bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between waist‐to‐hip ratio, BMI index and cognitive impairment in those aged 40 years or above: A cross‐sectional study in a rural area of Xi’an, China
Authors: Shang Suhang , Zhang Binyan , Wang Jin , Jiang Yu , Chen Chen , Dang Liangjun , Qu Qiumin
Published: December 2020

Background

The relationship between obesity, body weight and cognitive impairment is still controversial. To analyze the correlation between BMI index, waist‐to‐hip ratio and cognitive impairment.

Method

This study is a cross‐sectional survey conduct during October 2014 to March 2015. Subjects who aged 40 and above and lived in a village in the suburbs of Xi'an, China were selected as the research sample. Cognitive function was assessed using the Mini Mental State Scale (MMSE). Cognitive impairment was defined as a Mini‐Mental State Examination (MMSE) score lower than the cutoff value. Specifically, the cutoff value was ≤17 for the illiterate, ≤20 for the primary school educated, and ≤24 for those educated at the junior high school level or above. Height and weight were measured to calculate the BMI index; waist circumference and hip circumference were measured to calculate the waist‐hip ratio. Multivariate logistic regression was used to correct for confounding factors.

Result

A total of 1792 subjects were enrolled in the study, including 726 males (40.5%), and were aged 40‐85 (average 55.53 ± 9.92) years. 230 subjects (12.8%) were diagnosed as having cognitive impairment. BMI index was 25.29 ± 3.14 kg/m2, and 433)24.2%( had BMI index <23 kg/m2. WHR was 0.88 ± 0.06, and 462 subjects had WHR> 0.92. Univariate analysis showed that those with a BMI index <23 kg/m2 (<23 vs 23‐25 vs 25‐27 vs ≥27 kg/m2, 16.2% vs 12.0% vs 12.1% vs 11.3%, P = 0.120), and those with WHR >0.92 (<0.84 vs 0.84‐0.88 vs 0.88‐0.92 vs ≥0.92, 12.1% vs 11.9% vs 11.0% vs 16.2%, P=0.082) tended to have higher risk for cognitive impairment. Multivariate logistic regression analysis showed that WHR ≥ 0.92 (OR = 1.619, 95% CI 1.161‐2.258, P = 0.005) and BMI <23 kg/m2 (OR = 1.366, 95% CI 0.969‐1.927, P = 0.075) was ( or tend to) positive correlated with cognitive impairment.

Conclusion

In the population aged 40 or above in rural areas of Xi'an, China, abdominal obesity and low body weight were positive correlated with cognitive impairment.
Estrogen‐modulating breast cancer therapies and the incidence of Alzheimer’s disease
Authors: Branigan Gregory L , Soto Maira , Neumayer Leigh , Rodgers Kathleen E , Brinton Roberta Diaz
Published: December 2020

Background

Globally, neurological disorders rank as the leading cause of disability‐adjusted life‐years, and the second‐leading cause of deaths. The high global prevalence and economic impact of Alzheimer’s disease presents a significant public health challenge while the identification of therapies to prevent Alzheimer’s disease (AD) remains a challenge. Worldwide, breast cancer is the most common non‐skin cancer in women. Approximately 1 in 8 women will be diagnosed with breast cancer during their lifetime. Currently, Alzheimer’s disease affects 1 in 9 persons in the US over the age of 65, two thirds of whom are women.

Method

The objective of this study was to determine whether exposure to hormone modulating therapies targeting estrogen for the treatment of breast cancer impact the risk of AD using medical informatics and the Symphony claims data set. The Symphony data set contains claims from private‐payer and Medicare insurance data sets from across the United States. Survival analysis was used to determine the association between estrogen modulating therapy exposure and diagnosis of AD in the post index date follow‐up period. A propensity score approach was used to minimize measured and unmeasured selection bias.

Result

In this cohort study of propensity score matched perimenopausal to postmenopausal aged women with breast cancer, estrogen modulating therapy exposure was associated with decrease in diagnosis of neurodegenerative disease, most specifically Alzheimer’s disease. Kaplan‐Meier curves for AD‐free survival were analyzed to measure the overall rate and proportion of patients in each treatment group who went on to develop neurodegenerative disease.

Conclusion

Among female patients with breast cancer, exposure to estrogen modulating therapies, specifically tamoxifen and steroidal aromatase inhibitors, was associated with a decrease in diagnosis of AD and Dementia. As a result, translational studies investigating the mechanisms by which these therapeutics impact AD risk are currently underway.
Beta‐amyloid‐associated episodic memory variation correlates with subicular volume in non‐demented old aged individuals
Authors: Kagerer Sonja M , Schroeder Clemens , Van Bergen Jiri M. G. , Schreiner Simon J. , Meyer Rafael , Steininger Stephanie C. , Laetitia Vionnet , Gietl Anton F. , Treyer Valerie , Buck Alfred , Pruessmann Klaas P. , Hock Christoph , Unschuld Paul G.
Published: December 2020

Background

The aggregation of cortical Amyloid β (Aβ) is a hallmark of Alzheimer's Disease (AD). Aβ accumulates during the preclinical stage and characterizes old aged adults at increased risk for AD. Also, low episodic memory (EM) performance within the normal range is linked to an increased risk for AD. This study is aimed at identifying hippocampal subfield atrophy associated with increased risk for AD, as reflected by cortical Aβ burden, and low EM.

