical areas associated with cognition as an abnormal structure in cingulo‐cerebellar circuitry (Walsh K., PARKER, K.L., 2018).

Conclusion

Beyond brain regions of altered glucose metabolism in cognitive decline like parietotemporal regions, cerebellar tonsil shows changes that could indicate early conversion of cognitively unimpaired older adults to MCI.
The troubles and needs of family caregivers of older adults with moderate to severe dementia
Authors: Leng Minmin
Published: February 2022

Background

To investigate the troubles and needs of family caregivers of older adults with moderate to severe dementia.

Method

A total of 401 family caregivers from Beijing, Tianjin and other regions were recruited to complete a self‐designed questionnaire.

Result

The top 5 safety risks among older adults with moderate to severe dementia were irritating cough (30.2%), falls (28.4%), outreach (27.2%), lost (19.0%), and fall of bed (12.2%). The main troubles reported by family caregivers were daily care (82.5%) and coping with psychological and behavioral problems (51.9%). The top five support needs were instruction on psychological adjustment skills (88.5%), skills to cope with psychological and behavioral problems (75.8%), daily care skills (73.1%), safety risk prevention skills (72.8%), case management and referral services (70.8%). The top five ways to access support services were online training (86.5%), online counseling (86.0%), face‐to‐face counseling (84.0%), handbooks (78.8%) and community‐based lectures (74.6%).

Conclusion

Family caregivers have a variety of needs in the long‐term care of older adults with dementia. It is suggested to establish a needs‐led care support service system for family caregivers that integrates skills instruction, education and training and care services by online and off‐line approaches.
Cross‐sectional comparison of psychosocial and executive function outcomes between low and high adherers of the MIND diet in a sample of middle‐aged Latinos
Authors: Soto Yuliana , Guzman Jacqueline , Aguiñaga Susan
Published: February 2022

Background

It is estimated the number of Latinos with Alzheimer’s disease (AD) will reach 3.5 million by 2060.1 Evidence suggests that lifestyle factors, such as adhering to diets like the Mediterranean‐type diet and the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet may be associated with lower risk of AD2, improved cognition3, and better psychosocial outcomes.4 The purpose of the present study was to compare psychosocial outcomes and executive function (EF) between low and high adherers of the MIND diet in middle‐aged Latinos.

Method

A cross‐sectional study was conducted to assess MIND diet adherence, cognition, and psychosocial outcomes of middle‐aged Latinos. The MIND Diet consists of 15 food groups, 10 healthy food items and 5 unhealthy food items. Adherence to the MIND diet was assessed using the 114‐item Block 2005 Food Frequency Questionnaire.5 Frequency of consumption of each food item was assigned a score of 0,.5, or 1, scores ranged between 0‐15. MIND diet scores were dichotomized between low‐adherers (< 8.5) and high‐adherers (≥ 8.5). NIH Toolbox was used to assess psychosocial outcomes (stress, depressive symptoms, general life satisfaction, and loneliness). EF was measured as a composite score of the Trail Making6, Stroop7, Symbol Digit Modalities8, and word fluency9 cognitive tests. One‐way analysis of variance (ANOVA) was conducted to compare psychosocial outcomes and EF between low and high adherers.

Result

Data from 61 participants (Mage=58.6±8.7, MMMSE=27.93 ±2.28, 67% female) indicates that high‐adherers self‐reported significantly higher general life satisfaction (F[1,58] =11.16, p=.001, MSE=382.05, η
2=0.19) and lower stress levels (F[1,58]=3.88, p=.05, MSE=146.25, η
2=0.06). However, no significant differences between low and high adherers were detected for depressive symptoms, loneliness, or EF.

