bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I single ascending dose safety study of NTRX‐07 in normal volunteers
Authors: Foss Joseph , Naguib Mohamed , Giordano Tony
Published: December 2020

Background

NTRX‐07 is a selective cannabinoid receptor type 2 (CB2) agonist that has been shown in animal models to be effective for the treatment of Alzheimer’s disease (AD). CB2 agonists have been shown to be neuroprotective in preclinical models and the lack the psychotropic adverse effects normally seen with CB1 agonists1‐4. NTRX‐07 has acceptable drug metabolism, pharmacokinetic and preclinical safety profiles.

Method

This is a double‐blind, placebo controlled single ascending dose study with 6 cohorts of normal volunteers 18‐65 years of age (n=∼48). The primary outcome is the safety and tolerability of NTRX‐07. Each cohort is randomized with 6 subjects receiving active drug and 2 placebo. Doses range from 0.3 to 8 mg/kg of NTRX‐07 in a HPMCAS‐MG excipient administered orally. Subjects are admitted to the site the night before dosing, and are observed for 24 hours post‐dose, with a safety visit 7 days later. Subjects are observed for changes in physical exam or symptoms (including questionnaires of drug effect), vitals, laboratory values and adverse events (AEs). Blood samples are obtained to determine the pharmacokinetics of NTRX‐07 in humans.

Result

At submission three cohorts have completed dosing and all cohorts will be completed for final poster submission. No treatment related AEs have been observed. Plasma levels have been higher than predicted based on preclinical studies suggesting differences in absorption or metabolism compared to animal models. Pharmacokinetics (PK) have demonstrated dose linearity and support feasibility in clinical use.

Conclusion

There are currently no commercially available CB2 agonists. NTRX‐07 would represent the first‐in‐class of a new therapeutic agent to treat microglial‐mediated neuroinflammation in a variety of diseases where the CB2 receptor has been shown to be active such as AD, ALS and FTD. The next study will be a 28 day repeat dose of NTRX‐07, in patients with MCI or early AD, for safety, PK and exploratory biomarkers. References: 1 Naguib, M. et al. Br. J. Pharmacol. 155, 1104‐1116 (2008). 2 Diaz, P. et al. ChemMedChem 4, 1615‐1629 (2009). 3 Wu, J. et al. Neurobiol. Aging 34, 791‐804 (2013). 4 Wu, J., et al. Eur. J. Pharmacol. 811, 12‐20, (2017).
Multiple sclerosis is associated with lower amyloid but normal tau burden on PET
Authors: Zeydan Burcu , Lowe Val J. , Reichard Ross R. , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Parisi Joseph E. , Machulda Mary M. , Vemuri Prashanthi , Mielke Michelle M. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Kantarci Orhun H. , Kantarci Kejal
Published: December 2020

Background

While β‐amyloid and tau PET imaging are widely studied in cognitive aging and Alzheimer’s disease (AD), little is known about findings in aging multiple sclerosis (MS) patients. As aging is an essential factor in developing neurodegeneration in MS, β‐amyloid and tau biomarkers may be utilized to understand the influence of AD pathophysiology on cognitive aging in MS.

Method

We studied patients with MS (n=16) and controls (n=80) matched for age, sex and APOE ε4 status from the population‐based Mayo Clinic Study of Aging who underwent Pittsburgh compound‐B (PiB) PET imaging. Twelve of the 16 patients with MS and 60 matching controls also underwent flortaucipir (AV1451) tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVr) from previously determined AD signature regions and from the entire cortex were calculated for group comparisons and testing for associations with age.

Result

AD signature PiB SUVr (p=0.044), total cortical PiB SUVr (p=0.048) and the frequency of abnormal PiB SUVrs (p=0.040) were lower in patients with MS than controls. Although AD signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (p=0.041) in patients with MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls (Figure 1). The AD signature PiB SUVr increased more with increasing AD signature AV1451 SUVr in controls than in patients with MS (p=0.03) (Figure 2).

Conclusion

In patients with MS, cortical β‐amyloid deposition was lower than age‐matched controls, while cortical tau deposition was not different between the groups. This suggests that some aspect of MS pathobiology retards the accumulation of β‐amyloid, but not the accumulation of tau.
Dementia‐friendly sport and physical activity: A meta‐analysis
Authors: Nguyen Thuy Trang , Vo Tuong Kha , Vo Van Giau
Published: December 2020

Background

Physical activity has been suggested as relevant to many health outcomes, including: cardiorespiratory health, musculoskeletal health, cancer, functional health and prevention of falls, depression as well as dementia.

Method

Meta‐analyze publicly available PubMed, Science Direct, and Willey data between 2006 and 2019. Keywords such as “dementia,” “sport” and “physical activity” were applied in searching for papers. As a result, 12 studies were selected in the second screening of the study.

Result

The enhancement in the dementia symptom of physical capacity was 1.3 (95% CI: 0.05 to 0.8), ability of activity of daily living was 0.81 (95% CI: 0.13 to 1.6), cognitive function was 0.5 (95% CI: 0.32 to 0.67), and psychological state was 0.40 (95% CI: 0.02 to 0.82).

