bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluid biomarkers of Alzheimer’s disease in the Systolic Blood Pressure Intervention Trial
Authors: Pajewski Nicholas M , Elahi Fanny M , Ix Joachim H , Nasrallah Ilya M , Reboussin David M , Tamura Manjula Kurella , Wright Clinton B , Hinman Jason , Miller Lindsay M , Sudduth Tiffany L , Wilcock Donna M , Williamson Jeff D
Published: December 2020

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive treatment (systolic blood pressure (SBP) target <120 mm Hg) reduces the risk for mild cognitive impairment and slows the progression of white matter lesions detected via magnetic resonance imaging (MRI) as compared to standard treatment (SBP<140 mm Hg). However, it is unclear what pathway(s) mediate this effect.

Method

We measured plasma beta‐amyloid 40 (Aβ40), beta‐amyloid 42 (Aβ42), total tau, and neurofilament light (NfL) at baseline and during follow‐up (median follow‐up = 3.8 years) in a subgroup of participants 60 years or older that also participated in SPRINT’s MRI imaging substudy (N=542). We modeled changes in each AD biomarker using robust linear mixed models.

Result

The average baseline age of this subgroup of SPRINT participants was 69.8 ± 7.1 (standard deviation) years; with a mean SBP of 138.2 ± 17.0 mm Hg; and 42.1% were female. At baseline, the strongest plasma biomarker correlations were with age (Spearman’s rho = 0.27 for Aβ40 and 0.43 for NfL, both P<0.001) and estimated Glomerular Filtration Rate (eGFR; rho ranged from –0.21 for Aβ42 to ‐0.42 for NfL, all P<0.001). We observed larger increases in each AD biomarker for participants that experienced ≥30% decline in eGFR during follow‐up, which occurs more frequently with intensive treatment. There were no significant between‐group differences for Aβ40, Aβ42, or total tau, however intensive treatment was associated with larger increases in NfL during follow‐up (mean change per year (MCPY) = 2.6 pg/ml, 95% CI: 1.8‐3.3), as compared to standard treatment (MCPY = 1.6 pg/ml; 95% CI: 1.3‐1.8). This difference was explained by changes in eGFR (between‐group difference in MCPY adjusting for eGFR = 0.04 pg/ml; 95% CI: ‐0.76 ‐ 0.84).

Conclusion

In this pilot study of SPRINT participants, after accounting for kidney function, intensive treatment was not associated with significant changes in fluid biomarkers of AD. Our results highlight the need for future studies of blood‐based AD biomarkers to account for renal function, especially within the context of hypertension and vascular disease.
The role of ABI3 in human induced pluripotent stem cell‐derived microglia
Authors: Rolova Taisia , Zhang Fuping , Koskuvi Marja , Koistinaho Jari
Published: December 2020

Background

Microglia are the main immune cells of the central nervous system clearing invaded pathogens, damaged cells and toxic aggregates, thus maintaining tissue homeostasis. However, in Alzheimer’s disease (AD), microglia do not perform their job that well anymore. Recent genome‐wide association studies (GWAS) have strongly implicated microglia in AD pathogenesis. One of the genetic variants recently identified is rs616338/p.S209F in ABI3 gene (OR 1.43), which is stronger expressed in microglia than other types of brain cells. ABI3 (ABI family member 3) is a structural component of WAVE2 complex known to regulate formation of lamellipodia, membrane ruffling and phagocytosis. However, the role of ABI3 and its functional difference from a similar protein ABI1 in microglia is not clear.

Method

We have used CRISPR/Cas9 technique to generate a knockout iPS line (ABI3 KO) producing truncated protein that lacks Src‐homology 3 domain crucial for the regulation of actin remodeling. We have further differentiated ABI3 KO line and the original isogenic control line (WT) into microglia according to the previously published protocol of McQuade et al (2018).

Result

We have found that ABI3 KO microglia exhibited significantly lower uptake of zymosan‐conjugated pHrodo beads, lower expression level of scavenger receptor MSR1 and higher expression level of glucose transporter SLC2A1 as compared to the WT control. ABI3 KO cells were also significantly less responsive to ADP in Transwell migration assay although the mRNA expression of P2RY12 receptor was higher in the KO cells. The protein level of WAVE2 was similar but the level of ABI1 was strongly increased in ABI3 KO cells suggesting a compensatory effect. ABI3 deficiency did not significantly affect secretion of Aβ42, phosphorylation of TAU at Ser214 and phosphorylation of APP at Thr668 in co‐culture with human iPS‐derived neurons harboring Swedish mutation in APP.

Conclusion

In conclusion, ABI3 deficiency in microglia significantly impaired phagocytosis and ADP‐induced migration but did not have an effect on AD‐like pathology in co‐culture with diseased iPS‐derived neurons.
Quality of life of informal caregivers for elderly people with dementia: A comparative study
Authors: Laranjeira Carlos
Published: December 2020

Background

The provision of informal care to the elderly with dementia, presenting a complex, demanding nature and with evident repercussions, affects the health, Well‐being and Quality of Life of the informal caregiver (CG). Thus, the main aim of this study was to assess the Quality of Life and Subjective Well‐being of informal caregivers of demented (non‐institutionalized) elderly, through two contrasting groups: Group A, of CG of elderly with little dependence diagnosed with mild dementia; and Group B, of CG of elderly dependents diagnosed with severe dementia.

