bluuebunny/crossref_metadata_2025 huggingface dataset:
Heneicosapentaenoic acid is produced from 2‐hydroxy‐docosahexaenoic acid via α‐oxidation: Implications for Alzheimer’s disease therapy
Authors: Parets Sebastià , Irigoyen Ángel , Ordinas Margarita , Cabot Joan , Miralles Marc , Péter Mária , Balogh Gábor , Rosselló Catalina Ana , Fernández‐García Paula , Busquets Xavier , Lladó Victoria , Escriba Pablo V. , Torres Manuel
Published: December 2020

Background

Alzheimer’s disease (AD) is a neurodegenerative disease with as yet no efficient therapies. Many drugs and therapies have been designed and developed against this neurodegenerative disease, although none has successfully terminated a phase‐III clinical trial in humans. To shift the perspective for the design of new AD therapies, membrane lipid therapy has been tested, which assumes that brain lipid alterations lie upstream in the pathophysiology of AD. A hydroxylated derivative of docosahexaenoic acid was used, 2‐hydroxy‐docosahexaenoic acid (DHA‐H), which has shown efficacy against hallmarks of AD pathology in a transgenic mouse model of AD (5xFAD).

Method

Lipid samples were obtained from cultured cells and blood plasma and brain from WT and 5xFAD mice. Both, cell cultures and animals were treated with DHA‐H and DHA under different conditions. Mice were subjected to the Radial Arm Maze test during the last month of treatment just before sacrifice. Fatty acid analysis was performed by GC‐FID and GC‐MS (Gas Chromatography‐Flame Ionization Detector and ‐Mass Spectrometry) and the lipidomic analysis carried out by ESI‐MS (Electrospray ionization‐Mass Spectrometry).

Result

Here, for the first time, DHA‐H is shown to undergo α‐oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n‐3) metabolite, an odd‐chain omega‐3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA‐H treatment. Interestingly, DHA‐H does not share metabolic routes with its natural analog DHA (C22:6, n‐3) but rather, DHA‐H and DHA accumulate distinctly, both having different effects on cell fatty acid composition. This is partly explained because DHA‐H α‐hydroxyl group provokes steric hindrance on fatty acid carbon 1, which in turn leads to diminished uptake by cultured cells and accumulation as free fatty acid in cell membranes. Finally, DHA‐H administration to mice elevated the brain HPA levels which in turn were directly and positively correlated with cognitive spatial scores in AD mice. This effect appeared in the apparent absence of DHA‐H and without any significant change DHA levels in brain.

Conclusion

The evidence presented in this work suggest that the metabolic conversion of DHA‐H into HPA could represent a key event in the therapeutic effects of DHA‐H against AD.
Association of cardiovascular risk burden with cognitive trajectories and structural brain differences
Authors: Song Ruixue , Xu Hui , Dintica Christina S. , Pan Kuan‐Yu , Qi Xiuying , Buchman Aron S , Bennett David A , Xu Weili
Published: December 2020

Background

The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.

Method

Within the Rush Memory and Aging Project, 1,588 dementia‐free participants (mean age=79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (the lowest, middle, and the highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n=378) of the participants underwent magnetic resonance imaging (MRI). Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed‐effects models and linear regression models.

Result

In all participants, FGCRS ranged from 4 to 28 (mean score=15.6±3.7). Compared with the lowest tertile of FGCRS, the highest was associated with faster decline in global cognition (β=‐0.019, 95% confidence interval [CI] ‐0.035 to ‐0.003), episodic memory (β=‐0.023, 95% CI ‐0.041 to ‐0.004), working memory (β=‐0.021, 95% CI ‐0.035 to ‐0.007), and perceptual speed (β=‐0.027, 95% CI ‐0.042 to ‐0.011) over the follow‐up. In MRI data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β=‐0.021, 95% CI ‐0.042 to ‐0.000), total gray matter (β=‐1.569 95% CI ‐2.757 to ‐0.382), and total brain (β=‐1.588, 95% CI ‐2.832 to ‐0.344), and greater volume of white matter hyperintensities (β=0.035, 95% CI 0.001 to 0.069).

Conclusion

Higher cardiovascular risk burden may predict decline in episodic memory, working memory and perceptual speed, and is associated with neurodegeneration and vascular lesions in the brain.
Pointer‐ZZZ: Sleep ancillary to U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk of Alzheimer's disease
Authors: Molina‐Henry Doris P , Baker Laura D. , Woolard Nancy , Espeland Mark A. , Leng Xiaoyan Iris , Lim Andrew , Redline Susan , Stone Katie L , Hayden Kathleen M. ,   U.S. POINTER Study Group
Published: December 2020

Background

Non‐pharmacological approaches that target modifiable risks through lifestyle interventions provide the most promising evidence to delay disease. In older adults, chronic sleep disturbances marked by sleep‐disordered breathing (SDB) and sleep fragmentation are associated with impaired hippocampal functioning, increased beta‐amyloid burden, and greater Alzheimer’s risk. These and other sleep abnormalities are associated with reduced vascular health. Although some evidence suggests that diet, exercise, and cardiovascular risk reduction can improve sleep and improved sleep benefits cognition in older adults, these effects have not been confirmed in a rigorous clinical trial.

