bluuebunny/crossref_metadata_2025 huggingface dataset:
Memorability analysis for diagnostic photographs in cognitive assessment: Linking behavioral performance with biomarker status
Authors: Bai Yuetong , Schütze Hartmut , Berron David , Ziegler Gabriel , Spottke Annika , Buerger Katharina , Schneider Anja , Peters Oliver , Priller Josef , Wiltfang Jens , Laske Christoph , Teipel Stefan J. , Wagner Michael , Jessen Frank , Düzel Emrah , Bainbridge Wilma A. ,   the DELCODE Consortium
Published: December 2021

Background

Recent work has found that memorability, an intrinsic image property predictive of memory, shows consistency across healthy controls (HC), subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Looking at memorability pattern differences between groups, certain images in which HC outperform MCI or SCD individuals can also better predict group membership with a reduced number of images. A key question is whether these diagnostic images reflect a strong link between behavioral performance and biomarker status.

Method

Behavioral and biomarker data was collected from 232 participants (64 HC, 99 SCD, 48 MCI, 21 AD) from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. Participants were tested for recognition of images from a pool of 835 scene images. Aβ42, total tau, phospho‐tau, Aβ42/Aβ40, and Aβ42/phospho‐tau were collected as biomarkers. We computed linear models predicting corrected recognition with each biomarker as a separate regressor. Using hold‐out cross‐validation (80% training) across 1000 iterations, we also identified three subsets of 50 images in which performance differences between HC and MCI were the highest (“top subset”), lowest (“bottom subset”), or close to zero (“middle subset”). We tested these subsets on the remaining 20% test data, by correlating each biomarker and the average hit rate for that image subset, and comparing their performance with independent t‐tests.

Result

All five biomarkers significantly predicted corrected recognition (p<10‐5) in the linear models (Table 1). For all biomarkers, the correlation coefficients acquired from the top subsets were significantly larger than those acquired from the middle subsets or bottom subsets (Fig. 1). In contrast, the middle and bottom subsets showed small differences that were inconsistent across biomarkers.

Conclusion

Our results reveal that images with larger memorability differences between HC and patient groups provide stronger links between behavioral performance and biomarker status. These images are more indicative of neuropathologic changes relevant to AD and are thus more diagnostic. Future study may provide more evidence with functional imaging data.
Dementia and mild cognitive impairment in China: From the public health perspective
Authors: Jia Jianping , Jia Longfei , Du Yifeng , Chu Lan , Zhang Zhanjun , Quan Meina , Wei Cuibai , Li Fangyu , Fu Yue , Tang Yi , Lyu Diyang , Li Yan , Zhu Min , Jiao Haishan , Song Yang , Shi Yuqing , Zhang Heng , Gong Min , Fang Boyan ,   the Project of Dementia Situation in China and the COAST Group
Published: December 2021

Background

China has the largest population of patients with dementia and mild cognitive impairment (MCI) in the world, imposing a heavy burden on the public and healthcare systems. The major concerns from the public health perspective include: prevalence, health economic burden, risk factors, and management strategy.

Method

Statistical analyses were performed on the largest and most comprehensive dementia and MCI cohort study (fig. 1) in China. Systemic review was also done on the studies from the past 10 years.

Result

For the prevalence, our data showed that, the overall prevalence of dementia was 6.0% and of MCI was 15.5%. This represented 15.07 million individuals with dementia and 38.77 million individuals with MCI (fig. 2). For the health economic burden, our systematic review showed that the annual total costs associated with dementia would be $248.71 billion in 2020, $507·49 billion in 2030, $1·00 trillion in 2040, and $1·89 trillion in 2050 in China; on a global scale, these costs would be $1·33 trillion in 2020, $2·54 trillion in 2030, $4·83 trillion in 2040, and $9·12 trillion in 2050 (fig. 3). For the risk factors, our study found that MCI and dementia shared 9 similar, modifiable risk factors, including rural residence, fewer years of education, living alone, smoking, hypertension, hyperlipidaemia, diabetes, and heart and cerebrovascular disease.