Method

This was a quantitative, cross‐sectional and comparative study design. The initial sample consisted of 65 informal caregivers of the elderly with a confirmed diagnosis of dementia. Information was collected regarding demographic characteristics and diagnosis; the functional capacity of the elderly in activities of daily living (Barthel Index); the global cognitive judgments of satisfaction with one's life (SWLS); and finally, the levels of Quality of Life (WHOQOL‐BREF).

Result

69% of the participants are female, aged between 53 and 89 years old (M=66.5; SD=9.4), being mostly elderly (59.7%) and with low levels of education. Male CG have a slightly more positive perception of the general facet of Quality of Life and the environment domain, compared to the female CG. The results obtained indicate that informal caregivers belonging to Group A have a more positive perception of Quality of Life and Subjective Well‐Being, compared to informal caregivers who constitute Group B, in all domains.

Conclusion

The profile of informal caregivers who make up the samples of the two groups under analysis is similar to that reported by studies researched in the existing literature. It should be noted that the multidisciplinary intervention model is basic, involving several health professionals who direct action plans according to the specific needs of demented elderly and their CG, covering all levels of care and biopsychosocial needs.
Support‐staging model for caregivers of adults with intellectual disability affected by dementia
Authors: Jokinen Nancy , Service Kathryn , Marsack‐Topolewski Christina , Janicki Matthew
Published: December 2020

Background

Adults with intellectual disability (ID) and dementia are a sub‐population of persons who are often un‐ or underserved. Most adults with ID are integrated within the general community (living autonomously, or in apartments/group residences); but significant numbers also reside with their families, particularly adults with Down syndrome. Family help/counseling approaches, such as the New York University‐Caregiver Intervention (NYUCI), might benefit from a support‐staging model assessment focus on what specific aid a family requires to meet their needs. Patterns of such needs have been identified that can help with providing dementia‐capable care. Objective needs include: (a) information on signs and symptoms, (b) diagnostic advice, (c) understanding behavioral changes and managing dementia‐related behaviors, (d) adapting homes, (e) determining daily routines most conducive to calming, (f) planning for the future, (g) finding and navigating resources, and (h) responding to end‐of‐life needs. Subjective needs include: (a) being informed at time of diagnosis and throughout the course of dementia, (b) coping with a profound sense of loss from knowing the diagnosis, (c) fearing the future [including financial concerns], (d) formulating long‐term plans, (e) accessing community‐based coordinated care, (f) facing difficulties from the medical community, (g) feeling overwhelmed by caregiving demands, (h) feeling a sense of isolation and abandonment, and (i) facing end‐of‐life issues. A working group emanating from the 2016 Glasgow Summit on Intellectual Disability and Dementia organized a schema encapsulating these concerns into a support‐staging model. The schema suggested four fluid stages: Diagnostic (seeking cause of changes in function, abilities, personality), Explorative (exploring dementia capable interventions), Adaptive (coping with and managing the symptoms/changes), and Closure (resolving / relief from responsibilities). Using this schema, a process (utilizing the NYUCI) is underway to operationalize a support‐staging assessment instrument which would enable counseling staff to frame the state of a family’s concerns, build relationships through this knowledge of the caregiver and provide tailored services to them. The outcome will enable systematic coding and organizing both objective and subjective data so that specific interventions and counseling can be adapted to meet both intermittent and continuous caregiver needs.
Neuropsychiatric symptom burden across neurodegenerative disorders and its association with function
Authors: Kapustin Daniel , Zarei Shadi , Wang Wei , Black Sandra E. , Finger Elizabeth , Freedman Morris , Hink Heather , Kwan Donna , Lang Anthony , Masellis Mario , McLaughlin Paula , Pollock Bruce G. , Saposnik Gustavo , Strother Stephen C , Sunderland Kelly M , Swartz Richard H. , Tan Brian , Tang‐Wai David F. , Tartaglia Carmela , Turnbull John , Zinman Lorne , Rajji Tarek K. , Fischer Corinne E. , Kumar Sanjeev
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are common in neurodegenerative disorders such as Alzheimer’s disease/Mild Cognitive Impairment (AD/MCI), Parkinson’s disease (PD), Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and in those with Cerebrovascular disease (CVD). The relationship between symptoms, cognition, and function in these cohorts is unclear.

Method

Data was obtained from the Ontario Neurodegenerative Disease Research Initiative study. We used the Neuropsychiatric Inventory Questionnaire‐ severity scale (NPIQ) to measure NPS, Montreal Cognitive Assessment (MoCA) for cognition, and Lawton’s informant based questionnaires to measure basic and instrumental activities of daily living (ADLs/iADLs). Linear regression was performed to investigate the effects of NPS on ADL and iADL function while controlling for age, education and cognition. Results were bootstrapped by resampling residuals (n=1,000) to control for non‐normal sample distribution.

Result

520 participants were enrolled: AD/MCI (n=126), VCD (n=161), PD (n=140), FTD (n=53), and ALS (n=40). There were significant differences between these cohorts on NPIQ scores (AD/MCI=16.77±0.18, VCD=16.94±0.12, PD=16.34±0.17, FTD=21.44±0.15, ALS=14.19±0.22, p < .001). Across combined cohorts, NPIQ was inversely correlated with MoCA (rs=‐0.15, p=.001), iADLs (rs=‐0.32, p<.001), and ADLs (rs=‐0.34, p<.001). NPIQ (alone) predicted iADLs in FTD, and (together with MoCA) in MCI/AD and PD (Corrected p values < .05) but not in CVD or ALS. Further, NPIQ alone predicted ADLs in AD/MCI, FTD and PD (Corrected p values < .05) but not in VCD or ALS.