Conclusion

Findings suggest that middle‐aged Latinos adhering to the MIND diet exhibit lower levels of stress and higher general life satisfaction. However, no difference was detected in depressive symptoms and EF. Future interventions should consider culturally‐tailoring the MIND diet to increase adherence and acceptability of it to improve psychological distress and cognitive function among middle‐aged Latinos to reduce the risk of AD.
Association between cancer treatment and progression of all‐cause dementia
Authors: Fowler Mackenzie E , Kennedy Richard E , Wright Nicole C , Irvin Marguerite R , Triebel Kristen L , Rocque Gabrielle B
Published: February 2022

Background

Cancer treatments have been associated with cancer‐related cognitive impairment (CRCI). CRCI exhibits symptoms similar to those experienced with dementia syndromes, and could result from the cancer itself or as a consequence of cancer therapies. No studies have examined the potential effect of cancer treatments on cognition in dementia.

Method

Electronic health record data from the University of Alabama at Birmingham were extracted July 2003 to February 2020. Baseline cognition and cognitive progression on the Alabama Brief Cognitive screener (ABCs) among dementia patients based on receipt of various cancer treatments were evaluated using adjusted linear mixed effects models.

Result

Hormone therapies were associated with faster decline on the ABCs compared to other treatments (b: ‐1.39, 95% CI: ‐2.73, ‐0.04). Similar results were seen for hormone therapies compared to neither hormone nor immunotherapy (b: ‐1.55, 95% CI: ‐3.02, ‐0.08). No cognitive differences were detected for other cancer treatments.

Conclusion

Hormone therapies may lead to faster cognitive decline in cancer survivors who develop dementia later in life. Larger studies of long‐term effects of cancer therapies are needed to allow for stratification by cancer type and cancer staging and evaluate modification by race and socioeconomic status.
Altered brain functional connectivity and cardiovascular and metabolic risk factors in middle‐aged and older adults
Authors: Rashid Barnaly , Schwab Nadine A. , Carlyle Becky C. , Terpstra Melissa , Bookheimer Susan Y. , Ances Beau M. , Salat David H. , Arnold Steven E.
Published: February 2022

Background

Metabolic and cardiovascular dysfunction accelerates biological aging and increases risk for many diseases, including Alzheimer's disease (AD) and AD‐related dementias (ADRD). The cumulative negative effects that the body and brain sustain due to the exposure to metabolic (e.g., insulin resistance, dyslipidemia), cardiovascular (e.g., blood pressure), and immune (e.g., C‐reactive protein) risk factors (i.e., MCI‐RFs) have been associated with increased vulnerability to cognitive decline later in life. This project examined whether the functional connectivity (FC) measures of core brain networks are altered due to MCI‐RFs, and how such alterations may relate to cognitive functioning.

Method

Resting fMRI scans were collected in 217 participants (aged 36‐90+ years) of the Human Connectome Project Aging study, and preprocessed using FreeSurfer’s standard stream. Using a seed‐based approach functional maps of the default mode network (DMN), amygdala, and hippocampus seeds were created. The vertex‐wise partial correlation (i.e., FC) measures to the seeds (i.e., correlation between mean seed time series and all other brain voxels’ time series, later transformed onto cortical surface) were computed and used for further group‐level analyses. Connectomes were evaluated in relation to a MCI‐RF index (higher index score corresponds to greater risk) including measures of body mass index, insulin and glucose, lipids, blood pressure, renal function, nutritional parameters and C‐reactive protein. Cognition was assessed using a multi‐domain composite index (CCI) encompassing aspects of general cognition, memory, processing speed, and executive functioning.

Result

With increasing age, all three networks showed reductions in network integrity with loss of both within‐network and between‐network functional connections in regions outside of the task‐positive network hubs. After correcting for age effects, associations between FC and MCI‐RF index were mostly observed in the DMN and amygdala. Increased MCI‐RF was associated with reduced negative connectivity (i.e., loss of between‐network connections) in amygdala map, suggesting less regulated networks. Associations with CCI were observed across all three networks’ FC maps but mostly in the amygdala.