Methods

The U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), funded by the Alzheimer’s Association, was launched in the Fall of 2018. It is investigating whether lifestyle interventions ‐ Self‐Guided (SG) versus a Structured (STR) lifestyle intervention ‐ influence cognitive trajectories over 2 years in 2000 older cognitively normal adults (aged 60‐79 yrs) who are at increased risk for cognitive decline, Alzheimer’s disease and other dementias. The NIH‐funded POINTER‐zzz ancillary study adds in‐home objective sleep assessments for 700 participants to examine the effects of lifestyle modification and cardiovascular risk management on sleep disturbances that are linked to cognitive decline and Alzheimer’s disease and that may improve with U.S. POINTER interventions.

Results

POINTER‐zzz methods and study design will be presented, which will permit over 2000 objective sleep assessments to be completed over 2 years. These assessments will provide extensive oximetry and actigraphy data for analysis by lifestyle intervention group assignment. Sleep data will be examined relative to intervention effects on cognition and other parent trial and ancillary study outcomes, including MRI and amyloid/tau PET brain imaging. POINTER‐zzz leverages resources provided by the parent trial and other funded ancillary studies, and by well‐established collaborations with sleep experts.

Conclusions

POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep abnormalities that are linked to cognitive decline and Alzheimer’s in a well‐characterized, diverse cohort of at‐risk older adults. The study may identify an effective strategy for improving sleep that could have important consequences for reduced risk of Alzheimer’s disease and related dementias.
Validation of the Cognitive Telephone Screening Instrument (COGTEL) for detecting mild cognitive impairment and dementia due to Alzheimer's disease (AD)
Authors: Alexopoulos Panagiotis , Skondra Maria , Charalampopoulou Marina , Aligianni Souzana , Kontogianni Evangelia , Lentzari Iliana , Vratsista Aikaterini , Kliegel Matthias , Politis Antonis
Published: December 2020

Background

Cognitive assessment is necessary for diagnosing cognitive impairment. In epidemiologic surveys and genetic family studies cognitive tests that can be administered over the telephone are valuable tools. The Cognitive Telephone Screening Instrument (COGTEL) is a brief instrument for capturing interindividual differences in cognitive functioning, with the advantage of covering more cognitive domains than traditional screening tools such as the Mini‐mental State Examination (MMSE), as well as differentiating between individual performance levels in healthy older adults. Here, we report first evidence of the utility of the COGTEL in detecting mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (AD).

Method

The COGTEL was translated into Greek. Thereafter a bilingual expert not familiar with the original COGTEL made a back translation into English. The new version was very similar to the original one. The study refers to 30 and 22 patients with MCI and dementia due to AD, respectively. They fulfilled the international NIA‐AA diagnostic criteria. The study included 45 cognitively normal elderly individuals, too. The COGTEL was compared to the conventional modified Mini Mental State Examination (3MS). They were validated against an expert diagnosis based on a comprehensive diagnostic workup which included the Montreal Cognitive Assessment (MoCA). Statistical analysis was performed using the receiver‐operator‐characteristics (ROC) method.

Result

The COGTEL outperformed the 3MS in the distinction between cognitively unimpaired individuals and patients with MCI (Area under the curve, AUC: 0.94 vs. 0.89), whilst both instruments were excellent in identifying patients suffering from dementia due to AD (AUC in both cases 0.99).

Conclusion

The COGTEL is a short, practical and reliable telephone test for the identification of both MCI and dementia due to AD. It can serve as a useful instrument in studying normal cognition and cognitive impairment in aging in both clinical diagnostics and research projects. The lack of difference between COGTEL and 3MS in their capacity to detect dementia due to AD is probably attributable to the fact that healthy aging can in most cases be unambiguously distinguished from dementia due AD, while the distinction between MCI and healthy aging is more ambitious.
Sedative use by older adults with dementia is higher among women than men and exceeds recommendations
Authors: Trenaman Shanna Claire , Bowles Susan K , Kirkland Susan , Andrew Melissa K
Published: December 2020

Background

Sedative medications (benzodiazepines and Z‐drugs) are used to treat responsive behaviours in those with dementia despite association with adverse drug events and accepted status as potentially inappropriate medications. The objective of this study was to complete a sex‐based analysis of sedative use in a cohort of older adults with dementia in Nova Scotia, Canada.

Method

We examined sedative use in a cohort of adults aged 65 years and older with dementia in Nova Scotia, Canada. Prescription data was examined from April 1, 2010 to March 31, 2015. Concordance with prescribing guidelines was compared for men and women using descriptive statistics and unadjusted odds ratios.