Conclusion

NPS burden was different across neurodegenerative disease cohorts. NPS were the main determinants of function in FTD, and in AD/MCI and PD when combined with cognition. However, NPS did not determine function in VCD or ALS. These findings indicate the need for further research into biomarkers of NPS and function, and targets of clinical interventions in neurodegenerative disorders.
Geodesic path differences in neural networks in the Alzheimer's disease connectome project
Authors: Adluru Nagesh , Nair Veena A , Prabhakaran Vivek , Li Shi‐Jiang , Alexander Andrew L , Bendlin Barbara B
Published: December 2020

Background

Neural networks derived from diffusion‐weighted MRI (DW‐MRI) may shed light on disease progression and pathology propagation in Alzheimer’s disease in vivo. In this work analysis of the path properties of such networks are presented. Geodesic or shortest paths are fundamental in understanding key network phenomenon such as the propagation rates of information, infection or pathology. For example, the ubiquitous small‐worldness property of natural occurring biological and social networks is based on having short paths between any pair of entities in the network.

Method

Connectome protocol based DW‐MRI data acquired from n=68 participants (Table 1) were analyzed. Neural networks were extracted from the data using state‐of‐the‐art image processing and tractography algorithms available in MRtrix3 (overview panel in Figure‐1). The average geodesic path lengths between frontal, temporal, parietal, occipital, subcortical regions were computed using Dijkstra algorithm. The regions were identified based on the IIT‐Desikan gray matter atlas. The paths can be used to reason about the average efficiency of communication of electrical signals or propagation of pathology between brain lobes. Statistical analysis was performed to test the geodesic path length differences between the CU, MCI and the AD groups controlling for age and sex. The path lengths were normalized so that they were at unity for the AD group, and differences were considered significant at p<=0.05.

Result

Statistical effects of consensus diagnosis on the relative geodesic path length (RGPL) differences between lobes are shown in Figure‐2. 80% of the connections showed statistically significant higher path lengths in AD compared to CU and 60% when compared to MCI. The distributions of the mean geodesic path lengths are shown in Figure‐3. For all the different pairs of lobes, the mean length was higher for the AD compared to the CU and MCI groups.

Conclusion

The path lengths between all of the major lobes are higher for the AD group compared to both the CU and MCI groups. These findings suggest that network efficiency is reduced in AD and may explain cognitive dysfunction observed in the Alzheimer’s clinical syndrome. Future work entails incorporating better constraints on tractography using structural T1‐weighted images and separating disease groups by AD‐biomarker status.
A national dementia care pathway explored and compared
Authors: Palumbo Mary Val , Rambur Betty , McKenna Lori P
Published: December 2020

Background

A national, systematic diagnosis and care pathway has the potential to alleviate pressing challenges experienced by individuals with dementia, their carers, and healthcare providers. International exemplars were sought to compare/contrast dementia care with current practice in the United States (US). Specifically, the 2013 New Zealand (NZ) Framework for Dementia Care was explored. The aim was to better understand this systematic, primary care‐led, home and community‐focused dementia management approach from the perspective of those delivering care. To better understand its potential for adoption, US providers were similarly studied.

Method

Maximum variation purposive sampling was used in this qualitative descriptive study of 28 participants (18 New Zealand, 10 United States) including providers, case managers/social workers and government officials. Following review and approval by the IRB, investigator‐developed semi‐structured interviews were used, with recruitment of participants continuing until data saturation was reached. Data were then explored for themes using qualitative content analysis, the preferred approach for qualitative descriptive design, and supported by HyperResearch. Throughout the study, qualitative research quality enhancement strategies follow the classic approach of Guba and Lincoln (1994).

Results

National standards in NZ provide a progressive pathway grounded in early primary care diagnoses and adaptable teams that foster caregiver support to decrease their burden (See Figure 1). The approach also ensures streamlined access to specialists by integrating dementia care in primary care. This is in contrast to the US, where a reactive rather than proactive approach requires providers to navigate unpredictability as they strive to weave together insufficient, inadequate, inconsistent, and inequitable resources to cobble a family’s foundation for an uncertain future.

Conclusion

Compared to the US where only 2.12% of the Medicare spend is on primary care (Bannow, 2019), NZ is grounded in a strong primary care foundation as are many of the world’s most highly functioning health care systems (Schneider, Sarnak, Squires, Shah & Doty, 2017). Individual states exploring total cost care models, do have the capacity to redesign primary care for enhanced capacity for dementia management both within practice and community settings and should take action. Further implications for translating promising practices to the US are detailed.
Clearance of seed‐dependent tau aggregation by lithium‐induced autophagy: Implications of strain‐specificity
Authors: Uddin Mohammad Nasir , Elahi Montasir , Shimonaka Shotaro , Kakuta Soichiro , Ishiguro Koichi , Motoi Yumiko , Hattori Nobutaka
Published: December 2020

Background

Tau protein aggregation is the major constituent of Alzheimer’s disease (AD) neurofibrillary tangles. Lithium, act as a drug to treat bipolar disorders, has been shown to have various neuroprotective effects including promoting autophagy and acting as an inhibitor of major tau kinase GSK‐3. Our laboratory previously reported that lithium treatment decreased the amount of insoluble tau and motor disturbance with increased LC3‐II positive puncta in tau transgenic mice (Neurobiol Dis, 2012.46). Here, we sought to examine whether lithium influences tau aggregation in different tauopathy via autophagy promotion using a seed‐dependent cell model.