Method

69 non‐demented old aged adults were administered 11C‐PiB‐PET and 18F‐Flutemetamol‐PET for measuring Aβ. Ultra high‐field 7 Tesla MRI (TR/TE = 4.8 ms/2.1 ms, 0.6mm3) was used for assessment of hippocampal subfields volumes. Subjects were dichotomized in high versus low levels of cortical Aβ and high versus low EM, as measured by the Verbal Learning and Memory Test (VLMT).

Result

Multiple analysis of Variance (MANOVA) showed significant differences in hippocampal subfield volumes. Most distinguished effects on variation of volumes resulted for coexistent criteria "high‐ Aβ" and "low EM" (λ=0.34, p=0.039). Strongest effects resulted for subiculum and molecular layer (F(1,59)= 16.8, p = 0.002). The interaction between cortical Aβ and episodic memory performance was significant for subiculum only (F(1, 57) = 5.90, p = 0.018).

Conclusion

Our data indicate an association between low subicular volume and increased risk for AD in nondemented old aged persons. While our data is consistent with earlier data on subicular atrophy in preclinical AD, it also highlights promise of multivariate analysis for identifying biological risk phenotypes associated with sporadic AD.
Hyperphosphorylation, cytoskeleton and cell‐surface binding aptamers: Developing markers and understanding molecular changes in early stage Alzheimer’s disease
Authors: Parekh Parag A. , Mu Qingshan , Badchappe Andrew , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Ghaghada Ketan , Annapragada Ananth
Published: December 2020

Background

Hyperphosphorylated tau (pTau) is a characteristic of AD, leading to intracellular “tau tangles” followed by dementia. However, intracellular tau is difficult to measure in vivo, requiring a probe to enter the cell. Proteomic changes on the diseased cell‐surface however, provide a diagnostic target that eliminates the need for a probe to enter the cell. We therefore sought cell surface markers of pathological neurons in the process of hyperphosphorylating tau.

Method

SH‐SY5Y cells differentiated to a neuronal phenotype were rendered hyperphosphorylative by okadaic acid, and aptamers specifically binding these cells were captured using a modified cell‐SELEX methodology. Mass spectrometric proteomics identified the binding targets. Target presence was validated on SH‐SY5Y cells, P301S mouse brain tissue and human AD brain tissue by immunofluorescence. Gene‐expression data were analysed to identify the utility of the target as a diagnostic marker. A Gd‐bearing nanoparticle targeted using the lead aptamers was injected i.v. in 2‐month P301S mice and T1‐weighted MRI imaging was used to assess binding as a predictor of future tau pathology.

Result

Aptamers identified by sequencing of the enriched aptamer pools were demonstrated to specifically bind hyperphosphorylative SH‐SY5Y cells . Proteomic analysis suggested Vimentin and keratin6A/6B as potential binding targets. Analysis of hyperphosphorylative SH‐SY5Ycells, human AD tissue and P301S mouse brain tissue confirmed increased levels of cell‐surface Vimentin. Meta‐analysis revealed that Vimentin is expressed at higher levels in the diseased state. Further pathway analysis identified alternative targets related to desmosomes. Two month old P301S mice had no tau pathology, but the targeted MRI particles were still ∼80% accurate in identifying the transgenic mice and predicting future tau pathology.

Conclusion

Our results suggest that Vimentin and other related desmosomal molecules could be prognostic markers of future tauopathy, and also suggest a need to investigate cell‐surface changes under conditions that cause tauopathies. Targeted MRI particles are promising as an indicator of future tau pathology.
Polygenic risk scores can predict AD‐related pathologies
Authors: Cara Jared , Collens Julie , Beach Thomas G. , Cruchaga Carlos , Schneider Lon , Shah Kaanan P.
Published: December 2020

Background

Alzheimer’s disease is defined by the presence of amyloid plaques and tau tangles in the brain leading to cognitive decline. Risk for AD is multifactorial with genetic factors playing a large role in disease risk. Specifically, presence of the APOE e4 allele is a strong risk factor for late onset AD. Beyond APOE, many variants have been identified as risk factors for AD, however with smaller effects.

Method

Polygenic risk scores are a well‐established method for combining information across genetic factors with individually small effects on disease risk to predict an individual’s disease risk. We use this approach to develop genetic predictors of AD‐related pathologies such as amyloid. Specifically, we developed a PRS, that in combination with age and sex, is predictive of the presence of amyloid in an individual’s brain. We use pathological measures of protein aggregates in postmortem brain tissue as our training data set for model development however our tests can be applied antemortem via a blood test. We evaluate performance of our PRS and previously published scores in all individuals and subset by APOE e4 status.

Result

We show the performance of our PRSs to predict AD related pathologies in independent validation datasets. We also show performance metrics compared to PET and CSF measurements within the ADNI dataset as a comparison to established methods used in AD patients. Finally, in comparison to published AD PRSs, we found our pathology PRSs performed as well or better than in predicting specific pathology phenotypes. When used as a screening tool for clinical trial enrollment, our PRS assays can reduce the overall cost of patient enrollment by reducing the number of screen failures after a negative amyloid PET scan.