Conclusion

Our findings suggest that MCI‐RFs impact brain network organization, and that connectivity in the amygdala network might be a key to the interface between metabolic, cardiovascular and immune dysfunction and cognition.
Synaptic PET imaging using [11C]UCB‐J in frontotemporal dementia
Authors: Clarke Mica TM , Mansur Ayla , Rizzo Gaia , Passchier Jan , Lewis Yvonne , Evans Karleyton C , Chen Laigao , Schwarz Adam J. , Takano Akihiro , Gunn Roger N , Cash David M , Rabiner Eugenii A. , Rohrer Jonathan D ,   MINDMAPS Consortium
Published: February 2022

Background

A number of pathophysiological mechanisms are associated with neurodegeneration, including synaptic dysfunction and/or loss. Novel radiotracers which enable the quantification of synaptic proteins in vivo have not previously been explored in frontotemporal dementia (FTD). We used [11C]UCB‐J PET to measure the density of synaptic vesicle protein 2A (SV2A) in FTD.

Method

Six participants with behavioural variant FTD (mean age 61.8, SD 5.4) and 17 cognitively normal participants (63.7, 12.5) underwent 90‐minute dynamic acquisition PET scans following injection of [11C]UCB‐J, with metabolite corrected arterial input function. Thirteen regions of interest (ROIs) were defined on individual MR images using the CIC anatomical atlas. Regional density was evaluated using the regional VT normalised to the VT in the centrum semiovale (DVR‐1). Groups were compared using Mann‐Whitney tests with Bonferroni correction for multiple comparisons. W‐scores were computed from the 17 controls, with age and gender as covariates, to compare the magnitude of group differences in regional volumes versus [11C]UCB‐J distribution. Volumes were expressed as a percentage of total intracranial volume. A w‐score of <‐1.65 was considered abnormal.

Result

We found significant reductions in regional density of SV2A in FTD compared to controls in multiple cortical and subcortical regions: frontal, temporal, parietal, insula, anterior cingulate and posterior cingulate cortices (all 0.001), as well as the hippocampus, amygdala, thalamus and cerebellum (all 0.001). The w‐score analysis revealed significant reductions in SV2A density in FTD in all 13 ROIs, with the greatest reduction in the anterior cingulate (‐4.2), and in volume in 8 ROIs, with the greatest reduction in the temporal lobe (‐6.4). The magnitude of SV2A density loss was greater than the magnitude of volume loss in most ROIs (9/13), and there was more variability in the reduction in volume than there was in SV2A density (SD range [11C]UCB‐J 0.7‐2.1, volume 1.4‐3.9).

Conclusion

Significant reductions in [11C]UCB‐J distribution indicate reduced synaptic density in disease‐relevant regions in FTD, which surpass reductions in volume. This suggests that [11C]UCB‐J PET imaging could be a sensitive biomarker of synaptic dysfunction in FTD, with future studies focused on its relationship with symptoms and whether it becomes abnormal before symptom onset.
Synaptic density is associated with cognitive performance in Alzheimer’s disease: A PET imaging study with [11C]UCB‐J
Authors: van Dyck Christopher H. , Sharp Emily , O'Dell Ryan S. , Banks Emmie R. , Bartlett Hugh H. , Chen Ming‐Kai , Naganawa Mika , Toyonaga Takuya , Harris Joanna E. , Ni Gessica S. , Zhao Wenzhen , Nabulsi Nabeel B. , Wyk Brent C. Vander , Huang Yiyun , Arnsten Amy F. T. , Carson Richard E. , Mecca Adam P.
Published: February 2022

Background

For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer’s disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy in limited brain regions, largely at the moderate to severe stages of disease. With the recent advent of synaptic positron emission tomography (PET) imaging, we have begun to evaluate synaptic alterations in vivo. In this study we examined the relationship between synaptic density and cognitive performance in early AD using [11C]UCB‐J PET and an extensive neuropsychological test battery.