Conclusion

The above public health data indicated that dementia and MCI population has become a heavy burden not only in China but around the world, which called for us to develop systematic management strategies, including: 1) prevention strategy targeting the MCI population by controlling for the modifiable risk factors and increasing public awareness; 2) monitoring strategy for all people with MCI by anti‐dementia national surveillance network that does regular cognitive evaluation and training; 3) early diagnosis and treatment strategy for people with dementia by trained dementia professionals; 4) care strategy by an integrative dementia nursing system. These strategies would form the infrastructure that effectively control the prevalence of dementia in China.
Role of plasma ptau181, neurofilament light, and subjective cognitive decline in predicting progression to MCI in older adults from the Alzheimer’s Disease Neuroimaging Initiative
Authors: Banh Timothy , Tosun Duygu , Mackin R. Scott , Weiner Mike W. , Nosheny Rachel L.
Published: December 2021

Background

Accurate identification of AD risk using non‐invasive biomarkers is a critical need. Recently plasma biomarkers of amyloid, phosphorylated tau, and neurodegeneration have been shown to accurately identify mild cognitive impairment (MCI), and brain amyloid levels. However, little is known about whether baseline plasma biomarker predict future progression from cognitively unimpaired (CN) to MCI. The overall goal of this study was to examine the predictive utility of markers that can easily be collected remotely.

Method

We identified a set of non‐invasive markers in ADNI: plasma p‐tau181 and neurofilament light (NfL), Neuropsychiatric Inventory Questionnaire (NPIQ), self‐ and study partner versions of a subjective cognitive decline instrument (Everyday Cognition Scale; Ecog), and APOE. In 300 ADNI participants who were CN at baseline, we determined the associations between these markers and progression to MCI using logistic regression. Models covaried for age, gender, and education level. Area under the receiver operator curve (AUC) evaluated discrimination accuracy. Likelihood ratio tests (LRT) determined the best fitting model.

Result

42 (14%) of participants progressed to MCI (Table 1). In the full model including all predictors (AUC = .879; Table 2 and Figure 1), study partner Ecog score was the only significant predictor associated with progression to MCI. Excluding study partner Ecog decreased model accuracy (AUC = .779; Figure 1). The LRT between this model and the full model was significant (c2(1) = 5.04, p < .05).

Conclusion

Even when accounting for the contributions of ptau181 and Nfl, study partner‐reported subjective cognitive decline independently predicts future progression to MCI. This approach can be used in the future to efficiently predict MCI risk without the need for in‐clinic assessment.
Perceived needs and support services of families of people with dementia
Authors: Yurrebaso‐Macho Amaia , Orgaz‐Baz Begoña , Montes‐López Estrella , Valverde Eva María Picado , del Álamo‐Gómez Nuria ,   NEUROQUALYFAM group
Published: December 2021

Background

Dementia is one of the most important causes of dependency worldwide. These patients require constant care. This care is mainly provided by the families. Each family has specific needs and demands specific support services. To improve their quality of life, the family should be considered in the development of strategies that contribute to the provision of support services for them. Considering this, the objectives of this work are to analyse the support needs of these families, as well as the services they access.

Method

The FQOLS‐NDs instrument (Badía et al., 2020) was applied by telephone to a sample of 163 relatives of people with dementia in the Spain‐Portugal cross‐border area. The main characteristics of the research participants are: 69.9% are women, aged between 28 and 87, and do not work (63.8%). They are mainly daughters/sons (59.5%) or partners (32.5%) of the person with dementia. In addition, they are mostly their main carers (95.1%) and live with them (74.8%).

Results

The main research findings reveal that: 1) The support services most needed by families are information about the disease (53.4%); information about support services (52.8%), and information about where to get them (44.8%). 2) Family members report not being able to access the support services they need. Among them, those to which more than 80% of families do not have access stand out. These are support groups (92.3%), psychological help (90.3%), family respite (85.5%) and spending money (81.1%). 3) There are few support services that families need and consider that they have sufficient access to. The most positive data reveal that only 18.4% of participants perceive the information they receive about the disease as sufficient; only 16.3% consider that they have enough help to run the household, and only 12.8% claim to have access to sufficient information about legal rights.

Conclusion

Families are not receiving the support services they most need. Moreover, they do not value the services they access as sufficient. References: Badía, M., Orgaz, M.B., González, E., Vicario‐Molina, I., Gómez‐Vela, M. and NEUROQUALYFAM group (2020). Family Quality of Life Scale ‐ Neurodegenerative Diseases.
Subacute plasma neurofilament light predicts neurodegeneration after moderate‐severe traumatic brain injury
Authors: Graham Neil S.N. , Zimmerman Karl A. , Moro Federico , Bourke Niall , Zetterberg Henrik , Heslegrave Amanda J. , Magnoni Sandra , Bertolini Guido , Garbero Elena , Nattino Giovanni , Oddo Mauro , Maillard Samia Abed , Miroz John‐Paul , Gradisek Primoz , Bernini Adriano , Chieregato Arturo , Fainardi Enrico , Baciu Camelia , Sharp David J.
Published: December 2021

Background

TBI is an environmental risk factor for the development of dementia. Axonal injury is thought be a significant determinant of clinical outcomes post‐injury, which can now be assessed using novel techniques such as fluid biomarkers including plasma neurofilament light and advanced MRI assessment.

