bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual rating and automated brain volumetry for medial temporal lobe atrophy in differential diagnosis and early detection of Alzheimer’s disease
Authors: Zhao Lei , Liu Wenyan , Luo Yishan , Kung Wing Kit , Xiong Li , Mok Vincent C.T. , Shi Lin
Published: December 2020

Background

Visual rating of medial temporal lobe atrophy (MTA‐scale) has been well recognized as a biomarker for Alzheimer’s disease (AD), and automatic quantification of MTA (QMTA) based on the volume of hippocampus and inferior lateral ventricle (ILV) has been proposed. However, a comprehensive comparison of MTA‐scale, QMTA as well as the components of MTA (i.e. volume of hippocampus and ILV) is still lacking in differential diagnosis or early detection of AD. Also, it’s not clear about the difference of performance between the conventional MTA measures and the recently proposed AD resemblance atrophy index (AD‐RAI) that integrates multiple brain regions more than MTA.

Method

We included 132 AD, 132 normal control (NC) subjects, and 353 subjects with mild cognitive impairment (MCI) from ADNI. Among the MCI patients, 290 remained stable (MCIs) and 63 converted to AD (MCIc) in a two‐year follow‐up. The AD and NC subjects, and the MCIs and MCIc subjects were matched in age, gender and education, respectively (Table 1). MTA‐scale was visually rated by an experienced neuroradiologist. Baseline T1‐weighted images were processed with AccuBrain to quantify the volume of hippocampus and ILV as well as the AD‐RAI. Receiver operating characteristic (ROC) curve analyses were performed to compare these measured when differentiating AD from NC and MCIc from MCIs. Sub‐analyses were conducted by grouping the study cohort by age (>75 years or not) and gender. The optimal threshold was determined by Youden Index.

Result

The Spearmen correlation of QMTA and MTA‐scale was 0.805 (p<0.001). Regarding the ROC analyses, the AD‐RAI performed the best in differentiating AD from NC (AUC=0.860, Youden Index=59.1% for all individuals) and MCIc from MCIs (AUC=0.768, Youden Index=41.6% for all individuals), followed by the hippocampal fraction/volume, QMTA, MTA, and ILV fraction/volume (Table 2 and Table 3). For all the MRI‐based measures, the differentiation performance was better for those with age≤75 years in both classifications, and better for men in AD vs. NC and women for MCIc vs. MCIs.

Conclusion

MTA measures based on automated brain volumetry performed better than visual rating, and the superiority of AD‐RAI over MTA measures needs further validations in a larger population.
Antiviral therapy reduces the risk of dementia in patients with herpes zoster: A propensity score‐matched analysis
Authors: Bae Sungman , Yoon Woon , Choi Seong Won , Yun Sung‐Cheol , Kim Sung‐han , Kim Seong Yoon
Published: December 2020

Background

Some epidemiological evidences show that the herpes zoster (HZ) may be associated with dementia. We investigated whether HZ was associated with the subsequent dementia in a nationwide population‐based (dynamic) cohort, and evaluated whether antiviral therapy might reduce the risk of subsequent dementia.

Method

The National Health Insurance Service‐National Sample Cohort (NHIS‐NSC) database was used for analysis. This randomized one million people cohort representing the entire population of South Korea was followed up from 2002 to 2013. New events of HZ and dementia were identified using the diagnostic codes of claim data. Dementia was defined as the presence of the diagnostic codes and prescription of anti‐dementia drugs for more than 30 days. Each HZ patient receiving antiviral therapy was 1:1 matched with an untreated HZ patient having the same propensity score in the relevant year.

Result

A total of 229,594 individuals of ≥ 50 years were followed up for 11 years. The incidence of the first‐diagnosed HZ cases was 16.69 per 1000 person‐years, and that of the first‐diagnosed dementia was 4.67 per 1000 person‐years. The risk for dementia was higher in patients who had previous HZ episodes than in those who had never experienced HZ (incidence rate ratio [IRR] 1.94; 95% CI 1.83‐2.06 and adjusted hazard ratio [HR] 1.12; 95% CI 1.05‐1.19, respectively). Of the 34,505 patients who were diagnosed as the first‐ever HZ, 28,873 (84%) received antiviral treatment and 5,632 (16%) did not. The crude incidence rates of the subsequent dementia were 7.79 and 12.27 per 1000 person‐years for treated and untreated groups, respectively, giving IRR of 0.63 (95% CI, 0.56‐0.72) and the covariate‐adjusted HR of 0.79 (95% CI, 0.69‐0.90). The HZ patients who received antiviral therapy had a significantly lower risk of dementia than those who did not; HR after propensity score‐matching was 0.77 (95% CI, 0.64‐0.91). In addition, the patients treated with antiviral agents showed significantly lower mortality than untreated patients (HR 0.58; 95% CI 0.53‐0.64 by propensity‐score matched analysis).

Conclusion

HZ is associated with the subsequent dementia development, and the use of antiviral agents in patients with HZ significantly reduces the incidence of the subsequent dementia and the mortality.
Degeneration patterns on [18F]FDG‐PET predict amyloid deposition in corticobasal syndrome
Authors: Parmera Jacy Bezerra , Coutinho Artur M , Neto Adalberto Studart , Carneiro Camila de Godoi , de Almeida Isabel Junqueira , Aranha Mateus Rozalem , Barbosa Egberto Reis , Buchpiguel Carlos A , Nitrini Ricardo , Brucki Sonia MD
Published: December 2020

Background

Corticobasal Syndrome (CBS) is a neurodegenerative disease which phenotype is related to multiple pathologies, including 4‐repeat tauopathies ‐ Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) ‐ and Alzheimer’s disease (AD). Previous works with post‐mortem analysis established [18F]FDG‐PET patterns closely related to CBD, PSP or AD pathology.