Conclusion

The physical activity for patients with dementia had an effect on the enhancement of physical capacity and combined exercise was the most effective physical activity.
Mild Behaviour Impairment Checklist (MBI‐C): Is there a difference in ratings between patient and close informant?
Authors: Soo See Ann , Ng Kok Pin , Wong Fennie , Yatawara Chathuri , Chiew Hui Jin , Lyn Ng Adeline Su , Ismail Zahinoor , Kandiah Nagaendran
Published: December 2020

Background

Mild Behavioural Impairment‐Checklist (MBI‐C) is a validated questionnaire that measures sustained later‐life emergent neuropsychiatric symptoms among people with prodromal dementia. Using this checklist as a MBI case ascertainment instrument, the prevalence of MBI was found to be 5.8% in subjective cognitive decline (SCD) and 14.2% in mild cognitive impairment (MCI). While the MBI‐C can be self‐administered or administered through a close informant via face‐to‐face or phone interviews, it is unknown whether patients and close‐informants differentially report on the MBI‐C. Here, we aim to examine the differences in self‐administered and close‐informant administered MBI‐C scores in a specialty clinic population.

Method

87 (25 SCD and 62 MCI) patients from the Singapore National Neuroscience Institute memory clinic completed the MBI‐C and Geriatric Depression Scale (GDS)4. Close‐informants completed the MBI‐C and Zarit caregiver burden scale (Zarit)5. The MBI‐C is a 34‐item questionnaire organized into five domains; 1) motivation, 2) emotional regulation, 3) impulse control, 4) social cognition, and 5) abnormal thoughts. MBI is defined by an MBI‐C total score of >6.5 in MCI 3 and a >8.5 total score in SCI2. Paired sample T‐test evaluated the difference in MBI‐C scores between patients and close‐informants. Pearson correlation test evaluated the associations between MBI‐C with GDS and Zarit scores.

Result

Out of 87 participants (Mage= 67.62, SD=9.08), 29 participants were diagnosed with MBI. The frequency of MBI did not differ between SCI and MCI (40% in SCI and 30% in MCI). We found that MBI‐C domain scores did not differ significantly between patients and close‐informants (p>0.05). GDS scores positively correlated with MBI total score (p<0.01), motivation (p<0.01), emotional regulation (p<0.01), impulse control (p<0.01), social cognition (p=0.001) and abnormal thoughts (p=0.018). Zarit scores positively correlated with MBI total score (p=0.017) and impulse control (p=0.009).

Conclusion

MBI is common in our Asian clinic population with preclinical prodromal dementia diagnosed using the MBI‐C and was associated with greater caregiver burden and depressive symptoms. Importantly, we found that patients and their close‐informants do not report differently on the MBI‐C. Our findings suggest that both patients and close‐informants may provide reliable measures of the patient’s neuropsychiatric symptoms using the MBI‐C.
Masupirdine in combination with donepezil and memantine in patients with moderate Alzheimer's disease: Subgroup analyses of memantine regimen, plasma concentrations and duration of treatment
Authors: Nirogi Ramakrishna , Goyal Vinod Kumar , Bhyrapuneni Gopinadh , Palacharla Veera Raghava Chowdary , Ravulu Jyothsna , Jetta Satish , Jasti Venkat
Published: December 2020

Background

Masupirdine (SUVN‐502), a selective 5‐hydroxytryptamine‐6 (5‐HT6) receptor antagonist has demonstrated efficacy in animal models of cognitive impairment. To assess its clinical utility, a randomized, double blind, placebo controlled 26 week phase 2 study was conducted in moderate Alzheimer’s disease (AD) patients who were on stable treatments with donepezil and memantine.

Method

In the phase 2 study, a total of 564 moderate AD patients with MMSE scores between 12 and 20 were randomized to receive either 50 mg or 100 mg of masupirdine or placebo once daily for 26 weeks. All patients were treated with donepezil 10 mg + memantine 10 mg BID or Namenda XR 28 mg QD; or Namzaric (donepezil 10 mg + 28 mg Namenda XR). The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog11). In subgroup analyses, impact of memantine regimen, memantine plasma concentrations and memantine treatment duration on the efficacy of masupirdine in moderate AD patients was analysed.

Result

In participants whose memantine plasma concentrations were ≤100 ng/mL at Week 26, there was lesser decline in ADAS‐Cog 11 scores in participants taking masupirdine than in those on placebo. In participants taking the higher masupirdine study dose of 100 mg daily, there were also congruent signals for less decline on MMSE and CDR‐SB. Additionally, in participants whose memantine plasma concentrations were ≤100 ng/mL at Week 26, masurpirdine treatment was associated with Week 26 response rates on the ADAS‐Cog 11, for improved or stable scores compared to baseline, that were twice that of placebo. In participants on background memantine treatment for > 4 years, masupirdine treatment (versus placebo) was associated with lesser decline in ADAS‐Cog 11 scores.

Conclusion

Subgroup analyses of the masupirdine Phase 2 POC study to assess potential effects of memantine regimen, memantine plasma concentrations and duration of treatment on primary and secondary study outcomes revealed several potential signals for differential effects favoring masupirdine treatment. These observations merit better understanding and further possible investigations of masupirdine as a potential treatment for AD dementia.
Effects of serum homocysteine, depression and instrumental daily living ability on cognitive function in elderly people at high altitudes
Authors: Zhu Aiqin , Hou Yonglan , Li Guofeng
Published: December 2020

Background

To explore the level Homocysteine (Hcy), depressive state and daily living ability on the decline of cognition ability in elderly under hypoxic environment.

Method

Between June 2017 and June 2019, 288 participants of elderly (mean aged 67.13 years) Han subjects living in Xining City (altitude 2,260 meters) of Qinghai Province were divided into three groups: 125 Mild cognitive impairment (MCI), 20 Alzheimer’s disease (AD), 83 control. Serum HCY level was determined by BECKMAN COULTER biochemical analyzer. The cognition ability were used by Mini‐mental State Examination (MMSE), Geriatric Depression Scale (GDS), Auditory Verbal Learning Test (AVLT),Digit Span Test)DST),Activities Daily Living (BADL), Instrumental Activities of Daily Living (IADL). Fund project: National Key R&D Program of China (No : 2018YFC1315201).