Method

BIO‐AX‐TBI (Developing and Validating Blood and Imaging BIOmarkers of AXonal Injury Following Traumatic Brain Injury, NCT03534154) is a multi‐centre cohort study of patients after acute moderate‐severe TBI. Patients admitted to major trauma units underwent baseline clinical assessment, serial blood biomarker and MRI over one year, with detailed outcome ascertainment. Blood concentrations of neurofilament light (NFL), total‐tau, S100‐B, ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and glial fibrillary acidic protein (GFAP) were quantified.

Result

197 patients after TBI had acute blood biomarker assessment with clinical outcomes ascertained at 6 and 12 months. 95 healthy participants with imaging and blood biomarker workup were assessed, alongside 28 healthy controls with longitudinal neuroimaging and 24 trauma patients with extracranial injuries (non‐TBI trauma, ‘NTT’). TBI patients had significant elevations of blood biomarkers including NfL and tau compared with controls and NTTs. Diffusion tensor imaging (DTI) showed reduced fractional anisotropy in TBI patients, which remained abnormal into the chronic phase and correlated with subacute NFL. Grey matter atrophy rates were elevated in the first 6 months post injury and correlated with peak plasma tau levels, which additionally predicted cognitive performance. Abnormal chronic (6‐12) month white matter atrophy, particularly of the right internal capsule/posterior thalamic radiation, was predicted by subacute plasma NFL, which furthermore predicted functional outcome.

Conclusion

In this longitudinal investigation, subacute plasma NFL was highly sensitive to axonal injury after TBI, predicted functional outcome at 6 and 12 months and predicted accelerated white matter atrophy in the chronic phase. Early plasma tau predicted grey matter atrophy post‐injury and 12 month cognitive function. Plasma NFL and tau appear to be a valuable non‐invasive means to diagnose significant injuries and identify those patients at high risk of chronic neurodegeneration, which may inform recruitment into clinical trials of anti‐neurodegenerative therapies in future.
Cardiorespiratory fitness and cognition in healthy elderly and MCI patients
Authors: Velde Pia Marie , Müller Patrick , Müller Notger , Hökelmann Anita
Published: December 2021

Background

Current research indicates a positive impact of physical activity on healthy ageing, on brain plasticity and on the risk for dementia. Furthermore, several epidemiological, cross‐sectional and interventional studies have shown that cardiorespiratory fitness is associated with cognitive performance, especially regarding executive functions.

Method

Here, we investigated the relationship between cardiorespiratory fitness and cognition in both healthy elderly (n=33; age: 68.8 ± 6.9) and in patients with mild cognitive impairment (MCI; n=27, age: 70.8 ± 6.1). Cardiorespiratory fitness was assessed using bicycle spiroergometry (cosmos torqualizer 600ef med; Germany) with an incremental step test. To determine the metabolic status, capillary blood samples were taken from the ear at rest (baseline), after each step and one, three and five minutes after the incremental step test was finished. The lactate concentration was measured with lactate scout sensors (SensLab GmbH Leipzig, Germany). Cognitive abilities were measured with the extended CERAD plus neuropsychological test battery (including Trial making test & verbal fluency S words).

Result

Statistical analysis revealed significant between group differences in cognitive functions (e.g. MMSE, p<.001 TMT‐A, p<.001), but no significant differences in cardiorespiratory fitness (e.g. VO2peak, Wpeak, lactate). Furthermore, correlation analysis showed a significant correlation between VO2peak and MMSE in healthy elderly (p=.029, r=‐0.333)), but not in MCI patients (p=.317, r=‐0.096).