Result

Of the 30,703 older adults with dementia in the cohort 11,647 (37.9%) received at least one prescription for a sedative. Women were more likely to receive a benzodiazepine (OR 1.44; 95% CI [1.36‐1.53]) or a Z‐drug (OR 1.10; 95% CI [1.01‐1.19]). Lorazepam was the most commonly prescribed sedative (52% of sedative users). Zopiclone was the second most commonly prescribed (27% of sedative users). Sedative use (37.9% of cohort) which is potentially inappropriate was almost two times greater than cholinesterase inhibitor use (19.3% of cohort) which is potentially appropriate for older adults with dementia.

Conclusion

Among older adults with dementia, sedatives are more commonly prescribed than cholinesterase inhibitors. Sedatives are more often used by women, suggesting that targeted interventions toward reducing sedative use in women is needed. This pattern of sedative use is not in accordance with prescribing guidelines for older adults with dementia.
18F‐PI‐2620 tau‐PET in corticobasal syndrome (ActiGliA cohort)
Authors: Brendel Matthias , Palleis Carla , Prix Catharina , Finze Anika , Boetzel Kai , Danek Adrian , Höllerhage Matthias , Beyer Leonie , Sauerbeck Julia , Rauchmann Boris , Stephens Andrew W , Drzezga Alexander , van Eimeren Thilo , Barthel Henryk , Patt Marianne , Sabri Osama , Villemagne Victor LL , Bartenstein Peter , Perneczky Robert , Haass Christian , Levin Johannes , Höglinger Günter
Published: December 2020

Background

The pathology of Corticobasal syndrome (CBS) is characterized by 4‐repeat (4R)‐tau aggregation in Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) in ∼50%, or by (3/4R)‐tau aggregation in Alzheimer’s disease (AD) in ∼25% of patients. The second generation tau‐PET ligand 18F‐PI2620 showed high affinity to 3/4R‐tau in AD and also revealed affinity to 4R‐tau pathology. The aim of this study was to investigate 18F‐PI2620 in patients with CBS that are part of the interdisciplinary AD study “Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer‘s Disease (ActiGliA)”.

Method

ActiGliA comprises a comprehensive clinical assessment, multimodal prospective imaging in vivo and fluid biomarker analyses. Thirty‐five patients (70±8y) with probable or possible CBS according to MDS‐PSP or Armstrong‐criteria underwent 18F‐PI2620 PET together with ten age‐matched healthy‐controls. Distribution volume ratios (DVR, 0‐60 min) of subcortical and cortical brain‐regions were generated using cerebellar reference tissue. DVR‐data were quantitatively and visually compared between CBS and healthy‐controls. Regional 18F‐PI2620 binding was compared with clinical severity (PSP rating scale, PSPRS), and disease duration. Amyloid‐PET served for assessment of β‐amyloid status.

Result

26% (9/35) of CBS patients (PSPRS: 25±13) were amyloid‐positive. Overall, a visually discernible 18F‐PI2620 was observed in 26 subjects (74%) and in 89% of amyloid‐positive CBS patients. Significantly elevated 18F‐PI2620 DVR was observed in the whole group of CBS patients versus healthy controls in the putamen, globus pallidus and subthalamic nucleus (Cohen’s d: 1.19/ 1.44/ 1.11, all p<0.01). The cortical signal was higher in amyloid‐positive when compared to amyloid‐negative CBS patients (DVR: 1.05±0.15 vs. 0.95±0.05, p=0.005, Figure 1). Cortical binding in CBS was heterogeneous (positive in 49%; 17/35, Figure 2). Asymmetry of PET tracer uptake matched the contralateral clinical dominance in 94% of CBS cases. 18F‐PI2620 binding showed a correlation with disease severity in the globus pallidus after controlling for age, sex and β‐amyloid‐status (R=0.426, p=0.021).

Conclusion

The application of 18F‐PI2620 in the ActiGliA study shows that 18F‐PI2620 is a potential biomarker for evaluation of CBS, facilitating detection of heterogeneous neuropathology and variable cortical and subcortical deposition sites, which could serve for monitoring disease status, progression, and target engagement.
Metformin treatment attenuates tau seeding in neuritic plaques
Authors: Zhao Shuai , Chen Yanxing , Fan Ziqi , Zhang Baorong
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by deposition of amyloid‐β (Aβ) plaques, neurofibrillary tangles. Metformin has been reported to decrease Aβ plaque load , reduce spatial memory deficit in APP/PS1 mice and reduce tau phosphorylation in the P301S mutant human tau (P301S) transgenic mouse. However, the effect of metformin on Aβ plaque‐associated tau pathogies remains unclear.

Method

Female 9‐month‐old APPswe/PS1DE9(APP/PS1) mice were used. Mice in the treatment group received 4 mg/ml metformin in the drinking water for 2 months. Brain extract containing tau aggregates isolated from P301S transgenic mouse brain was unilaterally injected into the right hippocampus and overlying cerebral cortex two weeks after the initial administration of metformin. Tau pathology, its effect on Aβ pathology and plaque‐associated microgliosis were assessed by immunohistochemical staining and immunofluorescence analysis 50 days after infusion.