Result

1. There was no significant difference in age, gender, educational level among the three groups. 2. Compared with controland MCI groups, Hcy of AD group was significantly increased (p<0.05). GDS and IADL scores of AD group was significantly higher than MCI and control groups (p<0.05,p<0.01). 3. Compared with control group, BADL score of AD group was significantly increased (p<0.01), while there was no significant difference the BADL score between control and MCI group (p> 0.05). 4. The scores of DST, AVLT and MMSE in the forward and reverse direction, delayed memory, attention, calculation and working memory and visuospatial ability of HHcy group were significantly lower than those of normal Hcy group (p<0.01, p<0.05, p<0.05). 5. MMSE score was negatively correlated with Hcy, IADL and GDS (r=‐0.324, ‐0.228,‐0.191;p<0.01,p<0.05). Logistic analysis showed that HCY was the risk factor of cognitive dysfunction (OR=1.005, 95% CI: 1.005‐1.109, p<0.05).

Conclusion

The decline of cognition ability in the elderly at high altitude is correlated with Hcy, IADL and GDS. HHcy is the major risk factor for cognitive dysfunction. Combined MMSE, GDS and IADL scale scores provide objective basis for the warning, prevention and control of early cognitive dysfunction in the elderly under hypoxic environment.
Association between mean corpuscular volume and cognitive impairment in an 8‐year cohort study in the community‐dwelling elderly
Authors: Li Yi‐Ming , Chen Yen‐Ching , Chen Jen‐Han , Chiou Jeng‐Min , Chen Ta‐Fu , Lai Liang‐Chuan
Published: December 2020

Background

Mean corpuscular volume (MCV) is the average volume of red blood cells (RBC). Larger MCV reduces the amount of RBC reaching the brain, while smaller MCV was associated with iron‐deficiency anemia and the subsequent cognitive impairment. Few studies have relating MCV levels to cognitive impairment and their findings were inconsistent. This study aimed to explore this association in community‐dwelling older adults.

Method

This study is part of an ongoing cohort study Taiwan Initiatives for Geriatric Epidemiological Research (TIGER, 2011‐ present). A total of 605 non‐demented older adults (age 65+) were recruited at baseline (2011‐2013). After exclusion of participants with dementia at baseline, history of stroke, brain tumor, loss of consciousness, missing data of MCV, 319 elderly were included for analysis. Global and domain‐specific cognition (logical memory, attention, verbal fluency, and executive function) were assessed for each participant at baseline, 2‐year, 4‐year, and 6‐year follow‐ups. MCV was assessed at baseline and then tertitled; high MCV indicates the highest tertile (≥92.7 fL); low MCV indicates the lower tertiles (<92.6 fL). The generalized linear mixed models (GLMM) were used to estimate the association between MCV and cognitive impairment adjusted for important covariates.

Result

At baseline, the mean age of the study participants was 71.6 years old and the mean MCV at baseline was 90.7 fL. For the multivariable analyses, the effect of baseline MCV on global cognition (assessed by Montreal Cognitive Assessment–Taiwanese version, MoCA‐T) increased as age increased [MCV×age interaction: β= ‐0.07, 90% confidence interval (CI)= ‐0.14 to ‐0.004, p‐value= 0.04], which became more evident in women (β= ‐0.15, 95% CI= ‐0.23 to ‐0.06). After stratification by age groups, the increase of baseline MCV was associated with poor global cognition in the older group (age ≥75: β= ‐0.90, 95% CI= ‐1.65 to ‐0.15). No significant findings were observed in cognitive domains or other strata.

Conclusion

High baseline MCV was associated with an increased risk of cognitive impairment as age increased. MCV may be used an early marker for dementia in the community‐dwelling older adults.
Effect of multidomain interventions on estimated dementia and cardiovascular risk reduction: An individual‐participant data meta‐analysis from FINGER, MAPT, and pre‐DIVA
Authors: Barbera Mariagnese , Ngandu Tiia , Levälahti Esko , Coley Nicola , Mangialasche Francesca , Hoevenaar Marieke P , Peltonen Markku , Andrieu Sandrine , Richard Edo , Soininen Hilkka , Meiller Yannick , Kivipelto Miia , Solomon Alina
Published: December 2020

Background

Multidomain interventions based on management of vascular and lifestyle risk factors could potentially reduce the risk of dementia and cardiovascular disease. Given the slow progressive nature of these conditions, dementia in particular, clinical endpoints may not be achievable within trials’ time‐frame. Well‐established risk scores could be useful surrogate outcomes. In this individual‐participant data meta‐analysis, we assessed the effect of three multidomain dementia prevention interventions on the CAIDE and FINRISK risk scores for dementia and cardiovascular disease, and the impact of baseline characteristics on the response to such interventions.

Method

Baseline and 24‐month data from the FINGER, MAPT, and preDIVA dementia/cognitive decline prevention trials carried out in three European cohorts of older adults, were pooled at individual‐participant level (N=6465). Linear mixed‐model with maximum likelihood estimation and random effect by trial and study‐site was used to estimate changes in CAIDE and FINRISK risk scores in the intervention group vs control. Subgroup‐treatment effect interactions were tested to assess the influence of sex, baseline age, education, MMSE, and dementia or cardiovascular disease risk on the response to the interventions. The effect of the interventions on individual modifiable risk factors relevant for both risk scores was also investigated.