Methods

SH‐SY5Y cells were transfected by C‐terminal tau fragment, Tau‐CTF24 (243‐441), and introduced AD and other tauopathy brain seeds (Progressive supranuclear palsy [PSP], Corticobasal degeneration [CBD]). After 48‐hours LiCl treatments, sarkosyl‐insoluble fractions were prepared. For Transmission Electron Microscopy (TEM), cells were cultured on 35 mm dishes and stained with 2% OsO4. Double labeled cells harboring GFP‐CTF24 and mCherry‐LC3 were established.

Results

Cells expressing Tau‐CTF24 exposed to AD seeds exhibited a profoundly decreased amount of insoluble tau accompanied with LC3‐II elevation upon treatment with 10 mM LiCl for 2 days. Electron microscopic analysis demonstrated the increase of multilamellar bodies and autophagic vacuoles (AVs). Therapeutic concentration of LiCl (0.2 ‐ 1.0 mM) also demonstrated decreased propensity of insoluble tau in a dose‐dependent manner. The number of puncta stained with both GFP‐CTF24 and mCherry‐LC3 were observed only in LiCl‐treated cell soma. An autophagy inhibitor, 3‐Methyladenine (3‐MA), antagonized LiCl effect. One of IMPase inhinbitor (L690, 330) decreased insoluble tau in cell models and subsequently decreased activity as well as elevated AVs, which mimics LiCl effcts Interestingly, the LiCl effect on insoluble tau reduction was much smaller in CBD than in AD, although reduction of aggregation by PSP is comparable with AD.

Conclusion

These results suggest that aggregated tau protein is degraded by LiCl‐induced autophagy in a strain‐specific manner, implying that the mechanism might include IMPase signaling cascade.
Local senile amyloidosis in age‐related macular degeneration and Alzheimer's disease
Authors: Ermilov Victor Vladimirovich , Dorofeev Nikita Alekseevich
Published: December 2020

Background

The development of the eye and brain from one germ layer, the community of etiopathogenetic and morphological manifestations of age‐related macular degeneration (AMD) and Alzheimer's disease (AD), the common pathway of β‐amyloid precursor protein (APP) are associated with pathological aggregation of fibrillar β‐amyloid protein (Aβ ) and the development of β‐amyloidopathy in the structural elements of the eye and brain.

Method

Using electron microscopy and selective methods for detecting amyloid and its proteins, 111 eyes with morphological signs of AMD and a brain taken from 56 corpses were examined.

Result

Our studies have shown that senile amyloidosis of the eye in combination with senile cerebral amyloidosis occurs in the eighth decade of life, and their frequency increases with age. The cumulative accumulation of β‐amyloid deposits in the structures of the eye and brain was detected in 50.6% of cases. Amyloid‐β deposits were specific for eye druses from AMD and for senile plaques in brain tissue in patients with AD (Fig. 1, 2). In AMD, amyloid deposits are most often found in the Bruch membrane (64.5%) (Fig. 3). Vascular vessels (61.2%) took second place in frequency of occurrence (Fig. 4, 5). The combination of local forms of amyloidosis was characterized by concomitant deposition of β‐amyloid in the vessels of the brain and vessels of the choroid (amyloid angiopathy), as well as in the structural elements of the back of the eye and brain with a typical histochemical characteristic of local forms of senile amyloidosis. Moreover, amyloid angiopathy was more pronounced in the vessels of the brain than in the vessels of the choroid (Fig. 6).

Conclusion

The authors demonstrated that changes in the vessels of the brain and the structural elements of the retina and choroid in patients with AMD with AD can be considered as concomitant neurodegenerative processes in these two diseases, which are based on pathological aggregation of β‐amyloid protein. This view of the problem creates the prerequisites for the development of new strategies for the creation of ophthalmogeriatric and neuroprotective drugs that affect pathogenesis and include all stages of Aβ formation and pathological aggregation.
Depression and bone loss as risk factors for decline in cognitive function: A systematic review and meta‐analysis
Authors: Mehta Kanika , Thandavan Sathya Priya , Gupta Veer Bala
Published: December 2020

Background

Several reports have postulated depression and bone loss as risk factors for dementia. However, these studies only focus on incidence of dementia as an outcome and non‐demented individuals who display prospective cognitive decline are often not included. Therefore, the present study investigates whether the presence of depression and/or bone loss among cognitively healthy individuals at baseline is associated with a decline in cognitive function (including presentation of dementia) during follow‐up assessment.

Method

The search was conducted in four databases; MEDLINE Complete, Embase, PsycINFO and CINAHL Complete on 28th November 2019. The search terms comprised 4 search blocks; Population (Adult), Exposure (Depression, Osteoporosis), Outcome (Cognitive decline) and Study design (Longitudinal). Additionally, in order to make the search comprehensive, database‐specific subject headings were incorporated in the search. The restrictions included English language, human studies and peer‐reviewed articles, however, no restriction was imposed on the publication period.