Methods

Forty patients with probable CBS were evaluated concerning their movement disorders and cognition. They were underwent [18F]FDG‐PET/CT and, according to their brain metabolic patterns, distributed into two groups: likely related to AD (CBS FDG‐PET AD) (figure 1) and likely unrelated to AD (CBS FDG‐PET nonAD) (figure 2). Twenty‐five patients underwent [11C]PIB‐PET on a hybrid PET/MRI equipment to assess their amyloid status. Both [18F]FDG‐PET and [11C]PIB‐PET were analyzed based on visual and 3D‐SSP semi‐quantitative parameters. Each examination was blind to other modalities.

Results

Based on the patterns at [18F]FDG‐PET, we classified 12 patients (30%) in the CBS FGD‐PET AD group and 28 patients (70%) in the CBS FDG‐PET nonAD group. All patients (100%) previously classified as CBS FDG‐PET AD tested positive for amyloid deposition at [11C]PIB‐PET and 88,9% classified as CBS FDG‐PET nonAD tested negative (p=0,001 for [11C]PIB positive status; sensitivity 77,8%; specificity 100%). There were no significant differences in age, gender, symptoms duration and schooling at CBS FDG‐PET groups or [11C]PIB status. Demography is shown in table 1. Functional and cognitive impairment was markedly more severe in the CBS FDG‐PET AD group, which had worst scores regarding memory, attention and visuospatial domains (table 2). CBS FDG‐PET AD group also presented more frequently myoclonus (100% vs. 53,6%, p=0,004), displayed less frequently dystonia (16,7% vs. 57,1%, p=0,035) and had more neglect syndrome (p =0,041) and hallucinations (p=0,039) (figure 3). Patients with positive status at [11C]PIB also presented worst cognitive performance on memory, attention and visuospatial domains.

Conclusion

[18F]FDG‐PET was useful to predict CBS variants depicting their degeneration patterns, being able to detect a CBS‐AD group with brain amyloid deposition, worst functional and cognitive decline, also showing high accuracy to exclude AD pathology in the CBS‐nonAD group. Motor and cortical symptoms such as dystonia, myoclonus and neglect syndrome might potentially aid biomarkers in distinguishing pathologic variants.
Validation of the RUDAS for the identification of dementia in illiterate and low‐educated older adults in Lima, Peru
Authors: Caipa Maritza Pintado , Custodio Nilton , Montesinos Rosa
Published: December 2020

Background

To evaluate the performance of the Peruvian version of the Rowland Universal Dementia Assessment Scale (RUDAS‐PE) to discriminate between controls and patients with mild cognitive impairment (MCI) and dementia in an illiterate population with low‐levels of education.

Method

We compared the cognitive performance of 187 elderly subjects who were illiterate (controls n=60; MCI n=64; dementia n=63). Neuropsychological measures included the RUDAS‐PE, Mini‐Mental State Examination (MMSE), INECO Frontal Screening (IFS), and Pfeffer Functional Activities Questionnaire (PFAQ). Results were compared to a neuropsychological evaluation (gold standard), including use of Clinical Dementia Rating (CDR) scores.

Result

We found a Cronbach’s alpha was 0.65; Spearman’s correlation coefficient was 0.79 (p < 0.01). The area under the receiver operating characteristics curve for the RUDAS to discriminate dementia from MCI was 98.0% with an optimal cut‐off <19; whereas, to differentiate MCI and controls was 98.0% whit an optimal cut‐off <23.

Conclusion

Based on its excellent psychometric properties, we find the RUDAS‐PE suitable to aid in the opportune detection of dementia in a geriatric illiterate population with low‐levels of education.
PSMD, a novel marker of small vessel disease, and its association with cognitive function in the community
Authors: Satizabal Claudia L , Beiser Alexa S , Maillard Pauline , Himali Jayandra J , DeCarli Charles , Fornage Myriam , Seshadri Sudha
Published: December 2020

Background

Peak width of skeletonized mean diffusivity (PSMD) has been proposed as a novel neuroimaging marker for small vessel disease (SVD), which contributes to vascular cognitive impairment and dementia. Although this marker has been related to lower cognitive function in clinical samples with inherited and sporadic SVD, additional research is needed to assess its utility for risk prediction in large, well‐characterized population‐based cohorts.

Methods

We included 929 stroke‐ and dementia‐free participants from the Offspring cohort of the Framingham Heart Study. PSMD was derived from DTI using an automated algorithm, and further log‐transformed to normalize its distribution. To evaluate general cognitive function, we created a composite cognitive score including Logical Memory – immediate and delayed recall, Digit Span Forward and Backward, Category Fluency – animals, Phonemic Fluency – FAS, Trail Making Test A and Test B, and the Boston Naming Test. We used linear regression models to relate PSMD to general cognitive function adjusting for age, sex and educational level. In a secondary model, we additionally adjusted for diabetes, smoking and hypertension. Finally, we included white matter hyperintensity (WMH) volume as percentage of total intracranial volume in the primary and secondary models to assess the contribution of PSMD beyond WMH.

Results

Higher PSMD values were associated with lower general cognitive function (Beta (SE), ‐0.61 (0.10), p<0.001). Results remained virtually unchanged after additional adjustment for vascular risk factors in the secondary model (‐0.60 (0.10), p<0.001). After the inclusion of WMH, associations remained significant in the primary (‐0.58 (0.11), p<0.001) and secondary (‐0.57 (0.11), p<0.001) models, with PSMD explaining an additional 2% of the variance in cognition beyond WMH.