Result

The interventions led to a significant reduction of both CAIDE (estimated effect: ‐0.173; 95% CI: ‐0.268 to ‐0.077; P<0.001) and FINRISK (estimated effect: ‐0.108; 95% CI: ‐0.181 to ‐0.035; P=0.001) scores. A significantly larger reduction of CAIDE score was reported in women compared to men (P value for interaction=0.007) and a similar, but not significant, pattern was reported for FINRISK score. Interactions by other baseline characteristics were also not significant. Significant reduction of blood pressure (P≤0.001), and waist circumference (P=0.027), but not of BMI nor serum cholesterol, was observed. No baseline characteristic affected the response on these outcomes.

Conclusion

Multidomain interventions had beneficial effects on the estimated risk of dementia and cardiovascular disease, measured by the CAIDE and FINRISK scores. Women benefited more than men in terms of dementia risk, whereas effects of baseline age, education, cognitive status, and risk of dementia or cardiovascular disease on the response to the interventions could not be demonstrated.
SUVN‐I6107: A novel muscarinic M1 receptor‐positive allosteric modulator (M1‐PAM) for the treatment of cognitive deficits
Authors: Abraham Renny , Goura Venkatesh , Grandhi Venkata Ramalingayya , Tadiparthi Jayaprakash , Ganuga Narender , Medapati Rajesh Babu , Muddana Nageswara Rao , Palacharla Veera Raghava Chowdary , Bhyrapuneni Gopinadh , Bojja Kumar , Mekala Venkat Reddy , Srirangavaram Maheswari , Badange Rajesh Kumar , Reballi Veena , Goyal Vinod Kumar , Pandey Santosh Kumar , Jayarajan Pradeep , Nirogi Ramakrishna
Published: December 2020

Background

Muscarinic acetylcholine receptors (mAChRs) belong to family of G protein coupled receptors (GPCRs) which are widely expressed throughout the body. Muscarinic receptors have been implicated in the pathophysiology of various central nervous system disorders. M1 muscarinic receptor subtype plays a vital role in cognition, attention mechanisms and sensory processing. Discovery and development of selective M1 muscarinic ligands have been largely unsuccessful mainly due to high conservation of the orthosteric binding site among this receptor family. Thus, ligands that positively modulate the less conserved M1 muscarinic allosteric site may be advantageous over the orthosteric agonists

Method

SUVN‐I6107 is a lead compound from the M1 positive allosteric modulator (PAM) program. The effects of SUVN‐I6107 on the allosteric site of the M1 receptor was evaluated using the reporter gene assay. In addition, binding potential towards the orthosteric site across the muscarinic receptor subtypes was also studied. The pharmacokinetic properties of SUVN‐I6107 were studied both in rodent and non‐rodent species. The pro‐cognitive potential of SUVN‐I6107 was studied in diverse models of learning and memory. The safety of SUVN‐I6107 was assessed using in‐vitro and in‐vivo systems.

Result

SUVN‐I6107is a selective M1‐PAM with no agonistic activity across the muscarinic receptor subtypes. SUVN‐I6107 has good oral bioavailability in animal models. It also has excellent brain penetration with adequate protein free fraction. SUVN‐I6107 reversed the time induced memory deficit in the object recognition task. It also attenuated the scopolamine induced memory deficits in the object recognition as well as the contextual fear conditioning task. SUVN‐I6107 enhanced the cerebral blood flow in rats, potentiated the effects of donepezil, and promoted non‐amyloidogenic APP processing in rats. SUVN‐I6107 did not have the side effects associated with the stimulation of the cholinergic system. SUVN‐I6107was found to be safe in the cardiovascular safety assays and early stage animal toxicity studies.

Conclusion

SUVN‐I6107is a novel, selective and potent M1‐PAM,demonstrating efficacy in animal models and devoid of cholinergic side effects.
Blood‐brain barrier dysfunction and perioperative neurocognitive disorders: Cognitive Recovery after Elective Surgery (CREATES) study design and methods
Authors: Daiello Lori A , Wang Danny JJ , Jones Richard N , Boxerman Jerrold , Tremont Geoffrey , O'Bryant Sid , Kendall Mark , Cioffi William G , De Oliveira Gildasio S. , Ott Brian R , Inouye Sharon K
Published: December 2020

Background

Impaired blood‐brain barrier (BBB) function is observed in preclinical models of postoperative cognitive dysfunction and has been identified as an early indicator of neurodegeneration in those at risk for Alzheimer’s disease. Using a novel brain imaging technique, water exchange index mapping MRI (WEI‐MRI), the CREATES study will investigate the extent to which BBB dysfunction predicts the incidence of perioperative neurocognitive disorders (postoperative delirium and postoperative cognitive dysfunction).

Method

CREATES is an 18‐month cohort study that will enroll older adults without dementia (N=230) scheduled for major elective non‐cardiac surgeries under general anesthesia. The preoperative baseline evaluation includes WEI‐MRI brain imaging, neuropsychological tests, and blood sample collection for analysis of selected biomarkers associated with inflammation and microvascular dysfunction (soluble vascular adhesion molecule 1, soluble intercellular adhesion molecule 1, thrombopoietin, interleukin‐18, fatty acid binding protein, pancreatic polypeptide Y, chemokine I309, serum amyloid A, C‐reactive protein, alpha‐2‐macroglobulin, beta‐2 microglobulin, factor VII, adiponectin, apolipoprotein J, and neurofilament light). Delirium will be assessed daily during hospitalization using the Confusion Assessment Method diagnostic algorithm. Baseline assessments, including WEI‐MRI brain imaging will be repeated at postoperative month 3. Subsequently, neuropsychological testing and blood sample collection will be performed during follow‐up (months 6, 12, & 18). Incidence of mild cognitive impairment and Alzheimer’s disease will be evaluated by an expert panel using NIA‐AA diagnostic criteria at postoperative months 12 and 18.