Method

Using [11C]UCB‐J binding to SV2A, synaptic density was measured in 45 amyloid positive participants with AD (17 amnestic mild cognitive impairment and 28 mild dementia) and 20 amyloid negative cognitively normal (CN) participants aged 50‐85 years. Synaptic density was calculated as the distribution volume ratio (DVR) in a composite region of interest (ROI) of AD‐affected regions (prefrontal, lateral temporal, medial temporal, lateral parietal, anterior cingulate, posterior cingulate, precuneus, and lateral occipital) using cerebellum as reference region. A neuropsychological test battery assessed performance in five cognitive domains. Domain scores were generated for each AD participant by averaging z‐scores within the domain, and global cognitive scores averaged the domain scores.

Result

In a multiple linear regression model controlling for age, sex, and education, synaptic density ([11C]UCB‐J DVR) was a significant predictor of global cognitive performance in participants with AD (β=3.21, η2=0.29, P=0.0001; Figure 1A), as well as Verbal Memory (P=0.022; Figure 1B), Language (P=0.001; Figure 1C), Executive Function (P=0.001; Figure 1D), Processing Speed (P=0.001; Figure 1E), and Visuospatial Ability (P=0.001; Figure 1F). The association between synaptic density and global cognition survived partial volume correction (PVC; β=2.16, η2=0.23, P=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume. Figure 2 shows correlation maps of global cognitive performance with regional synaptic density (DVR; without and with PVC) and gray matter volume.

Conclusion

These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.
Peak alpha frequency and N200 latency as predictors of neuropsychological performance in a memory disorders clinic
Authors: Marin Anna , Lahdo Naheer C. , Schiloski Kylie A. , Hajos Gabor P. , DeCaro Renee , Vives‐Rodriguez Ana , Budson Andrew , Turk Katherine W.
Published: February 2022

Background

Electrophysiological measures including alpha peak power and frequency, and N200 latency are potential biomarkers of Alzheimer’s Disease (AD) pathology. It is still unclear how these measures can be used in clinical settings to better diagnose AD and differentiate it from other cognitive neurodegenerative disorders. As an initial step towards better understanding clinical utility of electrophysiological measures within a dementia population, this study aims to determine how alpha and gN200 measures can help predict neuropsychological status among an heterogenous sample of patients from memory disorders clinic.

Method

Data was collected using a seven electrodes COGNISION™ rig. Older veterans with memory complaints aged 50‐100 were recruited from a memory disorders clinic at the VA Boston Healthcare system (N= 185) with a MMSE score of 13 and above. EEG/ERP data was recorded while participants completed a three‐tone auditory oddball task. Participants who failed an audiometry screening test and those with a BPA below 35% were excluded. All subjects were administered a neuropsychological battery to assess degree of cognitive impairment. Amyloid PET results were also available for a small subset of subjects (N=49).

Result

Linear regressions were computed for all cognitive measures that correlated with alpha peak frequency and N200 latency. Alpha peak frequency is a significant predictor of encoding (p=0.048) and delayed recall (p=0.014) in the CERAD list learning task, and of verbal category fluency (p=0.033). N200 target latency is a significant predictor of number of intrusions (p=0.0379) of the CERAD recognition task, and of Trails Making Test A (p=0.006) and B (p=0.048) time. Alpha peak frequency is also associated with amyloid PET status (p=0.040) using logistic regression.

Conclusion

Alpha peak frequency and N200 latency are useful predictors of cognitive status, especially of memory and executive function, among a memory disorders population. Alpha peak frequency is also an important factor in the prediction of amyloid PET status. Overall, alpha peak frequency and N200 latency represent a novel tool to better assess memory disorders patients, and characterize the cognitive profile of their underlying pathology in an heterogenous clinical setting.
Despite heightened risk of cognitive decline, no evidence of local atrophy in people with subjective cognitive decline compared to normal controls in ADNI
Authors: Morrison Cassandra , Dadar Mahsa , Shafiee Neda , Collins Louis
Published: February 2022

Background

People with subjective cognitive decline (SCD) are at increased risk for developing Alzheimer’s disease (AD). SCD may thus be a very early clinical manifestations of AD. However, identifying which individuals with SCD will develop AD is difficult with current biomarker techniques. To predict whether someone with SCD will progress to AD, it is necessary to determine whether people with SCD display neurodegeneration in brain regions associated with AD.