Conclusion

PSMD was strongly associated with general cognitive function in our sample, suggesting that this novel marker may be suitable for risk prediction for SVD in community‐based samples, and is potentially a better predictor than well‐established markers such as WMH. Additional validation and longitudinal analyses are currently underway in population‐based cohorts and clinical samples in the context of the MarkVCID consortium.
Subfoveal choroidal thickness and choroidal vascularity index on spectral‐domain optical coherence tomography in Alzheimer’s disease
Authors: Robbins Cason B , Grewal Dilraj , Powers James H , Thompson Atalie C , Polascik Bryce W , Agrawal Rupesh , Fekrat Sharon
Published: December 2020

Background

The involvement of the retina and its vasculature has previously been demonstrated in Alzheimer’s disease (AD). Choroidal parameters such as choroidal thickness (CT) and choroidal vascularity index (CVI) as measured on spectral‐domain optical coherence tomography (SD‐OCT) have the potential to be used as non‐invasive biomarkers for Alzheimer’s disease.

Method

SD‐OCT imaging of 42 participants with AD, 40 with mild cognitive impairment (MCI), and 139 cognitively healthy controls was obtained in a cross‐sectional study (NCT03233646). Exclusion criteria included diabetes, glaucoma, other non‐AD dementias, and any known vitreoretinal pathology. Subfoveal choroidal thickness (CT) was manually measured by two masked graders, with a third grader used as a tie‐breaker for any measurement discrepancy. Total choroid area and luminal area were calculated by automated image binarization techniques. Choroidal vascularity index (CVI) was measured as the ratio of luminal area to total choroid area. Generalized estimating equations were used to assess the difference in parameters between AD, MCI, and controls in univariable and multivariable analyses.

Result

Choroidal thickness (p = 0.009), total choroid area (p = 0.02), and luminal area (p = 0.02) were significantly less in AD versus controls in univariable but not in multivariable analysis after controlling for age, sex, and logMAR visual acuity. Choroidal vascularity index was not significantly different between individuals with AD and controls and was significantly different between individuals with MCI and controls only in univariable analysis (p = 0.04). However, CVI was significantly less in AD versus MCI in both univariable and multivariable analyses (p = 0.01).

Conclusion

Subfoveal choroidal thickness may not be associated with AD independent of aging. However, the choroidal vascularity index was less in AD compared to MCI, suggesting decreased vascularity of the subfoveal choroid in these patients. CVI may be useful as an adjunctive biomarker for the diagnosis of AD.
APOE4 status influences the amyloid and tau relationship
Authors: Dincer Aylin , Gordon Brian A. , Keefe Sarah J. , Flores Shaney E. , Schultz Stephanie A. , Paulick Angela M. , Feldman Rebecca L. , Shady Kristine E. , Hornbeck Russ C. , Zhou Yun , Morris John C. , Benzinger Tammie L.S.
Published: December 2020

Background

The apolipoprotein E ε4 (APOE4) allele is a well‐established genetic risk factor for late‐onset Alzheimer disease (AD). There is strong evidence that APOE4 enhances amyloid accumulation and previous research in animal models have demonstrated that APOE4 promotes tau pathology independently of amyloid. In this study, we investigate the relationship between APOE4 and tau to see whether the relationship between APOE4 and tau is mediated by, independent of, or interacts with levels of amyloid.

Method

347 participants from the Knight Alzheimer Disease Research Center (mean age = 69.7) underwent tau‐PET imaging with [18F]‐flortaucipir and amyloid‐PET with [18F]‐florbetapir within a year. Tau‐ and amyloid‐ PET data were converted to standardized uptake value ratios (SUVRs) for each region of interest. A summary amyloid measure was calculated for statistical analysis using the average of lateral orbitofrontal, medial orbitofrontal, rostral middle frontal, superior frontal, superior temporal, middle temporal, and precuneus regions. APOE4 carrier status was defined by the presence of at least one ε4 allele. We ran three separate linear models for our analysis. First we examined the APOE4‐tau and the amyloid‐tau relationship with model 1 predicting regional tau using amyloid, age, and sex as predictors and model 2 predicting regional tau using APOE4 status, age, and sex as predictors. Next we examined the relationship between tau and both APOE4 and amyloid in concert with model 3 predicting regional tau using amyloid, APOE4 status, an interaction between amyloid and APOE4 status, sex, and age as predictors.

Result

We found that the amyloid‐tau relationship was widespread throughout the brain and the APOE4‐tau relationship was predominately in the inferior parietal and temporal pole regions (figure 1). Most importantly, we found a significant APOE4 status and amyloid interaction that was most prominent in the entorhinal cortex and superior temporal regions (figure 2).

Conclusion

Our results show that there is a significant effect of APOE4 status and tau deposition that is above and beyond the effect of APOE4 on amyloid. This relationship is synergetic, where E4 carriers have more tau pathology for the same levels of amyloid deposition as non‐carriers.
Relative digit length is associated with cognitive abilities in women and men
Authors: Gatz Margaret , Pike Christian J , Beam Christopher R. , Reynolds Chandra A.
Published: December 2020

Background

Relative length of the index (second digit; 2D) and ring (fourth digit; 4D) fingers on the right hand (2D:4D) is taken to indicate prenatal hormone levels. Lower 2D:4D (i.e., 4D relatively longer) represents more androgen exposure, with men showing lower 2D:4D on average than women. Women from opposite sex twin pairs have lower 2D:4D compared to women from same sex dizygotic twin pairs. Lower 2D:4D correlates with higher scores on spatial and numerical tasks, while higher 2D:4D advantages verbal tasks. Findings, however, have been quite inconsistent.