Result

The search yielded total 27,792 references and after duplicate removal 15,148 references remained. These references were subjected to ‘Title & Abstract screening’ in Covidence, a widely used web‐based platform for conducting systematic reviews. The references were screened by two independent reviewers and 380 selected studies were subjected to a full‐text review. Longitudinal studies including adult participants and with a minimum of 1 year follow‐up period were selected. Studies with cognitive impairment at baseline or studies in which the focus was on specific cognitive domains were excluded. Following the full‐text screening, data extraction and risk of bias assessment was conducted.

Conclusion

Currently, the statistical analysis is under way. The effect size will be estimated as risk ratios or standardised mean differences for binary and continuous outcomes, respectively, for both depression and bone loss using a random‐effects model.
Blood‐brain barrier insulin resistance decreases insulin uptake and increases amyloid beta uptake in Alzheimer's disease brain
Authors: Zhou Andrew L , Swaminathan Suresh K , Gali Chaitanya C , Bruinsma Tyler J , Curran Geoffry L , Sarma Vidur V , Decklever Teresa , Sharda Nidhi , Wang Lushan , Min Paul H , Lowe Val J , Kandimalla Karunya K
Published: December 2020

Background

Decreased brain insulin levels exacerbate cognitive decline in AD. Insulin in the brain is derived from systemic circulation via the blood‐brain barrier (BBB). We hypothesize that type II diabetes (T2D) sequelae and Aβ peptide exposure disrupt insulin signaling at the BBB and inhibit insulin delivery to brain. Further, we propose insulin signaling defects at the BBB contribute to Aβ accumulation in AD brain.

Methods

The following studies were performed in wild‐type (WT) mice on regular chow (RC) diet, WT mice on high fat (HF) diet (manifest insulin resistance), APP/PS1 transgenic mice on RC diet (overexpress Aβ), and APP/PS1 mice on HF diet (overexpress Aβ + insulin resistance). After femoral injection of 125I‐insulin or 125I‐Aβ42, the brain accumulation was monitored between 0‐40 min by dynamic SPECT/CT imaging. The brain influx clearance was estimated by the slope obtained from Gjedde‐Patlak graphical analysis. Cerebral microvessels were harvested, and reverse phase protein array (RPPA) was performed to examine insulin signaling changes. Differentially expressed targets were subsequently confirmed by western blot. The brain influx of 125I‐insulin and 125I‐Aβ42 were further assessed in WT‐RC mice after internal carotid infusion with AG1024, a kinase inhibitor of the insulin receptor (IR) and insulin‐like growth factor receptor (IGF‐1R).

Results

Compared to WT‐RC, 125I‐insulin influx was decreased in WT‐HF and APP/PS1‐RC, and was further decreased in APP/PS1‐HF (4.1, 3.4, 3.5 and 2.6*10‐4 mL/min, respectively). Compared to WT‐RC, 125I‐Aβ42 influx was increased in WT‐HF and APP/PS1‐RC (8.6, 28 and 23*10‐4 mL/min, respectively). RPPA analysis revealed global disruptions in BBB insulin signaling pathways. Western blots confirmed reduced expression of IR‐β, p‐AKT and p‐GSK3β in WT‐HF and APP/PS1‐RC compared to WT‐RC. Moreover, the largest decreases were observed in APP/PS1‐HF. Infusion with AG1024 was shown to decrease 125I‐insulin influx, but increase 125I‐Aβ42 influx.

Conclusions

Both T2D and AD mice exhibited decreased brain influx of insulin and increased influx of Aβ42. This was associated with altered expression/activity of insulin signaling kinases at the BBB. Further, IR and/or IGF‐1R kinase activity were shown to differentially regulate BBB trafficking of insulin and Aβ42. Thus, BBB insulin signaling is important for delivering insulin to brain and restricting pathological uptake of Aβ.
Screening peripheral biopsies for alpha‐synuclein pathology using deep machine learning
Authors: Signaevski Maxim , Prastawa Marcel , Tabish Nabil , Marami Bahram , Koenigsberg Daniel , Bryce Clare , Chahine Lana , Mollenhauer Brit , Mosovsky Sherri , Riley Lindsey , Dave Kuldip D , Eberling Jamie , Coffey Chris , Adler Charles , Serrano Geidy E , III Charles White , Koll John , Fernandez Gerardo , Zeineh Jack , Cordon‐Cardo Carlos , Beach Thomas G , Crary John F
Published: December 2020

Background

Post‐mortem assessment remains the only option and a gold standard for a definitive diagnosis of Parkinson’s disease (PD). The antemortem diagnosis is challenging due to a variable clinical presentation and the abundance of mimicking conditions, obscuring the clinical picture and delaying the treatment. It is well established that while PD pathologically manifests in central nervous system with aggregation of α‐synuclein as Lewy bodies and Lewy neurites, this pathology is also found in the peripheral nervous system. Peripheral Lewy‐type synucleinopathy (LTS) is present in early PD, suggesting its utility as a diagnostic and prognostic biomarker. We have previously confirmed that detection of LTS in submandibular gland (SMG) biopsies is sensitive (.75) and specific (.90) for early PD. However, the assessment by a neuropathologist of multiple levels of such biopsy is laborious and time‐consuming.

Method

Here work we applied two Convolutional Neural Networks (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total number of 8,386 LTS were annotated following the interrater reliability study with kappa=.7. We used transfer learning to train a CNN model to classify image patches (40‐by‐40 pixels at 20x) with and without presence of LTS objects.