Result

Primary analyses will investigate associations between 1) preoperative BBB permeability and incident postoperative delirium; and 2) postoperative BBB permeability and incident postoperative cognitive dysfunction during follow‐up. Relationships between serum biomarkers, BBB permeability, and incidence of neurocognitive disorders will be modeled in exploratory analyses.

Conclusion

BBB dysfunction is an indicator of brain vulnerability and neurodegeneration that may also be an important risk factor for postoperative delirium and delayed or incomplete cognitive recovery. CREATES is the first study of perioperative cognitive outcomes to utilize WEI‐MRI brain imaging, an innovative technique to evaluate BBB integrity which does not require administration of intravenous gadolinium‐based contrast agent. The results will provide important insights into the underlying mechanism(s) of perioperative neurocognitive disorders and potential biomarkers of prognostic significance.
Isoform‐dependent neurotoxicity of the Alzheimer disease risk factor BIN1
Authors: Lambert Erwan , Abdelfettah Farida , Barois Nicolas , Vandekerkhove Dirk , Hermant Xavier , Ayral Anne‐Marie , Davoine Lindsay , Dupont Cloe , Lafont Frank , Amouyel Philippe , Chapuis Julien , Verstreken Patrik , Dermaut Bart , Lambert Jean‐Charles , Dourlen Pierre
Published: December 2020

Background

Using genome‐wide association studies, BIN1 was identified as the most associated risk gene for Alzheimer’s Disease (AD) after APOE. A 3bp insertion allele was shown to increase BIN1 expression in human brains and AD risk. BIN1 has more than 10 isoforms and the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. The aim of this work was to assess the neurotoxicity of BIN1 isoforms and understand the underlying mechanisms.

Method

We generated Drosophila transgenic lines expressing brain, muscular and ubiquitous human BIN1 isoforms 1, 8 and 9 respectively. We analyzed BIN1 isoform neurotoxicity using cornea neutralization, immunofluorescence, electrophysiology and electron microscopy in the fly eye photoreceptor neurons.

Result

We showed that adult eye‐specific expression of the brain BIN1 isoform 1 (BIN1‐1) resulted in an age‐dependent loss of photoreceptor neurons. Interestingly, the effect was specific of this isoform only. We tested truncated BIN1‐1 forms and showed that the BIN1‐1‐specific CLAP domain is necessary for the BIN1‐1 induced neurodegeneration. This domain is involved in endocytosis and vesicular trafficking. In addition, photoreceptor neuron degeneration was characterized by a strong accumulation of vesicles with endosomal markers suggesting a blockade of the endosome‐lysosome pathway. We further found that modulation of Rab5, Rab4 and Rab11, involved at the level of the early and recycling endosomes, abrogated photoreceptor degeneration, indicating that BIN1‐1 toxicity is due to the blockade of the endosome‐lysosome pathway likely at the level of early endosomes. Finally, as endosomes are involved in synaptic vesicles formation and postsynaptic receptor recycling, we tested the electrophysiological consequences of BIN1‐1 expression. Although not affected in young flies, we observed that expression of BIN1‐1 affected early photoreceptor neuron synaptic transmission.

Conclusion

Altogether, these results show that an increase of the BIN1 isoform 1 impairs the endosome‐lysosome pathway, thereby affecting synaptic transmission and inducing neurodegeneration. Interestingly, enlarged endosomes have been shown to be one of the first cytopathological markers of the disease and synaptic transmission is affected early in AD pathogenesis. These results suggest that an increase in BIN1 isoform1 could contribute to early steps of Alzheimer’s disease.
Protective genetic variants in the MS4A gene cluster modulate microglial activity
Authors: Deming Yuetiva , Filipello Fabia , Cignarella Francesca , Suárez‐Calvet Marc , Morenas‐Rodríguez Estrella , Van Hulle Carol A. , Jonaitis Erin M. , Blennow Kaj , Zetterberg Henrik , Asthana Sanjay , Johnson Sterling C. , Carlsson Cynthia M. , Bendlin Barbara B. , Engelman Corinne D. , Ewers Michael , Haass Christian , Benitez Bruno , Karch Celeste M. , Piccio Laura , Cruchaga Carlos
Published: December 2020

Background

Variants within the gene‐rich membrane‐spanning 4‐domains subfamily A (MS4A) gene region have been associated with increased or reduced risk for Alzheimer's disease (AD) by large genome‐wide association studies (GWAS). Although MS4A family members are known to be cell membrane proteins implicated in immunity, their role in AD pathogenesis has remained elusive. Another transmembrane protein with a key role in immunity is the triggering receptor expressed on myeloid cells 2 (TREM2) and low frequency variants in TREM2 have been associated with AD risk. Soluble TREM2 (sTREM2) measured in cerebrospinal fluid (CSF) has also been associated with AD. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of these immune‐related genes in AD may reveal important pathological mechanisms and identify distinct therapeutic targets.

Method

We measured sTREM2 in CSF samples obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 813) and used GWAS to identify genetic modifiers of CSF sTREM2. Bioinformatics approaches and RNAseq were used to identify expression quantitative trait locus (eQTL) effects. Finally, the genetic findings were functionally validated in human macrophages by lentivirus‐mediated overexpression and antibody knockdown.