Method

We included 1769 baseline and follow‐up MRI scans for 447 participants (177 normal controls, NC; 100 SCD; and 170 early mild cognitive impairment, eMCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). All scans were pre‐processed through a previously validated pipeline. Deformation‐based morphometry (DBM) was performed to examine the pattern of volumetric change over time. An atlas‐based approach was also used to examine mean volume differences for regions of interest (ROIs; lateral ventricles, entorhinal cortex, and amygdala from CerebrA atlas (Manera et al., 2020)) estimated by integrating the Jacobian of the deformation field within the ROI. A previously validated MRI analysis method (SNIPE) was used to determine volume and grading of the hippocampus (Coupe et al., 2012). We applied a linear mixed effects model for all analysis (volume ∼Diagnostic Group +Age +Sex +Amyloid Positivity +APOE e4 +Education +1|ID).

Result

Longitudinal volume analysis showed slight atrophy in eMCI compared to NC and SCD. ROI analysis revealed that eMCI had smaller volumes than SCD and NC in the amygdala (NC & SCD: p<.001) and entorhinal cortex (NC: p<.001; SCD: p=.01), and larger lateral ventricles (NC & SCD: p=.01). SNIPE volume and grading analysis revealed that eMCI hippocampal volume differed from both NC and SCD (p<.001). SCD and NC did not differ in any of the analyses. With respect to demographics, people with SCD had 2 years more education (p<0.001) than eMCI and NC.

Conclusion

The structural differences observed in eMCI may act as an early biomarker for AD. Although SCD participants’ brain volumes significantly differed from eMCI, they did not differ from NC. However, lack of SCD:NC differences may be due to confounds (e.g., greater education in SCD) within the sample.
The role of the hippocampus in mediating cognitive impairment in cerebral amyloid angiopathy
Authors: Perosa Valentina , Zotin Maria Clara Zanon , Schoemaker Dorothee , Sveikata Lukas , Etherton Mark , Charidimou Andreas , Greenberg Steven M. , Viswanathan Anand
Published: February 2022

Background

The interplay between cerebrovascular and Alzheimer’s pathology has an important role in the development of cognitive impairment1. Vascular risk factors and neuroimaging markers of cerebral small vessel disease (CSVD), have well been characterized in patients with Alzheimer’s disease (AD) in the past years2,3. Conversely, few studies asked how hippocampal neurodegeneration, a benchmark of AD, relates to cognition in CSVD patients4.

Method

We set out to investigate the relation between hippocampal neurodegeneration and cognition in a memory clinic cohort of 101 (75.8 ± 6.7 y, 58 F) patients with possible and probable cerebral amyloid angiopathy (CAA), a common CSVD form with defined diagnostic criteria. Linear regression models were used to assess the associations between the volume of hippocampal subfields and cognitive measures. Neuroimaging markers of CSVD were subsequently included in the analyses, to evaluate how they mediate the relation between cognition and hippocampal neurodegeneration.

Result

We found a significant positive association between CA1 volume and cognitive domains (memory: b=0.14, p=0.008; processing speed: b=0.15, p=0.03; language: b=0.14, p=0.03; executive function: b=0.20, p=0.01). CA1 volume was significantly related to memory and executive function, even when accounting for neuroimaging markers of CSVD. Furthermore, presence of cortical superficial siderosis and peak width of skeletonized mean diffusivity (PSMD), a measure of white matter (WM) integrity, were negatively associated with hippocampal and subfields’ volumes.