Method

We analyzed cognitive scores in a nationally representative internet panel who were asked whether their index or ring finger was longer (or whether they were the same). N=3525 (1521 men; 2004 women), aged 17 – 108, reported a difference in digit length on their right hands. Cognitive tests included IRT‐scored Number Series (NS), Picture Vocabulary (PV), and Verbal Analogies (VA), plus Serial Sevens (SS)–frequently part of mental status testing.

Result

More men (67%) than women (44%) reported relatively longer 4D, consistent with established findings. There were significant interactions by gender, digit length, and age/birthyear on all outcomes. Men outscored women on NS, PV, and VA, and reported higher educational attainment than women. Within women, those with relatively longer 2D reported higher education attainment and scored higher on VA compared to those with relatively longer 4D. However, there was a significant interaction between digit length and age/birthyear for both PV (p=.03) and VA (p=.005): women born more recently had longer 2D associated with higher scores, but older women had longer 4D associated with higher scores, with the crossover around age 65. Within men, those with relatively longer 4D scored higher on NS (p=.0003) and SS (p=.005) than men with relatively longer 2D. Findings were robust to including education as a covariate.

Conclusion

Findings add to evidence that sex differences in cognitive abilities in adult women and men may be influenced by differences in prenatal levels of sex steroid hormones, indirectly inferred from relative digit length. Results further suggest that prenatal testosterone exposure may confer an advantage in older women. Grant No. RF1 AG058068.
Synaptically preferred anti‐tau antibodies reduce in vitro tau seeding and in vivo neuronal loss
Authors: Tai Chin‐Yin , Ma Haou‐Tzong , Huang Sheng‐Chieh , Li Chung‐Lin , Wu Meng‐Fang , Wu Chia‐Lin , Jang Ming‐Kuei
Published: December 2020

Background

In Alzheimer’s Disease (AD) brains, pathological tau species accumulate at the synapses where the cell‐to‐cell transmission of tau has been experimentally demonstrated.

Method

A series of assays including: dot‐blot assay of synaptic versus cytosolic fractions, brain immunohistochemistry (IHC), HEK cell‐based tau seeding assay, mass spectrometry‐based epitope mapping and in vivo rTg4510 animal efficacy study were used to identify anti‐tau antibodies for therapeutic purposes.

Result

APRINOIA has characterized 12 anti‐tau antibodies bind to synaptic tau species isolated from AD brain tissues. These synaptic preferred anti‐tau antibodies were not only highly specific to pathological tau species in AD brains, but also exhibited diverse subcellular localization in rTg4510 tau transgenic mouse brains. Among them, we focused on 2 antibodies, APNmAb005 and 037. For 005, it localized at axodendritic compartments in the hippocampi of 3‐mo rTg4510 brains and was found to bind conformational epitopes in the mid‐region of tau protein. On the other hand, 037 localized in the somatic compartments with a conformational epitope in the repeat domain of tau. Moreover, both antibodies could block tau seeding from the rTg4510 mouse brain lysates or from the secreted tau of rTg4510 synaptoneurosomes. A 3‐month efficacy study was performed in rTg4510 animals for 005 and significant reduction of neuronal loss was observed.

Conclusion

The therapeutic potentials of anti‐tau antibodies are not judged by the location of epitopes or sub‐cellular localization, but by their abilities to recognize synaptically localized tau in AD brains.
Cognitive results after a FINGER‐like one‐year randomized controlled multidomain intervention: The GOIZ ZAINDU pilot project
Authors: Ecay Mirian , Tainta Mikel , Mugica Justo , Arriba Maria , Ros Naia , Barandiaran Myriam , Iriondo Ane , Garcia‐Sebastian Maite , Estanga Ainara , Aurtenetxe Sara , Saldias Jon , Clerigue Montserrat , Otaegui Ane , Gabilondo Alazne , Arrospide Arantzazu , Martinez‐Lage Pablo
Published: December 2020

Background

Previous trials in Europe (FINGER, MAPT and PreDIVA) have shown that interventions on risk and protective factors represent a window of opportunity for dementia prevention, especially in participants with increased risk. To fully understand the potential impact of these interventions, their feasibility and efficacy needs to be explored in contexts worldwide. GOIZ ZAINDU (“caring early” in Basque language) is a pilot study to adapt FINGER methodology in Southern Europe with the aim to evaluate the feasibility of a lifestyle intervention program in this cultural and social context. An additional exploratory aim is to assess the efficacy of the intervention on cognition.

Method

GOIZ ZAINDU is a one year controlled, randomized, multimodal intervention. Inclusion criteria were: age 60+; CAIDE dementia risk score of 6 points or higher; no dementia; and below‐than‐expected cognitive performance in at least one of three brief cognitive screening tests. Cognitive status (MCI or normal) and age were accounted for randomization to a multidomain intervention (MI) or to Regular Health Advice (RHA). MI includes cardiovascular risk control, nutritional counseling, physical activity program, and cognitive training. Cognitive outcomes include the modified Neuropsychological Test Battery (mNTB) composite score change, and domain Z score change for executive function, processing speed, and memory. Mixed‐effects regression models with maximum likelihood estimation to analyze change in cognitive scores as a function of randomization group, time and groupxtime interaction will be performed.

Result

125 participants were recruited. 64 people were assigned to MI and 61 to RHA. The study started in June 2018, last patient first visit was in March 2019. Up to date 94 participants have completed the study that will end in April 2020. Exploratory results of the efficacy analysis of the intervention on cognition change will be presented.