Result

The trained CNNs showed the following performance on image patches: sensitivity: .982/.988, specificity: .998/.999, precision: .852/.950, accuracy: .995/.998, and F‐1 score .912/.968 for ResNet30/InceptionV4 respectively. On test WSI the sensitivity in detecting LTS was .963/.971 respectively.

Conclusion

This work is first to demonstrate the practical utility of an CNN for screening for LTS, which can further translate into a practical screening tool facilitating the antemortem diagnosis of PD. We further plan to develop neural networks for accurate and precise detection and quantification of LTS in antemortem SMG biopsies. This, altogether, would offer a screening, confirmatory, prognostic, and quantitative tool for clinical assessment of early PD.
Does loss of interaction of progranulin and prosaposin promote neurofibrillary tangle development?
Authors: Mendsaikhan Anarmaa , Tooyama Ikuo , Serrano Geidy E , Beach Thomas G , Walker Douglas G
Published: December 2020

Background

Progranulin (PGRN) and prosaposin (PSAP) have lysosomal and neurotrophic properties. Reduced amounts of PGRN in mutant tau‐expressing Alzheimer’s disease (AD) model mice exacerbated phosphorylated tau pathology. The implication of PGRN in tangle formation in AD is not understood nor the association of PSAP with AD. Both features need further research.

Method

Fixed human brain tissue sections of middle temporal gyrus (MTG) from low plaque (LP)(n=4), high plaque (HP)(n=4) non‐demented (ND), and AD (n=4) cases, and superior frontal gyrus from a presenilin‐1 mutated case and frontal temporal lobar degeneration (FTLD) cases (n=3) with heterozygous granulin mutations were employed in this study. The interaction of PGRN and PSAP was identified with proximity ligation assay (PLA). The colocalization of PGRN and PSAP with tangle was identified by fluorescent immunohistochemistry and triple‐color confocal microscopy with antibodies to phosphorylated tau (p‐tau). PGRN and PSAP fluorescence intensity was measured in p‐tau positive neurons and compared to adjacent p‐tau negative neurons.

Result

Different p‐tau positive structures were measured and related to the levels of PGRN and PSAP. Extracellular neuropil threads appeared to have no association with these proteins. Reduced levels of PGRN and PSAP were detected in p‐tau positive neurons compared to control neurons in all groups. Average levels of PGRN in control neurons were decreased as disease developed. In the AD group, reduced signals of these proteins were observed overall in neurons without p‐tau, and absent in fully matured neurofibrillary tangles. The levels of PGRN and PSAP negatively correlated with p‐tau immunoreactivity. The presenilin‐1 mutated case with numerous tangles in frontal cortex had absence of PGRN and PSAP in tangles, but colocalization of PGRN and PSAP was evident in adjacent neurons. FTLD cases showed absence of PGRN in most neurons, but continued expression of PSAP. The interaction of PGRN and PSAP in neurons was verified with a PLA assay.

Conclusion

P‐tau positive neurons had significantly less PGRN and PSAP even in the non‐demented groups, which suggests this could be an early event of tangle formation. The insufficiency of both PGRN and PSAP in neurons might lead to accumulation of p‐tau protein due to deficits in lysosomal activity.
The differentiation of new neurons is impaired in Alzheimer’s disease patients
Authors: Terreros‐Roncal Julia , Moreno‐Jiménez Elena P , Flor‐García Miguel , Llorens‐Martin María
Published: December 2020

Background

Alzheimer´s disease (AD) is a devastating neurodegenerative disorder. The hippocampus, one of the brain areas primarily affected by disease progression, hosts one of the most unique phenomena that occur in the adult mammalian brain. This phenomenon, named adult hippocampal neurogenesis (AHN), encompasses the addition of new neurons throughout life, is crucial for hippocampal‐dependent learning, and confers an unparalleled degree of plasticity to the entire hippocampal circuitry. During AHN, in rodents, newborn dentate granule cells (DGCs) go through different maturation stages before acquiring the properties of a fully mature DGC. In this study, we aimed to determine whether immature DGCs at distinct maturation stages can be identified in the human dentate gyrus (DG) and whether the differentiation process of these cells is altered in AD patients.

Method

We used a unique collection of hippocampal samples obtained from 13 neurologically healthy control subjects and 45 AD patients distributed among the 6 neuropathological Braak‐Tau stages of the disease. These samples were obtained under tightly controlled conditions and state‐of‐the‐art tissue processing methodologies and histological protocols were applied.

Result

We studied the maturation of DGCs that expressed the gold standard marker of immature neurons, doublecortin (DCX) in the DG of these subjects. For that purpose, we co‐localized DCX with markers that characterize distinct maturation stages during AHN. These markers included calretinin for the most immature neurons or calbindin for neurons at more advanced stages of maturation. We observed remarkable morphological differences among these cell populations in control subjects, which suggested remarkable similarities between AHN in rodents and humans. Strikingly, the maturation of DCX+ DGCs was blocked at multiple levels in AD patients, as shown by the reduced percentage of DCX+ DGCs that expressed markers of mature neurons in these patients.