Conclusion

These results suggest that neurodegeneration of CA1 is related to cognitive impairment in CAA patients, and may further support established links between vascular pathology and loss of CA1 integrity and/or overlap of AD pathology in these patients5‐7. Moreover, further studies exploring the relationship between WM and hippocampal integrity may be warranted.
Comparison of neuronal activity profiles in Alzheimer’s disease and frontotemporal dementia measured by resting‐state fMRI
Authors: Haddad Seyyed Mohammad Hassan , Scott Christopher J.M. , Arnott Stephen R. , Ozzoude Miracle , Strother Stephen C. , Black Sandra E. , Borrie Michael , Finger Elizabeth , Trataglia Maria Carmela , Kwan Donna , Beaton Derek , Symons Sean , Soddu Andrea , Menon Ravi S. , Montero‐Odasso Manuel , Bartha Robert
Published: February 2022

Background

Neuronal activity (NA) and metabolism are impaired in the early stages of Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) leading to specific patterns of cognitive decline. Detailed disease models elucidating how and where in brain these NA disturbances commence and how they gradually progress remain incomplete. Recently, we introduced several NA metrics quantified based on fluctuations of the resting‐state fMRI (rs‐fMRI) signal. NA was significantly lower in AD and mild cognitive impairment compared to normal elderly controls (NEC). Here we extend this work using the most sensitive metric to examine NA profile differences between people with AD and FTD.

Method

3T MRI rs‐fMRI data (TR=∼2.4 Sec, 250 volumes) were obtained from the Ontario Neurodegenerative Disease Research Initiative (AD group: N=40, aged 71.8 ± 8.1, 42% female; and FTD group: N=50, aged 67.8 ± 7.3, 36% female), and Gait and Brain Study (NEC group: N=46, aged 71.0 ± 5.5, 33% female). The rs‐fMRI signal was pre‐processed and decomposed into independent components (ICs) using IC analysis. The ICs were classified into neuronal and non‐neuronal sources using a support vector machine classifier. Voxelwise NA was quantified based on the magnitude of neuronal ICs in the rs‐fMRI signal composition. This metric was utilized to create resting‐state NA maps in each subject, which were compared between groups voxel by voxel using a multiple comparisons permutation test (MCPT) with 1000 permutations.

Result

Group average NA maps are provided in Fig. 1. Average NA was lower in FTD (24%) and AD (40%) compared to NEC. There was a significant difference (adjusted p‐values from MCPT) between NEC and FTD (p<0.001), NEC and AD (p<0.001), and FTD and AD (p<0.05). Difference NA maps comparing the groups and associated significance maps are shown in Fig. 2. The FTD group had significantly higher NA compared to AD in ∼53% of brain voxels (Fig. 2).

Conclusion

Significantly lower NA was detected in AD and FTD compared to NEC. Localized significant NA differences between AD and FTD were detected emerging mostly as clusters in occipital and subcortical areas that are known to be less affected by FTD.
Differences in emotional health across cognitively normal adults and with mild cognitive impairment and Alzheimer’s disease: Results from the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study
Authors: Zhang Manrui , Ho Emily , Nowinski Cindy , Fox Rina , Novack Miriam , Dodge Hiroko H , Weintraub Sandra , Gershon Richard
Published: February 2022

Background

Changes in emotional health are common both as part of typical aging and for individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Thus, there is a critical need to identify differences in emotional functioning between adults with and without cognitive impairment. In the current study, we explore whether the NIH‐Toolbox Emotional Battery (NIHTB‐EB), a set of validated, reliable, and efficient measures of emotional functioning, can be used to potentially detect differences in emotional functioning across older adults with varying levels of cognitive impairment.

Method

Data were drawn from a longitudinal, multi‐site study ‐ the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA). Participants were recruited from 11 existing cohorts nationwide, and included 1) cognitively normal (NC) adults (N=276), 2) individuals with MCI (N=103), and 3) individuals with AD (N=69); Mage= 78 (SD = 8.25); 53.2% were female. Baseline emotional health was assessed from 2019 to 2020 using NIHTB‐EB. Univariate and ANCOVA analyses tested differences in a variety of emotion dimensions across three groups, adjusting for important covariates, and post‐hoc Tukey pairwise comparisons were performed.