Conclusion

The GOIZ‐ZAINDU study has proved that the FINGER methodology is adaptable and feasible in a different socio‐cultural environment. Exploratory efficacy results will support the design of the large‐scale efficacy FINGER‐like trial in the Basque Country.
Mild behavioral impairment is predictive of tau deposition in the earliest stages of Alzheimer's disease
Authors: Johansson Maurits , Smith Ruben , Stomrud Erik , Johansson Per , Janelidze Shorena , van Westen Danielle , Mattsson Niklas , Hansson Oskar
Published: December 2020

Background

In Alzheimer´s disease (AD), the emergence of cortical tau deposition has been related to the clinical onset of symptoms. However, associations between tau and Mild Behavioral Impairment (MBI), defined as a neurobehavioral syndrome characterized by late life development of neuropsychiatric symptoms (Table 1), have rarely been investigated. It is unclear if MBI precedes cognitive symptoms, and which manifestation best predicts neuropathology in AD. We cross‐sectionally explored associations between MBI and cortical tau‐pathology in AD and determined if MBI or memory deficit serve as the superior predictor of cortical tau, using Tau PET.

Methods

The study sample (characterized in Table 1), included cognitively unimpaired (CU) (n=50), mild cognitively impaired (MCI) (n= 53) and Aß+ AD dementia cases (n=62) from the Swedish BioFINDER study; all individuals were ß‐amyloid positive (Aß+) according to CSF. Neuropsychiatric assessments included the MBI‐Checklist (MBI‐C) and memory was evaluated using ADAS‐cog Delayed Recall (ADAS‐DR). CSF P‐tau181 was analyzed using ELISA. 18F‐RO948‐PET quantified the level of regional cortical tau deposition. Linear regression models, adjusted for age, sex, level of education and white matter lesions were used to test for associations.

Results

In the total sample, only tau deposition in the entorhinal cortex was associated with MBI‐C scores (right: b=5.857, p=0.034, left: b=5.592, p=0.034) (Table 2). In Aß+ CU cases, entorhinal tau deposition was predicted by MBI‐C (b=0.338, p=0.010), but not ADAS‐DR. A similar pattern was found for CSF P‐tau181. For the Ab+ subjects with MCI an opposite pattern was observed in which ADAS‐DR (b=0,299, p=0.037), but not MBI‐C, predicted the level of entorhinal tau deposition.

Conclusion

Our results suggest that MBI is associated with cortical tau deposition only in the entorhinal cortex, a region known to be one of the earliest accumulation sites in AD. MBI, but not memory deficit, also predicted entorhinal tau in Aß+ CU cases. These findings denote MBI as one of the earliest clinical symptoms associated with early tau pathology during the preclinical stages of AD.
Identification and validation of Alzheimer’s disease‐related metabolic pattern in patients with pathologically confirmed Alzheimer’s disease
Authors: Perovnik Matej , Rus Tomaž , Tomše Petra , Jensterle Luka , Emeršič Andreja , Grmek Marko , Jamšek Jan , Kramberger Milica G , Pirtošek Zvezdan , Trost Maja
Published: December 2020

Background

Alzheimer’s disease (AD) is marked by accumulation of Aβ and tau protein causing neurodegeneration in the brain. AD represents a pathological and clinical continuum, ranging from mild cognitive impairment (MCI) to dementia. A specific metabolic imaging biomarker of AD ‐ Alzheimer’s disease‐related pattern (ADRP) has been previously identified from 2‐[18F]fluorodeoxyglucose positron emission tomography (2‐[18F]FDG‐PET) scans of clinically diagnosed AD patients, using scaled subprofile model based on principal component analysis (SSM/PCA) 1–3. However the clinical diagnosis may be wrong in substantial number of cases 4. We aimed to identify ADRP on patients with Alzheimer’s pathological changes in cerebrospinal (CSF) fluid and to validate it in an independent group of AD and other dementia patients and compare it to the original ADRP 1.

Method

2‐[18F]FDG‐PET scans from 20 AD1 and 20 normal controls (NC1) were used for pattern identification. Additional 110 scans were analyzed for validation: 68 from AD patients (37 AD2, 13 atypical clinical presentation AD (atAD), 18 MCI), 21 with frontotemporal dementia (FTD), 8 non‐AD MCI and 13 NC2 (Table 1). AD was defined with CSF biomarkers as: Aβ42 < 815 pg/ml, pTau > 60 pg/ml, tTau > 400 pg/ml. Topographic profile rating algorithm was used to prospectively calculate ADRP Z‐scores from subjects scans3. Mini‐mental state examination (MMSE) was performed in all patients.

Results

ADRP was identified and voxel weights were found to be stable by bootstrap resampling, Figure 1. Pattern’s expression was significantly higher in AD1 than NC1 (p<0.001) and it strongly correlated (r=‐0.70) with MMSE. Pattern’s expression was also higher in AD2 than NC2 (p<0.001), MCI vs. NC2 (p<0.001), MCI vs. non‐AD MCI (p=0.02) and AD2 vs. FTD (p=0.02), Figure 2. Newly identified pattern moderately correlated (r=0.52) with the original one 1.