Conclusion

Our PRSs are predictive of AD related pathologies and can be useful as a screening tool within the context of a clinical trial. The cost savings for clinical trial enrollment varies based on the size of the trial. Thus, incorporating genetics early within a clinical trial will be valuable for enrollment. This information can also be used to identify important biomarkers of response as the trial progresses.
The impact of concomitant LATE‐NC on hyperphosphorylated tau pathology and cognitive decline in Alzheimer’s disease
Authors: Walker Lauren , McAleese Kirsty E. , Erskine Daniel , Attems Johannes
Published: December 2020

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is present in approximately 57% of Alzheimer’s disease (AD) cases and is associated with accelerated cognitive decline and accelerated disease progression. Hyperphosphorylated tau (HP‐τ) burden in AD is associated with cognitive deficits; it is unknown if LATE‐NC is associated with HP‐τ burden. In post‐mortem AD cases, we investigated the association between LATE‐NC and early and late HP‐τ and the impact of LATE‐NC on clinical measures of cognition.

Method

46 AD cases underwent neuropathological assessment for LATE‐NC [1] and quantitative assessment for early conformational HP‐τ (MC‐1) and intermediate/late stage HP‐τ (AT8) in the frontal, entorhinal, temporal, parietal and occipital cortices. Cognitive decline (n=20) was calculated from longitudinal mini‐Mental State Examination (MMSE; n =37).

Result

29 cases (63%) exhibited LATE‐NC (AD+). No significant differences in AT8 were revealed, however, observationally, AT8 was higher in all regions of AD+ cases. MC‐1 burden was significantly lower in the entorhinal cortex (P<0.05), and observational lower in all regions in the AD+ cases. No association between MC‐1 or AT8 with LATE‐NC score were revealed. MMSE score and cognitive decline was not significantly different between AD+ and AD‐ groups (both P>0.9) and linear regression revealed no influence of LATE‐NC on cognitive scores.

Conclusion

AD+ cases exhibit lower burden of MC‐1 and higher burden of AT8 pathology indicating possible advanced progression of the disease compared to AD‐ cases. The presence of LATE‐NC is not associated with differences in cognitive scores in AD. (1) Nelson et al (2019) doi:10.1093/brain/awz099.
Lobar distribution of white matter abnormalities in Alzheimer’s, vascular and mixed dementias
Authors: Lee Hyunwoo , Wiggermann Vanessa , Rauscher Alexander , Beg Mirza Faisal , Popuri Karteek , Tam Roger , Lam Kevin , Jacova Claudia , Sossi Vesna , Pettersen Jacqueline , Benavente Oscar R. , Hsiung Ging‐Yuek Robin
Published: December 2020

Background

Vascular dementia (VaD) is often difficult to distinguish from Alzheimer’s disease (AD).[O’Brien_2015] Areas of cognitive/clinical decline due to cerebrovascular diseases depend on the frequency and location of the lesions, and may overlap with those found in AD.[Suri_2014] Moreover, AD and cerebrovascular diseases frequently occur simultaneously, leading to heterogeneous ‘mixed dementia (MixD)’.[Wang_2012][Langa_2004] It is unclear whether the presence of both neurodegenerative and cerebrovascular pathologies further aggravates dementia‐related imaging abnormalities. We investigated whether the lobar distribution of white matter hyperintensities (WMHs) on MRI differed among AD, VaD and MixD.

Method

N=17 participants (cross‐sectional; subtypes:7 MixD/5 Subcortical VaD/5 AD; Sex: 11M/6F; Age: 75±8yrs) were scanned on a 3T Philips Achieva. T1‐weighted MP‐RAGE images were processed with Freesurfer 6.0. Areas of WMHs were segmented on Fluid Attenuated Inversion Recovery (3D‐FLAIR) images using a combination of intensity thresholding and manual correction. Left and right frontal, temporal, occipital and parietal lobes plus basal ganglia volumes were constructed using the Freesurfer segmentation outputs. Individual WMH masks were transformed to their respective T1‐weighted spaces, and the ratios of WMH volumes to different lobar volumes were calculated.

Result

Average WMH volumes were (mean±SD) AD: 5191±4693mm3, MixD: 34680±17059mm3 (sig. greater than AD), SVaD: 20896±14920mm3 (n.s. from MixD or AD). We used a linear model to predict the ratios of WMH to lobar volumes from the diagnosis subtypes, adjusting for age and sex. A significant diagnosis‐subtype effect was found in both the left and right frontal lobes. (p=0.012 and 0.045, respectively). In the left frontal lobe, the proportion of WMHs was significantly greater in the MixD subgroup compared to the AD (p=0.0045) or the VaD (p=0.026) subtypes. In the right frontal lobe, the proportion was greater in the MixD subtype compared to the AD (p=0.018) but not compared to VaD (p=0.074) subtype. AD vs. VaD were not significantly different in either sides (p=0.5).

Conclusion

The MixD subtype of our pilot study cohort was characterized by a significantly greater presence of WMHs in the frontal lobar areas. Future studies are warranted to investigate the characteristics of underlying tissue abnormalities that could be specific to the diagnosis subtypes.
Differences due to sex in cortical thickness and CSF biomarkers in normal aging and Alzheimer’s dementia
Authors: Sangha Oshin , MaLeePopuri DaSieunKarteek , Beg Mirza Faisal
Published: December 2020

Background

In normal aging, a thinner cortex in males has been reported by various studies. Longitudinal trends in cortical thinning in males and females in healthy aging and in Alzheimer’s Dementia (AD) have yet to explored. In addition, CSF biomarkers also play an important role in detecting AD. In this study, we explored the differences in cortical thinning and CSF biomarkers between males and females in both healthy and AD subjects.