Result

We observed seeded tau aggregates in dystrophic neurites surrounding Aβ plaques(NP tau) throughout the ipsilateral hippocmapus as well as spread to the contralateral hippocmapus in seeded mice using this experimental paradigm. NP tau aggregation was reduced after metformin administration. We found a decrease in the number of microglia around Aβ plaques in hippocampus of seeded mice and an increase of Aβ load in the bilateral cortex and the ipsilateral dentate gyrus of hippocampus in seeded mice. Metformin administration enhanced the activation of microglia around Aβ plaques and attenuates the Aβ load in the seeded mice.

Conclusion

These findings indicate that metformin can enhance plaque‐associated microgliosis, attenuate Aβ load and peri‐plaque tau pathologies, making it a potential therapeutic treatment for AD.
Preliminary results from the Partner Availability Limitations Study (PALS)
Authors: Largent Emily A. , Clapp Justin , Sykes Olivia , Abera Maramawit , Harkins Kristin , Grill Josh D.
Published: December 2020

Background

Alzheimer’s disease (AD) clinical trials, even trials recruiting cognitively normal populations, require participants to enroll with a “study partner” (SP). SPs serve as knowledgeable informants, reporting on participants’ cognitive and functional performance. The SP requirement can be a barrier to research participation, especially if an older adult doesn’t have someone able or willing to enroll with them.

Method

Participants in this qualitative study are adults aged 60‐85 who previously signed up to participate in either the University of California, Irvine Consent to Contact Registry (C2C) or the University of Pennsylvania Brain Health Research Registry. Respondents participate in semi‐structured interviews covering: (1) social supports; (2) willingness to ask someone to be their SP; (3) whom they would ask; and (4) ways of increasing SP participation. Individuals identified as likely to be asked to be a SP are subsequently recruited to participate in semi‐structured interviews covering similar domains. Sixty potential AD trial participants and 30 potential SPs are being interviewed. All interviews are recorded, transcribed, and coded. Coding is managed with NVivo 12.0. The University of Pennsylvania IRB approved this study.

Results

Most respondents identify at least one person—typically a family member or close friend—who could be their SP. When identifying a potential SP, respondents consider their relationship with and personal traits of the SP, as well as the logistics of research participation. Willingness to ask that individual to fill the SP role varies. The SP role is seen as burdensome, with the relative level of burden dependent on non‐research demands on the SP’s time and attention (e.g., family and work). Respondents believe that the SP role has numerous benefits for the participant (e.g., emotional/logistical support), the SP (e.g., positive feelings), and the researchers (e.g., additional source of data). Offers of payment to the SP and flexible study visits (e.g., nights/weekends or virtual appointments) would increase willingness to ask a SP.

Conclusion

Our results indicate that identifying someone able and willing to serve as a SP can be challenging for older adults interested in AD clinical trials, but modifications of study design may help overcome this barrier.
Inflammatory markers in Alzheimer's disease and mild cognitive impairment: A meta‐analysis and systematic review of 170 studies
Authors: Shen Xue‐Ning , Niu Li‐Dong , Wang Yanjiang , Cao Xi‐Peng , Liu Qiang , Tan Lan , Zhang Can , Yu Jin‐Tai
Published: December 2020

Background

Inflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively.

Method

Studies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity.

Result

A total of 170 studies were included in the meta‐analysis and systematic review, which demonstrated increased peripheral levels of high‐sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin‐6 (IL‐6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1‐antichymotrypsin (α1‐ACT) (1.217, p<0.005), IL‐1β (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL‐10 (0.434, p<0.05), monocyte chemoattractant protein‐1 (MCP‐1) (0.798, p<0.005), transforming growth factor‐beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL‐40 (0.849, p<0.001), α1‐ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin‐like protein‐1 (VILIP‐1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL‐6 (0.129, p<0.05) and MCP‐1 (0.779, p<0.05) and lower levels of IL‐8 (‐1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL‐40 (0.373, p<0.05), VILIP‐1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI.

Conclusion

Significantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.
Menopausal hormone therapy has beneficial effects on cognitive trajectories among homozygous carriers of the APOE‐ε4 allele
Authors: Mahoney Emily R. , Dumitrescu Logan , Maki Pauline M. , Rapp Stephen R. , Keene C. Dirk , Corrada Maria M.M. , Hayden Kathleen M. , Baker Laura D. , Espeland Mark A. , Resnick Susan M. , Hohman Timothy J.
Published: December 2020

Background

Two‐thirds of Alzheimer’s disease (AD) cases are females and increasing evidence suggests the greatest genetic risk factor for AD, the APOE‐ε4 allele, has a stronger association among females compared to males. Estrogen changes after menopause may contribute to cognitive decline, particularly among those at highest genetic risk for AD. While estrogen treatment has not shown a consistent association with reducing cognitive decline in late‐life, the modifying role of APOE on the cognitive consequences of menopausal hormone therapy (MHT) is not well‐characterized. We used a pharmacogenomic approach to evaluate the interaction between MHT and APOE on longitudinal cognitive change leveraging data from the Women’s Health Initiative (WHI).