Conclusions

We identified ADRP on a cohort of pathologically confirmed AD patients, which was not done before. ADRP has shown to be a reliable metabolic biomarker of AD related neurodegeneration. References: (1) Mattis,PJ. et al. Neurology 87,1925–33(2016); (2) Teune,LK. et al. Curr Alzheimer Res 11,725–32(2014); (3) Spetsieris,PG. & Eidelberg,D. Neuroimage 54,2899–914(2011); (4) Beach,TG. et al. J. Neuropathol. Exp. Neurol. 71,266–273(2012).
Effect of a probiotic administration on inflammatory profile and clinical features in patients with Alzheimer’s disease
Authors: Mombelli Elisa , Lopizzo Nicola , Marizzoni Moira , Mirabelli Peppino , Luongo Delia , Salvatore Marco , Frisoni Giovanni B. , Cattaneo Annamaria
Published: December 2020

Background

Increasing evidence shows that the gut microbiota (GMB) may affect the inflammatory status and influence the pathogenesis of several brain disorders, including Alzheimer’s Disease. Moreover, it has been suggested that probiotics may have potential beneficial effects on the immune system via microbiome composition, influencing in turn also cognitive performances.

Method

Sixty‐two old subjects with normal cognitive performance and 37 AD patients were recruited and stool and blood samples were collected. Moreover, the group of AD patients received a probiotic administration for three months and stool and blood samples were collected again at the end of the treatment. Plasma levels of a panel of pro‐inflammatory cytokines were measured by using the High Sensitivity 9‐Plex Human ProcartaPlex™ Panel (IFN‐ϒ, IL‐1b, IL‐2, IL‐4, IL‐6, IL‐10, IL‐12p70, IL‐17A and TNFα, Thermo Fisher Scientific) on Luminex Bio‐Plex® 200™ system. Moreover, we also measured the plasma levels of C‐Reactive Protein (CRP) using the CRP Human Instant ELISA Kit (Thermo Fisher Scientific). Bacterial composition of fecal samples was inferred using 16s sequencing; the levels of the short chain fatty acids acetate, propionate, valerate and butyrate were measured by mass spectrometry and adhesion molecules by FACS.

Result

We found higher levels of the pro‐inflammatory cytokines IL‐6, IFN gamma, TNF‐alpha, IL‐1beta, and il12p70 and of IL‐2 and lower levels of the anti‐inflammatory cytokine IL‐10 in AD patients as compared to control subjects (all p<0.05). Moreover, we found a positive correlation between MMSE score and the levels of pro‐inflammatory cytokine IL‐6 (p=0.03, r=0.56). Interestingly, the three months treatment with the probiotic composition was able to significantly reduce the level of IL‐6 (p=0.03) and increase the levels of IL‐10 (p=0.023). Bioinformatic analyses on the 16s sequencing data as well as on the SCFAs and endothelial markers are ongoing.

Conclusion

Inflammatory status is higher in AD patients as compared to control subjects and it correlates with cognitive performances. Interestingly probiotic composition is able to push down the inflammatory status in patients, possibly via changes in microbiome composition. Probiotics may be beneficial in delaying neurodegeneration and cognitive deficits in subjects at risk of developing Alzheimer Disease.
A study of alpha desynchronization, heart rate, and MRI during stroop testing unmasks pre‐symptomatic Alzheimer’s disease
Authors: Arakaki Xianghong , Hung Shao‐Min , Wei Ke , Tran Thao , Arechavala Rebecca Johnson , Kleinman Michael T. , Kloner Robert , Fonteh Alfred N. , King Kevin , Harrington Michael G.
Published: December 2020

Background

Alzheimer’s disease (AD) studies suggested the need to detect pre‐symptomatic stage, when cognitive challenges reveal changes of alpha power (brain hyperactivity). Heart rate (HR) regulates brain oxygen supply, is regulated by the brain (eg. hippocampus and amygdala), and correlated with resting state alpha power. We aimed to compare alpha power, HR, and hippocampal and amygdala volume between pre‐symptomatic AD and normal, aging individuals.

Method

We employed quantitative electroencephalography (qEEG) to monitor brain activity during resting and during Stroop interference testing. Cognitively healthy (CH) study participants (demographically matched) were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal amyloid/tau ratio (CH‐NAT, n=20) or pathological amyloid/tau ratio (CH‐PAT, equals pre‐symptomatic AD, n=21). Cognition was assessed using Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination‐7 (MMSE‐7). Participants were presented a series of colored words and asked to respond to each word for the color of the ink, including low load (congruent trials, when color matches the word) and high load (incongruent trials, when color does not match the word). Comparisons between two groups include: alpha desynchronization and alpha spectral entropy (SE), as well as the relationships of alpha desynchronization, HR after Stroop testing, and hippocampal and amygdala volumes (1.5T MRI, demographically balanced subgroups).

Result

No alpha differences were found during the resting state. Occipital alpha desynchronization of CH‐PATs was more negative than in that of CH‐NATs (p=0.024) during the congruent trials (Figure 1), indicating hyperactivity during low load. CH‐PATs had higher alpha SE during congruent trials (p=0.042 frontal, p=0.039 occipital), and lower frontal SE change from congruent to incongruent trials (p=0.012) (Figure 2), supporting reduced functional reserve. Alpha desynchronization positively correlated with HR in CH‐PATs but not CH‐NATs; alpha desynchronization correlated with hippocampal or amygdala differently between CH‐NATs and CH‐PATs (Figure 4). Multiple spectral frequencies revealed correlations in MMSE‐7 & MoCA that differed between CH‐NATs and CH‐PATs.