Method

Baseline differences and differences up to two‐ years were studied using the data from two publicly available datasets ‐ Alzheimer's Disease Neuroimaging Initiative (ADNI) [Baseline scans‐ healthy control (HC): 423, AD: 330; follow up scans ‐ HC: 1191, AD: 536] and Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) [Baseline scans only ‐ HC: 319, AD: 72.] Only stable subjects (diagnosis does not change in the follow up scans) healthy controls and AD subjects were used. Generalized linear regression models were used to control the effect for age, intracranial volume, and scanner effects. For analyzing the differences between CSF biomarker levels, only age was controlled.

Result

In the Healthy control group, males showed a thinner cortex than females at baseline. Both males and females showed significant cortical thinning in different regions over two years. In the AD group, males showed a thinner cortex than females at baseline and over two years; however, the number of regions showing a significantly thinner cortex in males compared to females were less as opposed to the case in the control group. On the other hand, no significant differences were observed in the level of CSF biomarkers between males and females at either baseline and follow up measurements for both control and AD groups.

Conclusion

In AD, females appear to experience greater cortical thinning than males such that the sex difference was less evident in AD than in controls. In the AD group, the sex difference in cortex continued to decrease through the two‐year study period. For CSF biomarkers, no significant difference was observed for males and females. This result suggests that neuro‐imaging is more sensitive to male and female differences than CSF biomarkers.
Vascular dysfunction in CAA in the presence of cardiovascular risk factors: The role of the mitochondria and therapeutic approaches
Authors: Parodi‐Rullan Rebecca M. , Sone Je Yeong , Fossati Silvia
Published: December 2020

Background

The accumulation of amyloid‐β (Aβ) on the brain vasculature, known as Cerebral Amyloid Angiopathy (CAA), induces vascular dysfunction contributing to neurodegeneration. Cardiovascular (CV) risk factors, which are also mediators of vascular dysfunction and may increase the risk for developing Alzheimer’s Disease and dementia, may potentiate CAA‐mediated neurovascular pathology. Mitochondria are key cellular organelles that have a dual role as mediators of cell survival and death and have an important role in disease pathogenesis. However, the role of brain endothelial mitochondria in vascular amyloidosis complicated with CV risk factors is unknown. The carbonic anhydrase inhibitors (CAi) methazolamide and acetazolamide were able to reduce amyloid‐induced cell death and mitochondrial dysfunction. Our work focuses on understanding the mechanisms of vascular dysfunction induced by Aβ complicated with CV risk factors. We aim to understand the protective role of CAi in preventing the pathological changes associated to neurovascular dysfunction and neurodegeneration.

Method

Immortalized human cerebral microvascular endothelial cells (ECs) were used to study the molecular changes that occur in the cerebral vasculature during amyloid challenge complicated with CV risk factors, such as hyperhomocysteinemia (HHC). We then tested CAi and their potential to prevent cell death and mitochondrial dysfunction in ECs challenged with Aβ in the presence or absence of CV risk factors such as HHC.

Result

Aβ and HHC increased EC barrier permeability and that the presence of HHC worsened amyloid‐induced barrier permeability. Aβ‐induced EC apoptosis was reduced by treatment with CAi. We further demonstrate that both Aβ and HHC decrease mitochondrial basal respiration. The presence of Aβ induces cytochrome‐c release, mitochondrial membrane potential loss, and ROS production which were reduced by treatment with CAi.

Conclusion

HHC and Aβ induce brain microvascular EC dysfunction and increase permeability of the EC barrier. Aβ induces cell death and mitochondrial dysfunction, which are both prevented by CAi. We also demonstrate that CV risk factors, specifically HHC, induce mitochondrial dysfunction on brain ECs which could further contribute to neurovascular dysfunction and neurodegeneration observed in CAA. Our studies suggest that CAi could serve as a novel therapeutic strategy towards vascular dysfunction during CAA complicated with CV risk factors.
Frontal tau pathology underlies behavioural / dysexecutive clinical presentations of Alzheimer’s disease
Authors: Therriault Joseph , Pascoal Tharick A. , Savard Melissa , Benedet Andréa Lessa , Chamoun Mira , Tissot Cecile , Lussier Firoza Z. , Kang Min Su , Soucy Jean‐Paul , Massarweh Gassan , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Increasing attention is being directed to atypical clinical presentations of Alzheimer’s disease. The behavioural/dysexecutive variant of Alzheimer’s disease is a rare clinical syndrome presenting with behavioural changes, apathy and executive dysfunction, similar to frontotemporal dementia. While initial autopsy studies identified pathology in the frontal cortex, recent studies challenge the notion of frontal involvement in this condition.

Method

We assessed 14 cases of behavioural/dysexecutive Alzheimer’s disease recruited from a tertiary care memory clinic, all of whom had biologically defined Alzheimer’s disease (amyloid and tau positive). They were compared with 24 disease severity‐ and age‐matched amnestic Alzheimer’s disease patients and a group of 131 cognitively unimpaired (CU) elderly individuals. All subjects were evaluated with [18F]AZD4694‐PET (amyloid‐b), [18F]MK6240‐PET (tau), MRI, genotyping for apolipoprotein E (APOE) and neuropsychological testing.