Result

Common variants in the MS4A gene region were associated with CSF sTREM2, which replicated in independent datasets (n = 580). These variants included a previously reported AD risk‐reducing allele in rs1582763, which associated with increased CSF sTREM2 (β = 735, P = 1.15e‐15). This variant was found to influence gene expression of a few MS4A family members including MS4A4A in blood and brain tissue. Using cell models, we validated the genetic findings by demonstrating that changes in MS4A4A expression influenced concentration of sTREM2.

Conclusion

Human genetic, molecular, and cellular findings strongly suggest that MS4A4A modulates sTREM2. As also reported by our group, CSF sTREM2 is associated with tau‐related neurodegeneration and rate of memory decline in AD. Combined, these findings provide a potential mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that sTREM2 is involved in sporadic AD pathogenesis.
Joint modeling of time‐varying exposure history and health outcomes: Identification of critical windows
Authors: Wagner Maude , Grodstein Francine , Samieri Cécilia , Proust‐Lima Cécile
Published: December 2020

Background

Life‐long exposures constitute a primary focus of research on the etiology of many chronic diseases. Yet, identifying the critical windows when risk factors mostly impact the risk of disease remains an open statistical question. Some methods have already been proposed to assess the effect of a time‐varying exposure history. However, research mostly focused on a continuously observed error‐free exposure, a binary or time‐to‐event outcome and a concomitant evaluation of exposure and outcome.

Method

We jointly model the trajectory of the exposure over time and its weighted cumulative effect on the subsequent trajectory of the outcome. As we consider separate time‐windows for the exposure and the outcome, inference can be obtained with a two‐stage approach. Subject‐specific predictions of exposure are computed from a flexible mixed model in stage 1, thus handling missing data and error in exposure measurement. In stage 2, weighted time‐dependent effects (modelled by splines) of these predicted exposures are included in the mixed model for the outcome. The method, which was evaluated in simulations, can be easily implemented in standard statistical software (see Figure).

Result

We studied the association between body mass index (BMI) history (collected from midlife) and cognition (evaluated after age 70) in the Nurses’ Health Study cohort. In a sample of 19,415 women, the method identified two major critical windows of association. Long before the first cognitive evaluation (roughly 24 to 12 years), higher levels of BMI were associated with poorer cognition. In contrast, adjusted for the whole history, higher levels of BMI became associated with better cognition in the last years prior to the first cognitive interview, thus reflecting reverse causation (changes in exposure due to underlying disease).

Conclusion

The proposed joint modelling approach provides a flexible tool to evaluate the trajectory of effect of a time‐varying exposure on a subsequent longitudinal outcome. It is particularly useful to explore complex dynamic relationships, as illustrated with BMI and cognition, and address for various clinical questions by identifying critical windows of lifelong exposures.
Mechanisms underlying the procognitive effects of intranasal insulin
Authors: Erichsen Jennifer M. , Woodruff Jennifer L. , Burzynski Hannah E. , Grillo Claudia A. , Reagan Lawrence P. , Fadel James R.
Published: December 2020

Background

Intranasal insulin (INI) represents a potential treatment for age‐related cognitive decline (ARCD), as numerous studies and multi‐center clinical trials have demonstrated that it enhances memory. However, the mechanism underlying these pro‐cognitive changes is unknown. Several methods were implemented to begin to uncover a neurochemical/molecular basis underlying the effects of acute and subchronic INI.

Method

Neurochemical and molecular techniques were employed in adult male Sprague‐Dawley rats following acute and/or subchronic INI. The animals received bilateral hippocampal injections of a lentiviral vector containing a selective insulin receptor antisense sequence (LV‐IRAS) or a control virus (LV‐Con). To measure neurotransmitter efflux following INI, probes were inserted into the medial prefrontal cortex (mPFC) and hippocampus for in vivo microdialysis. Levels of acetylcholine and glutamate were measured for three hours following acute INI or IN vehicle. To investigate insulin receptor signaling following acute and subchronic INI, a separate cohort of animals (no virus) were administered INI or IN vehicle for 10 days. The next day they were given another dose of INI to stimulate insulin signaling and euthanized at various time points post‐administration. Olfactory bulb and hippocampal extracts were processed for immunoblot analysis to assess changes in central insulin signaling.

Result

Baseline levels of glutamate were significantly decreased in LV‐IRAS animals compared to LV‐Con in the hippocampus but not the mPFC. Additionally, INI administration appeared to increase hippocampal glutamate efflux. Finally, a time‐dependent increase in insulin signaling in response to INI was observed after subchronic INI administration.

Conclusion

These results begin to uncover a mechanistic basis for the pro‐cognitive effects of INI. The effects of acute INI may be partially mediated by a neurochemical mechanism, specifically involving glutamate. This study also revealed that molecular changes were dependent on timing and length of dose; therefore a more chronic INI administration may affect neurotransmission differently. More studies are needed to fully understand the mechanistic changes following INI and to determine the most effective clinical dose and dosing regimen. It is important to understand the mechanism of action, as INI could eventually be used in the broader clinical setting to treat ARCD.
Level of plasma tau and depression, anxiety and worry in cognitively normal older adults
Authors: Hall James R , Petersen Melissa , Johnson Leigh Ann , O'Bryant Sid
Published: December 2020

Background

Neurobehavioral changes in cognitively intact individuals may represent early indicators of underlying pathophysiological processes such as the development of tau related changes in the brain. Research assessing tau pathology with PET has shown a relationship between tau accumulation in the inferior temporal lobes and entorhinal cortex and depression and tau accumulation in the right entorhinal cortex and loneliness. The current research investigated the relationship between levels of plasma tau and measures of depression, anxiety and worry in a community‐based sample of cognitively normal older adults.