Method

We evaluated data from 4,128 WHI participants who were randomized to receive conjugated equine estrogens with or without medroxyprogesterone acetate (n=2,030) or matching placebo (n=2,098). Cognition was measured biennially with the Modified Mini‐Mental Status Exam (3MSE). At baseline, average age was 70±4, average 3MSE was 96±3 and 25% of participants were APOE‐ε4 carriers. Mixed‐effects regression using a three‐way interaction (APOE x years from baseline x treatment group) assessed the potential modifying role of APOE on the cognitive consequences of MHT. Separate sensitivity analyses were run in the estrogen and estrogen+progestin treatment groups.

Result

APOE genotype significantly interacted with MHT on change in 3MSE scores (Figure 1, p=0.01), whereby homozygous ε4 carriers showed a benefit of MHT (p=0.01), while heterozygotes and non‐ε4 carriers showed none (p>0.07). This interaction was consistent between the estrogen‐alone and estrogen+progestin treatment groups.

Conclusion

MHT may have cognitive benefits among women who are at high genetic risk for AD. Literature on the cognitive effects of MHT among APOE‐ε4 carriers remains mixed, but this analysis of a large sample from a randomized trial of MHT adds critical information to the field. Additional work is needed to better understand how age, timing of MHT initiation, treatment duration and form, or other health conditions may contribute to the observed effect of MHT among APOE‐ε4 homozygotes. Regardless, these findings underscore the potential benefit of a precision medicine approach that integrates genetic modifiers of treatment response into clinical decision‐making.
Serum neurofilament light level in the clinical diagnosis of Chinese patients with Alzheimer’s disease
Authors: Chu Leung Wing , Pan Yining , Li Siwen , Chen Ruijun , Wong Dana , Song Youqiang
Published: December 2020

Background

Biomarkers are much needed to assist the clinicians in the diagnosis of Alzheimer disease (AD). Neurofilament light chain (NfL) was reported as a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) in previous Caucasian studies. In this study, we aimed to evaluate the diagnostic accuracy of the serum neurofilament light (NfL) level in the clinical diagnosis of Chinese patients with Alzheimer’s Disease.

Method

We performed a nested case‐control study on Alzheimer’s disease patients and cognitively normal older adults, who were recruited in a prospective cohort on aging and dementia in Hong Kong in 2004‐2005. Alzheimer’s disease (AD) was diagnosed in accordance to the National Institute of Neurological and Communicative Disorders and Stroke / Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) criteria. Normal control subjects had normal cognition without cognitive complaint or impairment on assessment. Blood samples were immediately processed and serum samples were stored in cryotubes in ‐80°C freezers. The serum samples of subjects were retrieved for assay of serum neurofilaments light (NfL) chain assays, using a highly sensitive single molecule array assay (SIMOA) with the Quanterix SIMOA HD‐1 Analyzer. For matching of APOE4 (with 1 or 2 copies of APOE4) status, we randomly selected 50% APOE4 positive and 50% APOE4 negative subjects.

Result

Three subjects who had inadequate serum were excluded. Finally, 149 subjects (75 AD and 74 normal control) subjects were included‐ (Table). AD subjects were significantly older (p<0.001). less educated (p<0.001), and had lower Mini‐Mental State Examination (MMSE) scores (p<0.001). Age showed a positive correlation with the serum NfL level (r=0.56, p<0.001). Multivariate analyses with general linear model showed the serum NfL level was significantly higher in AD than normal control, after adjustment for age, sex and APOE. Receiver Operating Characteristic (ROC) curve analyses showed the Area‐Under‐Curve (AUC) was 0.859 (p<0.001). The optimal cut‐off of the serum NfL level for the diagnosis of AD was >17.31 pg/ml, with sensitivity and specificity of 89% and 73% respectively.

Conclusion

In this study, we found the serum NfL level is a useful blood biomarker for the diagnosis of Alzheimer’s Disease in Chinese persons.
Cognitive impairment under treatment with second‐ and third‐generation antihistamines
Authors: Adler Georg , Baumgart Nadja
Published: December 2020

Background

Brain histamine is involved in the regulation of arousal, cognition, and memory mainly through interactions with histamine H1 receptors. Histamine H1 antagonists often prescribed for treatment of allergic disorders, may induce sleepiness and cognitive deficits. Sedation as a consequence of treatment with 1st generation antihistamines has led to the development of 2nd and 3rd generation anthistamines, which are thought to be free of cognitive side effects. This proved to be true in studies on the cognitive effects of single doses in healthy volunteers. However, the relationship between treatment with 2nd or 3rd generation antihistamines and cognitive performance so fas has not been examined within a naturalistic study under everyday conditions. This may be relevant for Alzheimer’s disease treatment studies, because cognitive side effects as a consequence of treatment with 2nd or 3rd generation antihistamines may act as a confounding variable.

Method

380 patients with chronic spontaneous urticaria (CSU) were assessed in 30 dermatological practices and outpatient clinics in Germany. Severity of disease was assessed by means of the Urticaria Activity Score (UAS‐7) and the Urticaria Control Test (UCT), quality of life by the Dermatology Life Quality Index (DLQI) and the Chronic Urticaria Quality of Life Questionnaire (CU‐Q2oL). Cognitive performance was studied by means of the computer‐based Memory and Attention Test (MAT). Sociodemographic data, current medication in treatment categories, comorbidities, obesity, smoking and drinking habits are taken by a questionnaire.