Result

Voxelwise contrasts against CU elderly identified patterns of frontal cortical tau aggregation in the behavioural/dysexecutive group, with peaks in the anterior cingulate, frontal insula and orbitofrontal cortices. Amnestic Alzheimer’s disease patients had larger differences in the lateral temporal, inferior parietal and posterior cingulate cortices. In contrast to tau‐PET, no differences were observed in the distribution of amyloid‐PET between both Alzheimer’s disease groups. Finally, voxelwise regressions demonstrated significant relationships between frontal cortical tau load and severity of executive dysfunction (FWE corrected at p<0.001), while memory dysfunction was related to temporal and parietal tau load (FWE corrected at p<0.001).

Conclusion

The association between frontal tau pathology and behavioural / dysexecutive clinical presentations provides in vivo support for a “frontal variant” of Alzheimer’s disease as initially identified by autopsy studies. Our results also highlight the need for consensus clinical criteria for behavioural/dysexecutive Alzheimer’s disease.
Online medical education improves knowledge of clinical trial data and mechanism of action of therapies studied for the management of dementia‐related psychosis among neurologists and psychiatrists
Authors: Finnegan Thomas , Arnaud‐Hevi Lisette , Hanley Kelly
Published: December 2020

Background

Psychosis is a consequence of dementia that occurs to varying levels depending on the type of dementia. Of note, it is estimated that up to 75% of people with dementia with Lewy bodies will experience psychosis compared with approximately 10% of people with frontotemporal dementia. Management of this condition is a challenge due to a lack of FDA‐approved therapies as well as the potentially serious adverse events associated with the medications currently employed. It is crucial that clinicians are aware of clinical outcomes and the mechanism of action of investigational approaches for the pharmacologic management of dementia‐related psychosis (DRP). An online educational activity was developed with the goal of improving knowledge among neurologists and psychiatrists regarding clinical trial outcomes for investigational therapies being studied in DRP.

Method

An online educational intervention was developed in the form of a 30‐minute video lecture with synchronized slides. Educational effectiveness was assessed with a repeated pairs pre‐/post‐ assessment study design in which each individual served as his/her own control. Responses to 3 knowledge‐based and 1 confidence‐based questions were analyzed. A chi‐square test assessed changes from pre‐ to post‐assessment. Cramer’s V was used to calculate the effect size of online education. Data from the assessment were collected between September 4, 2019 and November 25, 2019.

Result

A comparison of responses from pre‐ to post‐assessment questions demonstrated a considerable educational effect for neurologists’ (n=365; V=0.17; P<.001) and a noticeable educational effect for psychiatrists’ (n=1155; V=0.15; P<.001). Participation in this educational intervention showed improvements for both groups in the following areas (P<.05): the mechanism of action of pimavanserin; the impact of pimavanserin on cognitive function in patients with Alzheimer disease; and the mechanism of action of memantine. Activity participation resulted in 36% of neurologists and 34% of psychiatrists reporting an increase in confidence in their ability to manage DRP.

Conclusion

This study demonstrated the success of a targeted online, video lecture on improving neurologists’ and psychiatrists’ knowledge of the mechanism of and clinical trial outcomes for therapies studied for the management of DRP. Future education should continue to address the clinical developments and practical management of DRP.
Connectivity‐based differentiation of agrammatic and logopenic variants of primary progressive aphasia using a whole brain data‐driven approach
Authors: Jenkins Lisanne M , Behn Jordan Quinn , Khan Raiyan R , Wang Lei , Rogalski Emily J , Greicius Michael D , Mesulam Marsel , Bonakdarpour Borna
Published: December 2020

Background

Primary progressive aphasia (PPA) is a syndrome of progressive language impairment caused by neurodegenerative disease. We previously showed using seed‐based connectivity analysis that connectivity between three language network regions is decreased in PPA. Furthermore, we showed selective connectivity disruptions corresponding to grammar, repetition, naming and comprehension deficits. The current investigation used a data driven approach to uncover signatures of resting state connectivity disruptions differentiating agrammatic PPA subtypes (PPA‐G) from logopenic PPA subtypes (PPA‐L).

Method

One hundred and six individuals participated in this study, for which 73 PPA patients were compared to 33 healthy controls (Table 1). Diagnosis of PPA subtype was made by clinical consensus using established criteria. Resting state functional MRI (rsfMRI) was collected using a Siemens 3T scanner over 10 minutes with eyes open. Data were analyzed using FSL tools. A group independent components analysis generated 30 independent components (ICs). Participant’s individual time series and component spatial maps were estimated using dual regression. Voxel‐wise non‐parametric permutation testing (n=5000) tested for significant differences in connectivity within each IC across groups. Follow‐up one‐way ANOVAs with Tukey post‐hoc tests were conducted.

Result

Post hoc tests found PPA subgroup(s) had reduced connectivity than controls in three FSL‐identified ICs showing significant group differences (Figure 1). PPA‐L had significantly lower connectivity within IC1 in the cuneus. PPA‐G had significantly lower connectivity within IC14 in Broca’s area; and all three PPA subtypes had significantly lower connectivity within IC25 in the left middle temporal gyrus (MTG).