Conclusion

Our data do not only support that human AHN exhibits remarkable similarities with that of rodents, but also demonstrate that this process is blocked at different levels during AD. Given that AHN is regulated by lifestyle habits in rodents and these manipulations have a positive impact on cognition, modulating AHN in humans emerges as a potential therapeutic target for AD or other neurodegenerative diseases.
The development of appropriate care pathways for older prisoners with mild cognitive impairment and dementia
Authors: Heathcote Leanne , Forsyth Katrina , Senior Jane , Shaw Jenny , Domone Rachel
Published: December 2020

Background

No standardised specialised services or care pathways exist for older prisoners with mild cognitive impairment or dementia in England and Wales. Current service provision is suboptimal and ad hoc. Aim: Identify service needs and appropriate care pathways for older prisoners with cognitive impairment throughout custody and on release into the community;

Method

To identify service needs and develop an appropriate care pathway for older prisoners with dementia/mild cognitive impairment we adopted a Balance of Care approach. Data from the quantitative aspects of the study was used to create sub‐groups of people with similar care needs, from which were developed a series of representative case studies. Each case study was presented to multidisciplinary staff from prison and community settings at a series of workshops. Staff were asked to design an appropriate care package for each case study. Feedback notes from workshops were collated and summarised using a care plan template. Key themes were identified which formed an initial draft of as assessment and treatment care pathway. A further workshop was held with professionals to adjust and further develop the final pathway.

Findings

The final pathway (figures 1 & 2) outlines the steps to be taken within prison and community services to streamline the diagnostic process. Additional guidance is provided around environmental modifications in prison, the development of adapted, specialist wings and circumstances under which care out of the prison setting, for example release on temporary license or some type of secure nursing home/hospital accommodation should be considered.
Factors associated with cognitive performance in elderly caregivers of the community
Authors: Ottaviani Ana Carolina , Brigola Allan Gustavo , Oliveira Nathalia Alves , Luchesi Bruna Moretti , Pavarini Sofia Cristina Iost
Published: December 2020

Background

The loss of cognitive health of older caregivers can even become a risk to their own self‐care, functionality, autonomy, and independence.

Method

Cross‐sectional study carried out with 351 older caregivers attending primary healthcare services in Brazil. Sociodemographic, care variables and Addenbrooke's Cognitive Examination‐Revised (ACE‐R). The data were analyzed using the STATA / MP12 software and the ACER domains were used as dependent variables in the Tobit model with a cross section. All ethical aspects were respected.

Result

Most older caregivers were women (n = 267; 76.1%), with a mean age of 69.5 (± 7.0) years and who provided care to their spouse (n = 298; 84.9%). Higher levels of education were significantly associated with better cognitive scores in all domains of ACE‐R. Male sex was significantly associated with worse orientation scores and older age was significantly associated with worse scores on memory, language and visuospatial tests. Also, days per week spent caregiving, was associated with worse on memory and verbal fluency scores and having emotional help was associated with higher memory scores.

Conclusion

Age, education, male gender, days of care per week and emotional help were associated with the cognitive performance of the older caregivers. In this perspective, scalable interventions that aim to reduce the time spent on care and increase emotional support may be the most effective in preventing cognitive impairment in public policies.
Misconceptions in acquired brain injury
Authors: Tabernero Maria Eugenia , Gallo Maria Fernanda , Cores Evangelina Valeria , Deschle Florencia , Pavon Hernan Marcelo , Cancino Jorge Jose
Published: December 2020

Background

Several studies have shown misconceptions about Acquired Brain Injury (ABI) and it's sequelae on different populations. Considering the motor, sensory, cognitive or emotional consequences of ABI, and their impact in the patient and its relatives’ life, the information offered on ABI is essential to provide adequate care. Objectives: to acknowledge the presence of misconceptions regarding ABI in our population by applying a self‐administered questionnaire

Method

Three groups were formed. One for general population (GP), one for patients’ relatives with ABI (RP), and one for health workers (HW). Instrument: five questions were added to the Spanish survey about misconceptions in ABI published by Navarro Main et al. (2017). The survey includes twenty‐four mandatory true or false questions. Furthermore, demographical data was required (for e.g. age, years of education and place of residence), along with information regarding having a relative who has suffered from traumatic brain injury or a stroke. The survey was distributed virtually.

Result

648 surveys were obtained; 305 belonged to GP, 143 to RP, and 200 to HW. The median age of the respondents was 37, 42 and 36 years‐old respectively. Tertiary and college education have been referred by the 77,5%, 71,5% and 96,5% respectively. The highest number of errors was similar for the three populations for the questions that assessed misconceptions about the influence of cognitive symptomatology, giving the idea that only the behavior observation and physical state of a patient allows us to infer ABI, and that cognitive status is not related to functional independence. “The greater the effort, the faster the recovery” misconception was more prevalent in the RP group.

Conclusion

The results showed that having a direct relative does not improve the knowledge on ABI and it's possible sequelae, and this fact stands for the need of a better communication from the rehabilitation group to the relatives in order to adequate achievement expectations and to accomplish a better symptoms management. Moreover, although HW obtained the lowest rate of misconception, the lack of knowledge on ABI’s cognitive component was solid evidence.
Dysfunctional microglial phenotype in the hippocampus of aged amyloidogenic Alzheimer's model
Authors: Nuñez‐Diaz Cristina , Sanchez‐Mejias Elisabeth , Arboledas Angela Gomez , Mejias‐Ortega Marina , Sanchez‐Varo Raquel , Davila Jose Carlos , Vitorica Javier , Gutierrez Antonia
Published: December 2020

Background

The accumulation of amyloid beta (Aβ), giving rise to soluble toxic oligomers and insoluble amyloid plaques, is one of the main hallmarks of Alzheimer’s disease (AD). Aβ pathology triggers an inflammatory response mediated by activated astroglia and microglia. However, the specific role of the latter in the progression of AD and their relationship with plaques are not fully understood yet. Here we have analyzed, at cellular and subcellular levels, the progression of amyloid pathology and the associated activated microglia in the hippocampus of the model APP750SL/PS1M146L.