Result

The assessments were carried out in 380 subjects at ages between 19 and 73 years (mean +/‐ SD: 49 +/‐ 15). In patients under treatment with 2nd or 3rd generation anthistamines compared to patients not under treatment with antihistamines, we found a significant impairment of episodic working memory, particularly in the elder subjects. The impairment was found independently whether antihistamines were applied at dosages licensed for treatment or at higher dosages. Episodic short‐term memory and selective attention were unimpaired.

Conclusion

Treatment with 2nd or 3rd generation antihistamines may be associated with cognitive impairment, particularly in elderly patients. This effect should be considered regarding the handling of concomitant medications in Alzheimer’s disease treatment trials.
Characteristics and prognosis of patients with mild cognitive impairment by cerebrospinal fluid biomarker profiles
Authors: Estellés Teresa , Carmona‐Iragui Maria , Illán‐Gala Ignacio , Barroeta Isabel , Sánchez‐Saudinós Maria Belen , Sala Isabel , Morenas‐Rodríguez Estrella , Altuna Miren , Santos‐Santos Miguel A , Xucla Tomás , Blesa Rafael , Fortea Juan , Lleó Alberto , Alcolea Daniel
Published: December 2020

Background

Biomarkers have an important diagnostic and prognostic value in neurodegenerative diseases, especially in early stages. We analyzed the differences in baseline characteristics and clinical evolution of patients with mild cognitive impairment (MCI) according to their cerebrospinal fluid (CSF) Alzheimer Disease biomarkers profile.

Method

We retrospectively selected all patients evaluated in the Sant Pau Memory Unit that had a neuropsychological evaluation compatible with MCI, analysis of Alzheimer CSF biomarkers and clinical follow‐up for at least 6 months. Patients were classified applying our internal cutoffs for CSF levels of Aβ1‐42 as a marker of amyloidosis (A+/A‐) and CSF levels of pTau as a marker of Tau pathology (T+/T‐).We compared demographic characteristics, cognitive progression, and final clinical diagnoses between groups.

Result

We included 274 participants: 103 A‐/T‐, 43 A+/T‐, 40 A‐/T+ and 88 A+/T+. The mean follow‐up was 3.4 years. Patients in the A‐/T‐ group were younger (67.8 years) compared to those in the A+/T+ group (72.3 years, p=0.002). During follow‐up, the A+/T+ group showed greater global cognitive impairment (‐1.5 MMSE score/year; p <0.001)and higher risk of progression to dementia (OR=3,13, p<0.001). There were no differences in baseline neuropsychological scores between A+/T‐ and A‐/T+ groups. The proportions of patients with a final clinical diagnosis of Alzheimer's dementia (AD), Lewy body Dementia (LBD) and frontotemporal lobar degeneration related syndromes(FTLD) were 37%, 16% and 12% in the A+/T‐ group, and 25%, 10% and 5% in the A‐/T+ group, respectively. Compared to the A+/T‐ group, the A‐/T+ group had a higher proportion of patients whose final clinical diagnosis was non‐neurodegenerative or undetermined (60% vs. 35%, respectively; p=0.022) and a lower risk of progression to dementia (OR=0.37; p=0.032).

Conclusion

A CSF profile suggestive of AD pathophysiology is associated with greater global cognitive impairment and a higher risk of progression to dementia. Although we did not find differences in baseline neuropsychological scores between patients with positive markers of amyloidosis and those with tau pathology only, patients with amyloidosis showed a higher risk of progression to dementia in follow‐up. The benefit of using additional markers of amyloidosis and/or tau pathology in the assessment of prognosis of these patients needs to be further explored.
Grouping tau topologies in former boxers assessed by PET with 18F‐PM‐PBB3: A reappraisal of dementia pugilistica
Authors: Takahata Keisuke , Shimada Hitoshi , Kubota Manabu , Seki Chie , Tagai Kenji , Matsuoka Kiwamu , Miyata Mari , Sano Yasunori , Yamamoto Yasuharu , Saito Fumie , Mizushima Jin , Anamizu Sachiko , Kawamura Kazunori , Zhang Ming‐Rong , Muramatsu Taro , Tabuchi Hajime , Sahara Naruhiko , Mimura Masaru , Higuchi Makoto
Published: December 2020

Background

Accumulation of hyperphosphorylated tau is a core feature of late‐life sequalae of mild‐repetitive traumatic brain injury (mrTBI). Brain‐bank surveys have demonstrated that chronic traumatic encephalopathy (CTE), defined as tau accumulation at the depths of cortical sulci, is a typical neurodegenerative condition associated with mrTBI exposure. In contrast, early case‐reports of dementia pugilistica (DP) in former boxers described considerable heterogeneity of late‐life neurodegenerative changes. Despite such inconsistency, topology of tau accumulation in the living brain of mrTBI patients have not been fully investigated. The present study was aimed to characterize cerebral retention patterns of 118F‐PM‐PBB3 (18F‐APN‐1607) in the former boxers.