Conclusion

We identified three components in which PPA subgroup(s) had lower connectivity than controls. In PPA‐G, but not PPA‐L, reduced connectivity was within Broca’s area, consistent with this region’s importance for fluency and grammar. In PPA‐L, but not PPA‐G, reduced connectivity was within the cuneus. This finding may seem surprising, however, it may reflect higher incidence in PPA‐L of Alzheimer pathology, which is known to have the precuneus as a major target of degeneration. All PPA subtypes had reduced connectivity within the posterior MTG, reflecting the common occurrence of atrophy in this area.
Implication of ferroptosis iron‐dependent programmed cell death mechanism in neurodegeneration
Authors: Plascencia‐Villa German , Perry George
Published: December 2020

Background

Besides the abnormal accumulation of hyperphosphorylated tau, amyloid‐β plaques and neuroinflammation, progressive synaptic loss and neuronal cell death are persistent pathological hallmarks related to the development of neurodegeneration. However, the cellular pathways/mechanisms that trigger neuronal death in AD remain largely undefined. A detailed understanding and description of the molecular mechanisms related to neuronal loss processes in affected AD will be invaluable to the identification and development of new effective therapeutic targets. A novel form of iron‐dependent regulated cell death process termed ferroptosis was recently identified. Misregulated ferroptosis pathways have been speculated to trigger neurodegeneration, but the cellular mechanisms and signaling are not completely understood.

Method

Differentiated neurons were treated (0‐200uM) with different ferroptosis inductors or ferroptosis inductors+inhibitors to determine molecular responses. We employed analytical and advanced imaging techniques, including bioassays, transcriptomics, optical/confocal/electron microscopy and mass spectrometry to determine and compare cell responses, pathways and other features characteristic of ferroptosis. Then AD brain tissues were analyzed to image ferroptotic cells and transcriptomic profiles of pathways altered in ferroptosis.

Result

Some of the ferroptosis‐like biochemical and morphological features have been observed in AD: glutathione reduction, alterations in glutamate/cystine antiporter (Xc‐), lipid peroxidation, mitochondrial dysfunction, MAPK/ERK activation, GPX4 downregulation, and altered redox homeostasis. We determined that ferroptosis is activated in AD as a probable mechanism underlying neuronal loss in neurodegeneration, describing the mechanisms and cellular pathways involved. The results obtained showed alterations in cystine‐glutamate exhcnage, iron metabolism, glutathione metabolism and mevalonate pathway in neurons treated with ferroptosis inductors, particularly correlating with high oxidative stress and neuronal death, these responses were ameliorated when ferroptosis inhibitors were added to the neurons. These observations of altered ferroptosis were confirmed in AD brain and by determining their transcriptomic profiles of ferroptotic pathways.

Conclusion

Determine the molecular mechanisms related to ferroptosis in neuronal cells. Remarkably, the experimental approach allowed (1) establish a relationship between neuronal death and neurodegeneration in the context of ferroptosis, (2) impact our understanding of the AD pathogenesis and cell death mechanisms, and (3) determine novel strategies for early diagnosis and therapeutic interventions that target the molecular pathways of ferroptosis.
The interaction of amyloid and tau on decreased cortical neurite density in preclinical Alzheimer’s disease
Authors: Vogt Nicholas M , Hunt Jack F.V. , Adluru Nagesh , Van Hulle Carol A , Chin Nathaniel A. , Carlsson Cynthia M. , Ma Yue , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik , Alexander Andrew L , Blennow Kaj , Bendlin Barbara B
Published: December 2020

Background

Both MCI and AD dementia are associated with decreased cortical microstructure as measured by neurite orientation dispersion and density imaging (NODDI). Specifically, in MCI, neurite density index (NDI) – but not cortical thickness – is decreased in several key AD regions, suggesting NODDI may be more sensitive than conventional structural imaging for detecting early neurodegenerative changes. Given that AD pathology accumulates for years before cognitive and clinical symptoms arise, in this study, we tested the hypothesis that cognitively unimpaired individuals with greater AD pathology (as measured in CSF) will have decreased cortical microstructure in AD signature brain regions.

Method

219 cognitively unimpaired individuals (66.8±7.5 yrs, 58.9% female, 38.9% APOE4‐positive) underwent MRI (multi‐shell diffusion‐weighted for NODDI microstructure; T1‐weighted for cortical thickness) as well as CSF AD biomarker quantification (Aβ40, Aβ42, and pTau via ELISAs). The NODDI model was fit using optimized parameters for GM (intracellular parallel diffusivity=1.1μm2/ms), and cortical thickness (CT) was calculated using CAT12. Mean NDI and CT were extracted from a bilateral composite AD signature region as well as individual subregions (Fig1A). Linear regression models (controlling for age and sex) tested both main effects and the interaction of CSF Aβ42/Aβ40 and pTau levels on cortical measures (separate models for NDI and CT).

Result

While there were no main effects of CSF Aβ or pTau levels on NDI or CT, there was a significant Aβ‐by‐pTau interaction on NDI in the composite AD signature region, such that individuals with higher burden of amyloid showed lower NDI as a function of pTau (Fig1B). Notably, this interaction was not observed for cortical thickness. Examining individual subregions showed that this interaction effect was observed bilaterally and was strongest in inferior parietal, inferior temporal, and fusiform subregions (Fig1C&D).