Method

Participants were drawn from a community‐based, longitudinal study of cognitive aging in Mexican‐Americans. 415 cognitively normal Mexican Americans (328 females, 87 males) and 134 cognitively normal non‐Hispanic whites (95 females, 39 males) were administered the Geriatric Depression Scale (GDS), the Beck Anxiety Inventory (BAI)and the Penn State Worry Questionnaire PSWQ). Plasma tau was assayed via Single Molecule Array (Simoa) technology. Data were analyzed using t tests and ANOVA.

Result

There was no significant main effect for plasma tau on any of the emotional measures. To assess the possible impact of level of tau, the sample was divided into those in the highest quartile of tau (N=89) and those in the lower three quartiles of tau (N=460). Analyses controlling for age, education and gender revealed that those in the highest quartile scored significantly higher on GDS total score (p= .011), three of the four subscales of the GDS (Dysphoria p=.020; Apathy p=.021; Cognitive Impairment p=.029), the BAI (p=.005) and the PSWQ (.003).

Conclusion

In cognitively normal elderly, higher levels of plasma tau were significantly related to measures of emotional functioning with significantly greater endorsement of symptoms of depression, anxiety and worry. The presence of high levels of these symptoms and higher levels of plasma tau may be an indicator of preclinical Alzheimer’s disease. Longitudinal research is needed to assess the strength of these factors in later cognitive decline and may suggest areas for early intervention.
Developing CNS therapeutics for brain insulin resistance in Alzheimer’s disease (AD) and mild cognitive impairment (MCI)
Authors: Talbot Konrad , Wang Hoau‐Yan
Published: December 2020

Background

Brain insulin resistance is established as an early, common, and profound feature of AD dementia (ADd). This phenomenon can be induced by multiple AD risk factors and by early abnormalities in the disorder. Once induced, brain insulin resistance promotes many other AD‐associated abnormalities. Brain insulin resistance consequently appears to be a nodal abnormality in ADd and thus an efficient target for treating the disorder in general. We accordingly tested antidiabetic incretin receptor agonists (IRAs) shown to relieve AD‐related pathology in animal models of AD on brain insulin resistance in ex vivo hippocampal formation (HF) preparations from ADd and MCI cases.

Method

Fresh frozen HF tissue was obtained from age‐ and ‐sex matched Caucasians with no history of diabetes and low postmortem intervals (m ± SD = 6.75 ± 2.2 h). They were from non‐cognitively impaired, non‐amnestic MCI, amnestic MCI, and ADd cases (n = 10 per clinical group). Using our ex vivo stimulation protocol (Talbot and Wang et al., JCI 122: 1316‐1338, 2012), the ex vivo tissues were tested for their signaling responses at the level of the insulin receptor, insulin receptor substrate‐1, and Akt to 60 min incubation in 0, 1, or 10 nM insulin with or without 30 min pretreatment with 100 nM of single IRAs such a liraglutide activating just one incretin receptor (i.e., the glucagon‐like peptide‐1 [GLP‐1] receptor) or dual IRAs activating both incretin receptors (i.e., GLP‐1 + gastric inhibitory peptide [GIP] receptors). Statistical significance was defined as p < 0.05.

Result

HF responsiveness to 1 and 10 nM insulin was significantly reduced in all the clinical groups at all levels of the insulin signaling pathway tested. Pretreatment with single IRAs, as well as dual IRAs markedly improved insulin responsiveness of HF tissue from MCI cases. All the IRAs tested significantly increased such responsiveness in HF tissue from ADd cases, but the dual IRA was roughly twice as effective as the single IRAs.

Conclusion

IRAs are thus emerging as high priority candidates for development as AD therapeutics, especially since they have all passed phase II and/or III clinical on type 2 diabetics.
White matter hypertensity burden varies in empirically derived incident MCI subtypes
Authors: Machulda Mary M. , Lundt Emily S. , Albertson Sabrina M. , Graff‐Radford Jonathan , Jack Clifford R. , Mielke Michelle M. , Kremers Walter K. , Knopman David S. , Petersen Ronald C. , Jones David T. , Bondi Mark W. , Vemuri Prashanthi
Published: December 2020

Background

White matter changes and Alzheimer’s disease pathology frequently co‐exist in the population. Recently we empirically derived subtypes of incident mild cognitive impairment (MCI) and found that there was significant heterogeneity not only in cognitive impairment profiles but also gray matter atrophy suggesting that multiple etiologies may contribute to cognitive impairment in these subtypes. The aim of this study was to examine differences in white matter hyperintensity (WMH) volume in these same MCI subtypes and investigate amyloid deposition in a smaller subset.

Method

We analyzed data from 188 participants with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) identified as having one of four MCI subtypes: subtle cognitive impairment (SCI), amnestic, dysnomic, and dysexecutive. All participants completed 3T imaging at the time of the MCI diagnosis. Using WMH volume scaled by TIV and PIB SUVR, we compared each MCI subtype to 344 cognitively impaired (CU) participants (mean age 78; 46% women) and each other.