Method

Thirteen former boxers (46.2 ± 11.9 years) and 15 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐PM‐PBB3 and [11C]PiB. Standard uptake value ratio (SUVR) with the cerebellar gray matter as reference was calculated. Association of SUVR with neurocognitive symptoms and years of playing boxing was investigated.

Result

All subjects were [11C]PiB negative. Boxers showed higher 18F‐PM‐PBB3 accumulation than HC subjects in the gray (P = 0.0002) and white matter (P = 0.0001). There was a trend of correlation between SUVR values in the temporal cortex and years of exposure to concussions (p=0.07, r=0.40). Visual assessments revealed heterogeneity in 18F‐PM‐PBB3 retention patterns in boxers. First, the majority of boxers (7/13) demonstrated multiple 18F‐PM‐PBB3 accumulations around the depth of cerebral sulci, showing striking resemblance to previously reported tau topology of CTE. Subjects in this group tend to show severe memory impairment and depression. Second, a few boxers (3/13) showed diffuse 18F‐PM‐PBB3 accumulation, indicating some form of non‐AD tauopathy but currently unspecified. Subject in this group showed psychiatric symptoms such as psychosis and mania. Third, the other 3 boxers showed minimum 18F‐PM‐PBB3 retention regardless of clinical symptoms.

Conclusion

Our results indicates different forms of tau neuropathology underlying late‐sequalae of mrTBI in agreement with the classical concept of DP. These forms vary in where and how much tau accumulate, as well as in clinical features. The present study not only supports pathological heterogeneity of late‐sequalae of mrTBI, but also suggests utility of 18F‐PM‐PBB3 PET in detection of late‐life neurodegenerative diseases following mrTBI.
Plasma biomarkers of inflammation reflect disease state in autosomal dominant forms of familial frontotemporal dementia
Authors: Ljubenkov Peter A. , Staffaroni Adam M. , Casaletto Kaitlin B. , Rojas Julio C. , Vandevrede Lawren , Heuer Hilary W. , Elahi Fanny M. , Brushaber Danielle , Foroud Tatiana M. , Forsberg Leah K. , Karydas Anna M. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Kramer Joel H. ,   ARTFL and LEFFTDS Consortium Investigators
Published: December 2020

Background

Immune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.

Methods

We examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).

Results

Plasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.

Conclusion

Plasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.
Examining the effects of the microglial PLCG2 P522R mutation by transplantation of human stem cell‐derived microglia in chimeric AD mice
Authors: Claes Christel , Danhash Emma , Hasselmann Jonathan , Chadarevian Jean Paul , Shabestari Sepideh Kiani , Lim Tau En , Tu Christina , Silva Jorge , Coburn Morgan A. , Jairaman Amit , Cahalan Michael , Blurton‐Jones Mathew , Davtyan Hayk
Published: December 2020

Background

Genetic studies have uncovered several Alzheimer’s Disease (AD) risk genes that are highly expressed in microglia, suggesting that immune dysregulation plays a critical role in the development and progression of AD. In line with this, a recently discovered polymorphism (P522R) in the microglia‐expressed gene Phospholipase C‐Gamma 2 (PLCG2) was shown to be protective for AD. Interestingly, PLCG2 codes for a protein that regulates the release of calcium from ER stores and is also a component of the downstream signaling pathway of TREM2, another microglial AD risk gene. This underscores the need to improve our understanding of microglial calcium signaling, the effects of AD risk genes on this pathway, and the impacts of PLCG2 and calcium signaling on human microglial function.

Methods

CRISPR gene editing was used to produce isogenic iPSCs that express the AD protective mutation in PLCG2. Several in vitro assays were then performed to examine calcium signaling pathways and phagocytosis. PLCG2‐P522R and WT HPCs were also transplanted directly into xenotransplantation‐compatible mouse pups (MITRG‐5xfAD mice), where they readily differentiated into human microglia, exhibiting typical markers and morphology.. Xenotransplanted human microglia (x‐MG) were then examined by confocal microscopy and isolated from the brain for single‐cell RNA sequencing.

Results

Thus far our in vitro studies suggest that the P522R coding mutation increases both basal cytosolic calcium concentrations and amyloid phagocytosis. Additional functional experiments are further examining the interactions between PLCG2 mutations and calcium signaling during the uptake of AD‐relevant substrates. In addition, single cell RNA sequencing studies of chimeric mice reveal that the P522R mutation leads to an increased percentage of human microglia that have adopted a disease‐associated microglial (DAM) phenotype in vivo.