Conclusion

In cognitively unimpaired individuals with higher amyloid burden, higher pTau was associated with lower NDI – but not thickness – in AD signature cortical regions. These results suggest that amyloid alone (in the absence of tau pathology) is not associated with microstructural changes, and that NDI is a particularly sensitive marker for early AD‐related cortical changes occurring prior to gross atrophy or development of cognitive impairment.
In vivo validation of a lead compound targeting tau self‐association in two mouse models of tauopathy
Authors: Moe James G. , Lopez Patricia , Jimenez Heidy , Adrien Leslie , Davies Peter , Davidowitz Eliot J.
Published: December 2020

Background

Tau self‐association is the initial step in the formation of toxic tau oligomers and larger aggregates. Our program is highly differentiated in that it targets tau self‐association with small molecules to block the formation of all forms of tau aggregates, whereas other tau aggregation inhibitor programs have largely focused on inhibiting formation and/or dissociating large and relatively inert fibrils which could generate toxic tau oligomer seeds. Relative to immunotherapeutic approaches, small molecules are agnostic to specific post‐translational modifications, conformational changes or strains of tau aggregates, and have superior access to their target in the CNS.

Method

Preventive and therapeutic blinded studies in htau and JNPL3 transgenic mice were performed at an independent laboratory. Mice were treated for four months by administration of our lead compound in feed. For preventive studies, treatment was from 3 to 7 months‐of‐age; for preventive studies, treatment was from 7 to 11 months‐of‐age for JNPL3 and 9 to 13 months‐of‐age for htau. To quantify levels of Sarkosyl‐insoluble tau, self‐associated tau, and phosphorylated tau in the treated and control groups of mice ELISAs were performed. Immunohistochemistry determined levels of conformationally altered and hyperphosphorylated tau. Motor and cognitive behavioral testing are being performed as part of the ongoing therapeutic studies.

Result

The lead compound reduced self‐associated tau and caused a statistically significant, linear, dose‐dependent reduction of the levels of sarkosyl‐insoluble tau aggregates and phosphorylated insoluble tau aggregates in relationship to the levels of compound in the brain in male htau mice. The study of female JNPL3 mice showed dose‐dependent reduction below baseline and vehicle levels of self‐associated tau, insoluble tau aggregates and phosphorylated tau. The compound was well tolerated at all therapeutic doses; there were no adverse events due to the compound.

Conclusion

The lead compound reduced both soluble and insoluble phosphorylated tau aggregates in the htau mouse model representing tau aggregation in AD and in the JNPL3 mouse model of inherited tauopathy. These studies validated both the screening approach against tau self‐association as a target and the in vivo efficacy of the small molecule lead compound.
Cellulose ethers reduce amyloid‐beta pathology in in vitro and in vivo Alzheimer’s disease model
Authors: Ali Tahir , Klein Antonia N. , Vu Alex , Gilch Sabine
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent cause of dementia. Neuropathologically, AD is characterized by amyloid‐beta (Aβ) aggregation. This is thought to be a primary pathological event impairing cellular homeostasis, neurotransmitters, inflammatory response, induces misfolding of other proteins and consequently leads to synaptic/neuronal loss. To date, no therapeutics are available to cure AD. Hence, we aimed to determine the therapeutic effects of cellulose ether (CE)‐based compounds for the treatment of AD.

Method

We tested different concentrations of the CE TC‐5RW in vitro for its effect on Aβ aggregation by Thioflavin T assay. Similarly, we performed MTT assays to determine cell viability of human neuroblastoma (SH‐SY5Y) cells treated with Aβ aggregates formed in the presence or absence of TC‐5RW. In vivo, transgenic 5xFAD (expressing human APP and PSEN1 transgenes harboring in total 5 mutations associated with familial AD) mice were treated at the age of 6 weeks with a single subcutaneous injection of TC‐5RW at a dosage of 4g/kg. Following this treatment, the mice were euthanized at the age of 10 months and brains were harvested for further biochemical (Western blotting) and immunohistochemical analyses.

Result

Our in vitro Thioflavin T assay results indicated that TC‐5RW had beneficial effects and at 0.25 % and 1 % TC‐5RW concentrations inhibited Aβ aggregation and accumulation. The MTT results showed that TC‐5RW increased cell viability of Aβ exposed SH‐SY5Y cells. Likewise, in vivo, the treatment with TC‐5RW significantly reduced the amount of oligomeric and monomeric forms of Aβ in the brains of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. We performed Aβ6E10 immunofluorescence staining to analyse the number of Aβ plaques, and Aβ immunoreactivity in the hippocampus and cortex of the mice. The treatment with TC‐5RW significantly alleviated the number of Aβ plaques and immunofluorescence reactivity in the hippocampus and cortex of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. These in vitro and in vivo results indicate that TC‐5RW reduces Aβ pathology.

Conclusion

Taken together, our results and the safety profile (FDA approved) of CEs, suggest that these compounds have promising potential for the development of therapeutics against AD.
Higher perceived age‐related gains and losses relate to lower objective cognitive scores
Authors: Sabatini Serena , Ukoumunne Obioha , Ballard Clive , Collins Rachel , Anstey Kaarin J. , Diehl Manfred , Brothers Allyson , Corbett Anne , Hampshire Adam , Brooker Helen , Clare Linda
Published: December 2020

Background

Awareness of age‐related changes (AARC), including perceived losses (e.g., memory decline) and gains (e.g., wisdom), comprise an important component of the aging process. Indeed, subjective perceptions of aging and health can reveal critical information not captured by objective measures. In particular, growing biomarker evidence suggests that subjective cognitive decline (SCD) may be a risk state for dementia. However, whether perceived age‐related gains confer cognitive protection is not known. We examine the extent to which perceived age‐related gains and losses explain variability in cognitive performance across three stages of older adulthood.