Result

The amnestic (n = 83; mean age 80; 43% women), dysnomic (n = 30; mean age 84; 47% women) and dysexecutive subtypes (n = 49; mean age 83; 35% women) had significantly higher WMH volumes compared to CU (p < .02) while the SCI subtype (n = 26; mean age 80; 23% women) did not differ from CU (p = .76). Amongst the MCI subtypes, the amnestic (p = .04) and dysexecutive subtypes (p = .01) had significantly higher WMH volumes than the SCI subtype [Figure 1]. In a smaller subset of individuals who also completed PiB‐PET (17/26 SCI; 39/83 amnestic; 10/30 dysnomic, 28/49 dysexecutive), we found evidence for higher amyloid load in all MCI subgroups except the SCI group (p<0.05) in comparison to CU.

Conclusion

We found significantly elevated levels of WMH and amyloid burden in amnestic, dysnomic, and dysexecutive subtypes of incident MCI supporting the notion that both vascular changes and amyloid contribute to the development of clinical symptoms. Surprisingly, WMH and amyloid positivity were not high in SCI suggesting that the pathophysiology in this group needs further investigation.
In‐vivo characterization of progressive amnestic syndrome due to suspected neurodegenerative non‐Alzheimer’s disease
Authors: Bailly Laurent , Villain Nicolas , Houot Marion , Hourregue Claire , Paquet Claire , Leroy Melanie , Lebouvier Thibaud , Dubois Bruno , Epelbaum Stéphane
Published: December 2020

Background

Neuropathological bases of suspected non‐Alzheimer’s disease pathophysiology (SNAP) have recently been identified as frequent causes of progressive isolated amnestic non Alzheimer’s disease (AD) neurodegenerative diseases1,2. Nonetheless, their in‐vivo profiles have so far been only poorly characterized. The goal of this study is to specify their clinical, neuroimaging profile and evolution, compared to patients with amnestic AD and cognitively normal subjects.

Methods

We retrospectively selected patients with progressive amnestic syndrome of hippocampal type3, signs of neurodegeneration (elevated CSF t‐ tau concentration and/or brain hypometabolism and/or atrophy) and normal CSF Amyloid values (Aβ42 concentration ; Aβ40/42 ratio if available) from 3 tertiary memory centers (amnestic SNAP). They were compared to patients with prodromal typical (amnestic) AD (without impairment of instrumental functions, MMSE >20, elevated CSF p‐tau and abnormal CSF Amyloid values) and cognitively normal controls with normal CSF Amyloid values. We compared clinical data and neuropsychological tests between amnestic SNAP and the two other groups.

Results

25 patients with amnestic SNAP (median age=74.7), 24 amnestic AD (median age=71) and 35 controls (median age=75) were included. At baseline, controls had better global cognitive performances (MMSE=29 vs. 27 vs. 25 respectively, p<0.001) as well as verbal fluency performances than amnestic SNAP and amnestic AD but no significant difference were found between amnestic SNAP and AD (p=0.096). Executive functioning was significantly different between controls, amnestic SNAP and AD (FAB=17, 16 and 14 respectively, p<0.001) and there was a significant difference between amnestic SNAP and AD (p=0.034). We found no other significant difference between amnestic SNAP and AD: neither regarding memory performances (FCSRT) nor other cognitive functions (language, visuo‐spatial abilities).

Conclusion

Patients with amnestic SNAP show a weaker impairment in executive functions than patients with prodromal amnestic AD, highlighting a specific identifiable baseline neuropsychological pattern. This work will be completed by the analysis of clinical evolution, and the pattern of brain atrophy and brain metabolism that will be available at the time of AAIC. References: 1. Nelson et al. (2019). Brain, 142(6):1503‐1527. 2. Crary et al. (2014). Acta Neuropathol. 2014 Dec;128(6):755‐66. 3. Dubois B. & Albert M (2004). Lancet Neurol, 3 (4), 246‐8.
The sustainability of community interventions for people affected by dementia: A realist review
Authors: Morton Thomas Alexander , Atkinson Teresa , Brooker Dawn , Wong Geoff
Published: December 2020

Background

Community‐based support for people with dementia and their care partners (family/friends), such as regularly‐meeting groups and activities, can play an important part in post‐diagnostic care: from combating isolation and maintaining positive self‐image, to delaying decline and hospitalisation. However, in countries such as the UK these are typically delivered piecemeal by a variety of agencies with inconsistent funding. This has led to fragmented provision with significant gaps and, to add to this, many such interventions are forced to fold after only a short period. The SCI‐Dem review is investigating what can promote, or get in the way of, community interventions for people affected by dementia becoming sustainable over time.

Method

This review is utilising a Realist approach. Key sources of evidence were gathered using formal searches of electronic databases and grey literature, together with informal search methods such as citation tracking and snowballing. Data were interrogated, assessed and organised with the aid of NVivo software, and a Realist logic of analysis was applied to trace context‐mechanism‐outcome configurations as part an overall programme theory, indicating what works for whom, in what circumstances, in what respects and how, with regards to sustaining community interventions. Consultation with stakeholders, involved with a variety of such interventions in various roles, informed this process throughout.

Result

Due to complete in September 2020, this review will produce an evidence‐informed programme theory mapping how different contexts can trigger mechanisms (processes in people and organisations) to produce outcomes that help or hinder the sustainability of a community group or activity. Early findings suggest a range of factors affecting four key areas for sustainability: whether a group or activity can get or keep 1) members; 2) appropriate staff and volunteers; 3) necessary resources; 4) necessary funding.

Conclusion

Conclusions will focus upon how best to implement community‐based interventions, with recommendations to those commissioning, planning or running such schemes, based upon our programme theory. Accessible publications and online materials will be produced, aiming to provide an evidence‐informed ‘blueprint’ for other community settings. Recommendations about what could be useful at both regional and national policy and infrastructure levels will also be made.