Conclusion

These results suggest that hyper‐excitability during low load challenge and limited brain reserve is manifest with increasing interference load in pre‐symptomatic AD. We also find brain‐heart coupling is altered in pre‐symptomatic AD.
Towards harmonizing subtyping methods for PET and MRI studies of Alzheimer’s disease
Authors: Mohanty Rosaleena , Mårtensson Gustav , Poulakis Konstantinos , Rodriguez‐Vieitez Elena , Grothe Michel , Nordberg Agneta K , Ferreira Daniel , Westman Eric
Published: December 2020

Background

Identification of biological subtypes in Alzheimer’s disease (AD) has become a growing field for understanding the heterogeneity of the disease. Subtypes, originally identified by postmortem markers (Murray et al., 2011), have been translated to utilize in vivo biomarkers such as those based on structural magnetic resonance imaging (sMRI) and positron emission tomography (PET). While there exists methodological variability across studies, comparable characteristics are reported at group‐level. However, the question that remains to be explored and the motivation for this study is: do group‐level similarities translate to individual‐level agreement across subtyping methods?

Method

We compared five subtyping methods reported in previous studies in a two‐part approach: (a) we validated the methods in 89 AD dementia patients (reference group: 70 healthy individuals; HC) from ADNI using sMRI only; (b) we extended and applied the methods to 30 AD dementia and 53 prodromal AD patients (reference group: 200 HC) from ADNI with concurrent sMRI and tau PET. All AD patients were Aβ positive while all HC were Aβ negative. Subtyping methods included four hypothesis‐driven (Byun et al, 2015; Ferreira et al., 2017; Murray et al., 2011; Risacher et al., 2017) and a data‐driven (Poulakis et al., 2018) algorithms and were implemented as outlined in each original study. Up to four subtypes were identified, namely: typical AD (TAD), limbic predominant (LP), hippocampal sparing (HS) and minimal atrophy (MA). Group‐level and individual‐level comparisons across methods were performed.

Result

In cohort (a), similar frequencies of subtypes were observed between reproduced and published values, thus, establishing proof‐of‐concept. However, comparison of individual‐level subtypes showed disagreement across methods. In the extended cohort (b), large disagreements were observed at the individual level. This is reflected by the low values of Cohen’s kappa, measuring the agreement between methods (Figure 1).

Conclusion

Although characteristics of subtypes are comparable at group‐level, there exist large disparities in individual‐level agreement across subtyping methods. Study of subtypes is growing rapidly by incorporation of multiple biomarkers and application to AD continuum. Thus, there is an urgent need for consensus and harmonization across methods to push the field forward.
Liraglutide and semaglutide: Pooled post hoc analysis to evaluate risk of dementia in patients with type 2 diabetes
Authors: Ballard Clive , Nørgaard Caroline Holm , Friedrich Sarah , Mørch Lina Steinrud , Gerds Thomas , Møller Daniel Vega , Knudsen Lotte Bjerre , Kvist Kajsa , Zinman Bernard , Holm Ellen , Torp‐Pedersen Christian , Hansen Charlotte Thim
Published: December 2020

Background

Glucagon‐like peptide 1 receptor agonists (GLP‐1 RA) have previously shown improved measures of memory and reduced phospho‐tau burden in preclinical animal models relevant to progressive cognitive impairment (Hansen. J Alzheimers Dis.2015;46:877‐88; Hansen. Brain Res.2016;1634:158‐70). Liraglutide and semaglutide are structurally similar GLP‐1 RAs associated with potent glucose‐lowering effect, body weight loss and cardiovascular benefits shown in large cardiovascular outcomes trials (CVOTs) (Marso. N Engl J Med.2016;375:311‐22; Marso. N Engl J Med.2016;375:1834‐44; Husain. N Engl J Med.2019;381:841‐51). In order to investigate the potential effects of GLP‐1 RA on dementia in a clinical setting, a post‐hoc analysis was conducted based on pooled data from three CVOTs.

Method

LEADER, SUSTAIN 6 and PIONEER 6 were randomised, double‐blind, multicentre, placebo‐controlled CVOTs evaluating the cardiovascular effect of liraglutide or semaglutide vs. placebo, added to standard of care. The trials included patients with type 2 diabetes and established or high risk of cardiovascular disease. A post‐hoc analysis on pooled data from the three CVOTs was considered appropriate due to the similarities in trial design, patient population and treatment effects. Across all trials 15,820 patients with median follow‐up of 3.6 years were included in this analysis. Dementia‐related adverse events (AEs) were identified using Standardised MedDRA (version 21.1) Query for “dementia” narrow search terms. AE data collection across the trials differed in line with the regulatory requirements at the time of trial conduct. In LEADER and PIONEER 6 only serious AEs were systematically collected, while all AEs were collected in SUSTAIN 6. A time‐to‐event analysis based on the Cox proportional‐hazards model using treatment as covariate was used to estimate the hazard ratio for developing dementia.

Result

Across the three CVOTs, 15 GLP‐1 RA‐treated patients and 32 placebo‐treated patients were identified with development of dementia (Figure). Post‐hoc analysis on the pooled data showed a significant estimated hazard ratio of 0.47 [0.25; 0.86]95%CI in favour of the GLP‐1 RA treatment versus placebo.

Conclusion

Post‐hoc analysis based on pooled data from three double‐blinded CVOTs suggests, albeit with a low number of events, a reduced risk of dementia with liraglutide or semaglutide treatment in patients with type 2 diabetes.
Identification of clinical phenotypes of Alzheimer’s disease through the gut microbiota
Authors: Marizzoni Moira , Cattaneo Annamaria , Mirabelli Peppino , Luongo Delia , Mombelli Elisa , Salvatore Marco , Frisoni Giovanni B.
Published: December 2020

Background

The genetic, clinical and anatomical presentation of Alzheimer's disease (AD) is extremely heterogenous. Although increasing evidences show that alterations in the gut microbiota (GMB) composition are involved in AD, their contribution to AD pathology remain unclear. The aim of this study is to evaluate whether disease‐specific alterations of the microbiome are present in patients with AD pathology and can identify individuals with peculiar clinical features.