Result

Controlling for age, gender, marital status, and education, a significant main effect of clinical group was found on measures of sadness, fear‐affect, anger‐physical aggression, loneliness, self‐efficacy, and the negative affect composite score [all ps<0.05; see Figure 1]. Tukey post‐hoc pairwise comparison showed MCI and NC differed in negative affect (diff=4.18), sadness (diff=3.08), and anger‐physical aggression (diff=3.08); and AD and NC differed in negative affect (diff=3.65), anger‐physical aggression (diff=4.60), loneliness (diff=3.95), sadness (diff=4.60), and self‐efficacy (diff=‐3.18) [all ps < 0.05; Figure 1].

Conclusion

Individuals with MCI and AD reported higher levels of negative emotions and a lower level of self‐efficacy than normal controls. Based on a comprehensive set of emotional functioning measures, these findings extended our understanding of how older adults with and without cognitive impairment differ on aspects emotional functioning essential to quality of life. Importantly, we found that the NIHTB‐EB is a useful tool to assess and differentiate emotional health outcomes among cognitively normal adults as well as those with MCI and AD diagnoses.
Relationships among socioeconomic factors, quality of life, family stigma and psychological outcomes in family caregivers of patients with early onset Alzheimer disease due to E280A‐PSEN1 mutation and frontotemporal dementia in Antioquia‐Colombia
Authors: Velilla Lina M , Acosta‐Baena Natalia , Calle Andres , Allen Isabel Elaine , Lopera Francisco , Kramer Joel H
Published: February 2022

Background

Caregiving itself does not lead to adverse psychological outcomes, burden, stigma, and/or quality of life reduction but socioeconomic factors have been hypothesized as risk factors among dementia caregivers. We aimed to analyze the associations between socioeconomic factors and type of dementia as potential predictors of family stigma, Quality of life (QoL.), depressive symptoms, anxiety, and caregiver burden

Method

We assessed 151 family caregivers distributed as early‐onset Alzheimer disease group (EOAD), frontotemporal dementia (FTD), and late‐onset dementia group (LOAD) for comparative means. Participants underwent questionnaires about family stigma, caregiver burden, depression, anxiety, QoL., and a questionnaire to explore socioeconomic factors. We performed a multivariable regression model with socioeconomic factors and the group as predictors. We included age, education, patient’s clinical‐stage, and behavioral changes as covariates.

Result

Being a caregiver of an FTD patient reduced physical functioning (β=‐13,5 p=0,018), working part‐time increased physical functioning (β=22,1 p=0,032) while working from home increased general health (β=22,4 p=0,028). The perception of living in a safe neighborhood reduced role limitation due to emotional problems (β=46,2 p=0,013). The perception of financial problems related to patients' care or disease cost increased the role limitation due to emotional problems (β=‐29,8 p=0,007). The caregiver burden increased together with the perception of financial problems related to patient's care or disease cost (β=13,9 p<0,001) and was mediated by patient’s behavioral changes (β=0,47 p<0,001). Family stigma is increased by the perception of financial problems related to patient's care or disease cost (β=0,31 p=0,013) and was mediated by the caregiver’s education (β=0,04 p=0,026) and patient’s behavioral changes (β=0,10 p=0,001). Depression increased by the perception of financial problems related to patient's care or disease cost (β=2,01 p=0,033) and the mediation of patient’s behavioral changes (β=0,06 p=0,015).

Conclusion

Socioeconomic factors can predict disturbances in QoL. among dementia caregivers. Education, being an FTD caregiver, and patient’s behavioral changes mediated among socioeconomic factors and negative psychological outcomes. When a caregiver may have low education and is caring for a patient with FTD and/or behavioral problems the risk of negative outcomes and family stigma increases significantly.