Conclusions

By combining iPSC‐microglia, CRISPR gene editing, and chimeric AD mice these studies have begun to uncover the impact of PLCG2 mutations on human microglial function and reveal that the protective P522R mutation increases Ab phagocytosis and promotes the adoption of a DAM‐like microglial response.
Single nuclear RNA sequencing reveals microglia diversity associated with cognitive resilience in the AD‐BXD mouse model of human Alzheimer’s disease
Authors: Heuer Sarah E. , Zhang Jigang , Samuels Michael , Hadad Niran , Telpoukhovskaia Maria , Ouellette Andrew R. , O'Connell Kristen M.S. , Menon Vilas , Robson Paul , Philip Vivek , Kaczorowski Catherine C.
Published: December 2020

Background

An individual’s genetic background plays an important role in governing the risk (or resilience) to developing Alzheimer’s disease (AD) dementia. The goal of this study was to identify the molecular pathways and cell‐types conferring individual differences in cognitive resilience to human familial AD (FAD) mutations that drive high amyloid.

Method

A large set of genetically diverse mice harboring familial AD mutations (AD‐BXDs) and their non‐transgenic littermates (Ntg‐BXDs) were tested for short‐ and long‐term memory using contextual fear conditioning at 6m (AD‐BXD n=180, Ntg‐BXD n=174) and 14m (AD‐BXD n=121, Ntg‐BXD n=137). A subset of 14 AD mutation carriers that exhibited extreme resilience (n=7) or susceptibility (n=7) to cognitive decline were selected for hippocampal molecular profiling, along with their Ntg‐BXD littermates, at both 6m and 14m. Data from all hippocampi were aggregated and batch‐corrected using Harmony, and Seurat clustering was employed using the top 2000 variable genes. Known marker genes were used to associate clusters with cell‐types. The fraction of nuclei per sample (cluster composition) and within cell‐type differential gene expression were performed to determine changes in cell quantity and molecular profiles as a function of age, AD mutation carrier status, and resiliency to cognitive decline.

Result

There were no clusters that showed significant change in composition as a function of age. However, AD‐BXD individuals had significantly fewer astrocytes and more microglia than their Ntg‐BXD counterparts. We also found that resilient AD‐BXDs had fewer microglia than susceptible individuals, and the number of microglia at 6m was significantly negatively correlated with cognitive decline in AD‐BXD individuals. Additionally, microglia from resilient individuals showed up‐regulation of mitochondrial respiration and protein translation genes, proposing two pathways that dictate resilience in a microglia‐specific manner.

Conclusion

Our findings further implicate non‐neuronal cell‐types such as microglia in promoting resilience to cognitive decline in AD, and suggest several pathways by which microglia may be altered in resilient compared to susceptible individuals. We believe that by altering these microglia pathways within susceptible individuals, we can improve how non‐neuronal cells interact with CNS neurons to improve AD cognitive resilience.
MRI‐histopathology correlations of amyloid‐related imaging abnormalities (ARIA) in postmortem human brain samples
Authors: Scherlek Ashley , Kozberg Mariel , Nicoll James A.R. , Bacskai Brian , Greenberg Steven M. , Frosch Matthew P. , Boche Delphine , Veluw Susanne J.
Published: December 2020

Background

Amyloid‐related imaging abnormalities (ARIA) on MRI are frequently observed adverse advents in the context of anti‐Aβ immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and mechanisms of ARIA remain unknown, although coexisting Cerebral Amyloid Angiopathy (CAA) appears to be a risk factor.

Method

Ten cases were selected from the long‐term follow‐up study of patients who enrolled in the first clinical trial of active Aβ immunization for AD (AN1792; Elan Pharmaceuticals Inc) (iAD cases; mean age at death 81 years, mean survival time from first immunization 107 months). Eleven matched non‐immunized AD cases were used as “controls” (cAD cases; mean age at death 79 years). Formalin‐fixed coronal slabs from the occipital lobe were imaged on a 7T MRI scanner, including a T2*‐weighted gradient echo sequence (voxel size 200 µm3). Samples with and without ARIA were cut in serial sections and stained with Hematoxylin & Eosin (H&E), Perls’ Prussian blue (iron), Von Kossa (calcifications), and immunohistochemistry against Aβ (Dako; clone 6F/3D).

Result

On ex vivo MRI, ARIA were observed in 7/10 iAD cases (including one case with documented ARIA during life) compared to 1/11 cAD cases (p=0.004), in the form of cortical superficial siderosis, hypointense lining of the deeper cortical layers, and white matter rarefaction (arrows in Figure). Histopathologically, ARIA corresponded to intraneuronal, vascular, and extracellular iron depositions and calcifications (Figure). In iAD cases the degree of iron (p=0.0006) and calcium deposits (p<0.0001) was more severe compared to cAD cases. In contrast, Aβ plaque burden was less severe in iAD cases (p=0.0017), confirming the previously reported observation of Aβ plaque removal after immunotherapy. Although the degree of CAA was comparable between iAD and cAD cases, concentric splitting of the walls of leptomeningeal vessels (an advanced stage of CAA severity) was observed in iAD cases in areas with ARIA, but not in areas without ARIA (p=0.055).

Conclusion

These findings suggest that ARIA in the context of anti‐Aβ immunotherapy may result in lasting neuropathological alterations (perhaps even in the absence of clinical symptoms) and that advanced CAA likely plays a role in the pathophysiology of ARIA.