Method

We used cross‐sectional data from the PROTECT cohort (assessment in 2019); 6,377 UK residents (age range= 51‐95 years, mean age= 66.1 years, 75.9% women) without dementia completed measures of depression, AARC gains and losses, and undertook cognitive tasks. Structural equation modeling (SEM) was used to test whether AARC gains and losses predict scores on objective cognitive tasks. In the model, we included depressive symptoms as a mediator of the associations of AARC losses with scores on cognitive tasks. We also controlled for potential confounders. We tested the same model among three sub‐samples of individuals aged 50 to 60 (N= 1,628), 61 to 70 (N= 3,076), and 71 and over (N= 1,673).

Result

The model fit the data well among all three groups. The correlation between AARC gains and losses was negligible, yet higher levels of both predicted poorer cognitive scores among all groups. Associations of gains and losses with verbal reasoning were small to moderate, whereas associations with remaining cognitive tasks were of negligible size. Depressive symptoms mediated the effect of AARC losses on verbal reasoning in the two older groups.

Conclusion

As hypothesized, individuals with higher perceived losses demonstrated poorer cognition. In contrast, higher perceived gains did not confer protection; rather, perceived gains were also associated with lower cognitive performance. This unexpected pattern of results, seen across all age groups, underscores the complexity of mapping perceived experiences onto objective outcomes, and emphasizes the importance of considering subjective aging more broadly when refining the clinical construct of SCD as a reliable marker of cognitive decline.
Cognitive impairment and dementia among older prisoners: A report from an Italian prison
Authors: Fabbo Andrea , Neviani Francesca , Petrella Stefano , Beretta Roberto , De Salvatore Luigi , Mussi Chiara
Published: December 2020

Background

Prison population is aging. Older prisoners are increasing and age‐related problems are a new challenge for the prison officers. Dementia is under detected among old prisoners although life style, substance abuse, custody condition, jail environment increase dementia risk. Older prisoners either may be affected by dementia before the crime or develop dementia during the detention. In Italy in 2017 there were 3700 older prisoner aged 60 and over and 776 aged 70 and over.

Method

In Sant’Anna prison in Modena district currently there are 19 prisoners over 65. In our district is possible to require psychogeriatric evaluation for older prisoners .

Results

Since 2017 10 prisoners in sex offender section have been evaluated (mean age 73,7 ds 8,6): 4 of them (30%) have been identified as people with dementia (20% vascular dementia and 10% mixed dementia) and 30% have been diagnosed as neurocognitive minor disorder. 1 of them 87 years old (10%) had Alzheimer disease (MMSE20/30) at the moment of the crime. He needs to be supported by a younger prisoner who is now involved in his care, as educational program.

Conclusion

In our preliminary experience all older prisoners examined have challenging behaviour related to dementia or cognitive impairment, evaluated with NPI scale (mean 25, 3 min 18 max 38). This is a preliminary picture of Italian dementia reality in prison. This topic deserves future attention.
Comprehensive Alzheimer’s pathology is induced by P. gingivalis infection: COR388 and other gingipain inhibitors protect against synaptic loss
Authors: Ermini Florian , Haditsch Ursula , Roth Theresa , Rodriguez Leo , Broce Sean , Raha Debasish , Nguyen Mai , Hancock Sandy , Cecere Thomas , Detke Mike , Kapur Shirin , Holsinger Leslie J. , Lynch Casey C. , Dominy Steve
Published: December 2020

Background

Porphyromonas gingivalis and its proteolytic virulence factors lysine‐gingipain (Kgp) and arginine‐gingipain (Rgp) are emerging as major etiologic agents in the pathogenesis of Alzheimer’s disease (AD). We have previously reported that gingipains colocalize with neuronal cell bodies in over 90% of AD brains studied and the presence of gingipains strongly correlates with tau pathology. We have found tau protein to be a substrate for both Kgp and Rgp and have identified over forty cleavage sites combined. Here we used iPSC‐derived neuron cultures and neuron‐astrocyte‐microglia co‐cultures to investigate the neuropathological mechanisms resulting from persistent infection with P. gingivalis and gingipain exposure and highlight the therapeutic potential of gingipain inhibitors.

Method

IPSC derived neuron cultures and neuron‐astrocyte‐microglia co‐cultures were infected with P. gingivalis and analyzed by high content screening (HCS), confocal microscopy, transmission electron microscopy (TEM), protein and RNA expression analysis.

Result

Intracellular P. gingivalis bacteria were observed in neurons for 3 days or longer after infection. Infection produced significant synaptic loss that was completely prevented by Kgp and Rgp inhibitors including COR388. Using electron microscopy, we found an accumulation of autophagic vacuoles in dystrophic neurites reminiscent of ultrastructural findings in AD brains. Furthermore, gingipain exposure resulted in acute fragmentation of tau and increased tau phosphorylation, resulting in destabilized microtubules and disrupted vesicle transport. Transport disruption by gingipains accounted for the accumulation of autophagic vacuoles in dystrophic neurites, as no dystrophic neurites were observed in cultures treated with gingipain inhibitors. When co‐cultures of microglia, astrocytes and neurons were infected, activated microglia displayed the highest number of internalized bacteria and responded to infection by upregulation of inflammatory markers associated with AD pathology.

Conclusion

We demonstrate in an in vitro model system that P. gingivalis infection can result in a neurodegenerative phenotype consistent with pathology found in Alzheimer’s disease. With this model we show that exposure of neurons to P. gingivalis infection results in synaptic loss and dystrophic neurites which can be prevented by gingipain inhibitors.