Method

Immunohistochemistry for light and electron microscopy were performed in hippocampal samples from 4‐ to 18‐month‐old APP750SL/PS1M146L mice. Quantifications were done by image analysis and stereology.

Result

There is an age‐dependent increase in the amyloid burden and plaques grow, increasing both the size of the core and the halo, in the hippocampus of APP/PS1 model. Besides, a correlation exists between the size of plaques and the number of neuritic dystrophies surrounding them. Amyloid plaques are surrounded by activated microglia, showing a transcriptomic DAM profile. Microglial processes intertwine with the amyloid fibrils, acting as a barrier that isolates plaques and phagocytose Aβ, which might be toxic for these cells. Therefore, microglia surrounding amyloid plaques show ultrastructural signs of dysfunction, which might lead to a worsening of amyloid pathology and neurodegeneration.

Conclusion

Microglia surrounding amyloid plaques suffer a degenerative process with the progression of the pathology, which might affect their functions of phagocytosis/isolation/compaction of amyloid plaques. This could contribute to the progression of AD, with the plaques releasing highly toxic soluble Aβ oligomers to the brain parenchyma. Therefore, restoring microglial function or renewing this population might be a promising therapeutic approach for AD. Supported by: Instituto de Salud Carlos III, co‐financed by FEDER funds from European Union, projects PI18/01557 (to AG) and PI18/01556 (to JV), by CIBERNED (to AG and JV), and by Junta de Andalucia project UMA18‐FEDERJA211 (to AG).
Cerebral correlates of autobiographical memory in MCI and AD: Evidence from a positron‐emission tomography study
Authors: Frankenberg Claudia , Schröder Johannes , Haberkorn Uwe , Degen Christina , Buchsbaum Monte S.
Published: December 2020

Background

Autobiographical memory (AM) changes are the hallmark of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). In recent neuroimaging studies, AM changes were associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the cingulum. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake.

Method

In 109 patients with MCI or mild AD cerebral metabolic rates were determined using positron‐emission tomography with [18F] deoxyglucose. According to the analyses of the scree plot factor analysis with VARIMAX rotation was used to identify underlying dimensions in 34 cerebral sites involved in AM deterioration. Subsequently, the respective factor scores were correlated with AM performance of 22 patients, which was measured with a structured inventory assessing memories from primary school, early adulthood, and recent years.

Result

Factor analysis identified seven factors explaining 69 % of the variance (“frontal cortex,” “mesial temporal substructures”, “cingulum”, “occipital cortex”, “left temporo‐prefrontal areas”, “anterior cingulum”, “right temporal cortex”). Relative to controls, AD patients showed significantly lower values on the factors “frontal cortex” and “mesial temporal substructures”. The factor “mesial temporal substructures” was significantly correlated with both, episodic memories and personal semantic knowledge.

Conclusion

Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. These findings don’t necessarily contradict the multiple trace hypothesis as our sample only comprised patients with MCI or very mild AD for whom the relative preservation of semantic relative to episodic AM may not apply. In conclusion, our findings underline the importance of functional mesial temporal lobe changes in AD associated AM deficits.
A community‐based approach to advance care planning for lower socioeconomic status African Americans living with dementia
Authors: Hurst Laurel Myers , Moss Karen , Grieff Abigail M , Wills Celia
Published: December 2020

Background

Despite multiple decades of research on advance care planning and existing evidence‐based national models, there remains a persistent lack of effective interventions to facilitate this process among lower socioeconomic status older African Americans living with dementia. African Americans are less likely than Caucasians to complete advance directive. This lack of advance directive documentation results in a higher likelihood of unwanted, costly, and often‐futile healthcare near the end of life that reduces quality‐of‐life. The purpose of this research study is to describe key stakeholder perspectives regarding needs and preferences for advance care planning, including desired intervention content and delivery format to assist caregivers of lower socioeconomic status African American older adults living with dementia, using the novel corona virus pandemic as an exemplar.

Methods

For this qualitative descriptive study, up to n=40 family caregivers (n=20 current) and (n=20 former) of lower socioeconomic status African American older adults living with dementia, healthcare providers (n=10), and community organization stakeholders (n=10) are being recruited. These stakeholders will complete up to two audio‐recorded interviews about needs and preferences for advance care planning, including desired intervention content and delivery format. SPSS software will be used for demographic data analysis and Dedoose software will be used to enhance thematic content analysis of transcribed interview data.

Results

Study findings will be used to develop a decision support prototype intervention that is ready for efficacy testing. We anticipate that it will fill essential gaps in existing advance care planning interventions for lower socioeconomic status African American older adults with dementia and their caregivers. This co‐created prototype will go beyond education only and will include culturally‐tailored psychosocial and problem‐solving approaches to advance care planning through processes such as storytelling (an effective and culturally acceptable‐to‐the‐population process) as a narrative form of advance care planning through communication. Study results will be provided to participants at study completion.

Conclusions

By engaging with this population to develop and test a co‐created culturally‐focused intervention, we expect to improve advance care planning outcomes for lower socioeconomic status African American older adults living with dementia and their caregivers.