Method

Sixty‐two cognitive impaired subjects underwent Florbetapir amyloid PET and stool collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum (SUVRs) in the frontal, parietal, temporal, anterior cingulate, posterior cingulate and precuneus regions of interest. Amyloid positivity was defined as global PET florbetapir SUVR>1.11. Bacterial composition of fecal samples was inferred using 16S metagenomic sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). We first compared amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific profiles. We then applied Principal Component Analysis (PCA) on those taxa found differentially abundant in Amy+ and Amy‐.

Result

Despite a similar GMB structure (Unweighted and weighted Unifrac, p>0,05) of Amy+ (n=29) and Amy‐ (n=33), taxonomic comparison showed that Amy+ were mainly characterized by rare genera. PCA identified a small subgroup of 6 Amy+ with lower amyloid SUVR uptake in the temporal cortex (p=0,009) and lower cognitive deficits, as showed by better performance at MMSE, ADAScog, logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (p<0.044) compared to the other Amy+ patients. Amyloid SUVR uptake in the temporal cortex was negatively associated with logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (moderate: rho£0.44, p£0.047) and MMSE (weak: rho=0.36, p=0.076) as well as negatively associated with FAQ (moderate: rho=0.47, p=0.010) in the whole Amy+ group.

Conclusion

Despite the small sample size, this study suggests that distinctive bacterial signatures might be associated with specific clinical AD phenotypes.
The impacts in caregiver burden of getting lost events on family caregivers of patients with Alzheimer’s disease
Authors: Hong Wei‐Pin , Pai Ming‐Chyi
Published: December 2020

Background

The prevalence of Alzheimer’s disease (AD) is increasing. The caregiver burden on family caregivers also increased. Behavioral and psychological symptoms of dementia not only reduce the quality of life of patients living with AD and their family caregiver, but also increase risk of institutionalization from their originally living community. Topographical disorientation is common in patients with AD, which may result in getting lost (GL) events. GL in patients with AD is not uncommon. From previous researches, the prevalence of GL events in community are about 30%‐70%. This study will focus on the impacts of GL events on family caregivers since this kind of studies have been never conducted before.

Method

In our preliminary research, we have interviewed the family caregivers of patients with AD who experienced their first ever GL event. The most prominent events after GL was emotional stress and astonishment. In this research, we will interview the family caregivers whose patients with AD and have GL events in recent 3 months. We will divide them into two groups, one is patients with first ever GL event, the other is patients with repetitive GL events. We expect to enroll 100 pairs of patients and their family caregivers and 50/50 in each group. The patients and their family caregivers’ demographic data, patients’ cognitive function, and navigational abilities, and family caregivers’ emotional stress are collected, including Cognitive Abilities Screening Instrument (CASI), Questionnaire of Everyday Navigational Abilities (QuENA), Perceived Stress Scale (PSS) and Chinese version of Startle, Physically Upset by Reminders, Anger, and Numbness scale (SPAN‐C).

Result

The research has been ongoing. The final results will be disclosed during AAIC 2020. We hypothesis that GL events in patients with AD will make great emotional stress on their family caregivers, especially those who suffered from first GL events.

Conclusion

Family caregivers of patients with AD should notice the potential risk of GL and make necessary prevention before it happened.
A comprehensive analysis of dementia cerebrospinal fluid biomarkers using GWAs, polygenic risk scores and Mendelian randomization in Parkinson’s disease
Authors: Ibanez Laura , Bahena Jorge Alberto , Dube Umber , Farias Fabiana H.G. , Yang Chengran , Harari Oscar , Cruchaga Carlos , Benitez Bruno A.
Published: December 2020

Background

Cerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers for diagnosis and progression of Alzheimer disease (AD). CSF levels of Alpha‐synuclein (α‐Syn) have not been very informative in Parkinson’s disease (PD). The burden of Aβ plaques and Tau tangles inversely correlates with cognitive status in PD cases with dementia. However. Lewy body aggregated correlates with dementia progression in PD. A systematic study of CSF biomarkers in PD is yet to be complete, thus, we aimed to investigate the relationship between dementia biomarkers and PD using polygenic risk scores and Mendelian Randomization.

Methods

Genome wide association analyses (GWAs) were performed in N = 1,960 individuals to define the genetic architecture of CSF biomarker levels (α‐syn, Aβ, tau and p‐tau). CSF values were normalized using Z‐score; linear regression was corrected by sex, age and population structure. We performed the same analyses in PD affected individuals only (N = 700) to evaluate if the signals were driven by the PD population. PD genetic architecture was obtained from the latest PD risk meta‐analysis (Nalls, et al 2019) summary statistics. .

Results

PRS analysis showed that CSF Aβ genetic architecture was correlated to that of PD (p = 2.5 × 10−11; R2 = 2.29%.), but not α‐syn, tau or p‐tau. Mendelian randomization methods found that CSF Aβ have a causal role in PD (p = 1.44 × 10−05); an effect mediated by a SNP near the APOE gene (rs769449). Additionally, a trend towards a causal association was found for α‐Syn and PD (p = 0.06). GWAs on PD only population did not reveal any new or known signal for those CSF proteins.

Conclusion

We demonstrated that Aβ is involved in the causal pathway of PD, even though APOE does not seem to be related to CSF Aβ levels or PD risk in PD cohorts. α‐Syn also seems to have a causal relation with PD, but studies with a larger number of samples are needed.