Conclusion

Our results indicate no differences in cardiorespiratory fitness between healthy elderly and MCI patients. However, cardiorespiratory fitness is associated with general cognition in healthy elderly. Why this correlation was not seen in MCI patients needs to be assessed in more detail in future research.
Language profile of primary progressive aphasia in a linguistically diverse cohort in India
Authors: Goyal Sheetal , Darshini K.J , Arshad Faheem , Varghese Feba Anna , Paplikar Avanthi , Vandana V.P , Ramakrishnan Subasree , Alladi Suvarna
Published: December 2021

Background

The accurate characterization of language and semantic memory deficits is crucial for diagnosis of primary progressive aphasia (PPA). In a linguistically diverse society like India, assessment with linguistically appropriate and culturally relevant tools is essential but challenging. This study aimed at developing language and culture specific tests to diagnose PPA and profile cognitive‐linguistic characteristics of a diverse cohort of PPA in India.

Method

Based on typical characteristics of Indian languages: free‐word order, rich system of morphology and case‐marking that are features that differentiate Indian languages from English, a language‐specific assessment battery was developed in seven languages: Hindi, Bengali (Indo‐Aryan languages) and Kannada, Telugu, Malayalam and Tamil (Dravidian languages). In the background of the importance of case‐markers in the syntax of Indian languages, a unique syntax assessment test was specifically developed. To evaluate semantic memory, the Indian Semantic Memory battery was developed using stimuli appropriate for a pan‐Indian cultural context. All patients underwent assessment of language proficiency and comprehensive cognitive evaluation by examiners proficient in the language of testing.

Result

36 patients with PPA: 22 with semantic variant (svPPA), 12 nonfluent variant (nfvPPA) and 2 logopenic variant (lvPPA) participated. The cohort consisted of proficient speakers of seven Indian languages. A particular difficulty in the appropriate use of case markers on the new test of syntax was revealed in nfvPPA compared to svPPA. Further, the core diagnostic feature of ‘agrammatism’ for PPA in English‐speaking nfvPPA was not as dramatic in Indian patients owing to the morphological richness of Indian languages, leading to reduced contrast between fluent versus non‐fluent aphasia. Consistent with diagnosis, a significant reduction in fluency was demonstrated in nfvPPA (p< 0.006 on fluency tasks). Semantic memory was significantly affected in svPPA as revealed on non‐verbal tasks i.e., word‐picture matching (p<0.02)and semantic association task(p<0.01) of Indian Semantic Battery.

Conclusion

Using language and culture specific assessment batteries tailored to the Indian context, a comprehensive clinical characteristics in PPA subtypes were identified. The need to re‐define agrammatism with respect to Indian languages with additional weightage to the use of case markers that assist in identifying the PPA subtype was a novel finding.
Astaxanthin‐s‐allyl cysteine diester attenuated high glucose‐induced oxidative stress toxicity in neuronal cells through protection of mitochondria in vitro
Authors: Loganathan Chitra , Sakayanathan Penislusshiyan , Thayumanavan Palvannan
Published: December 2021

Background

Cognitive dysfunction associate with diabetes is related to high glucose‐induced oxidative stress toxicity in neuronal cells. Hence, identifying compounds that protect the neuronal cells against high glucose toxicity is important to overcome cognitive deterioration under diabetic condition. Astaxanthin‐s‐allyl cysteine diester (AST‐SAC) was synthesized by esterification of AST from the source H. pluvialis with SAC, an allyl sulfur compound found in aged garlic extract. AST‐SAC has shown antidiabetic effect in in vivo rat model. Hence, in the present study the effect of AST‐SAC against high glucose‐induced oxidative stress toxicity in neuronal cell line in in vitro was studied.

Method

AST‐SAC was pre‐treated to neuronal cell line and high glucose toxicity was induced. The cell viability, reactive oxidant species generation, antioxidant status and apoptosis induction was studied. Further, mitochondrial membrane potential, mitochondrial oxidative phosphorylation activity and antioxidant status of mitochondria was measured.

Result

High glucose‐induced toxicity increased oxidative stress and decreased over all antioxidant status of the neuronal cells. Due to which functions (membrane potential and oxidative phosphorylation) and antioxidant status of mitochondria were reduced. All these dysfunction cumulatively lead to the induction of apoptosis in neuronal cells. However, AST‐SAC pretreatment has protected the neuronal cells against high glucose‐induced apoptosis through reduction of oxidative stress and protection of mitochondrial function.

Conclusion

Overall AST‐SAC attenuated high‐glucose toxicity induced neuronal injury in in vitro through preservation of mitochondrial function.
The mediating role of inflammation in the relationship between α‐synuclein and cognitive functioning
Authors: Dabiri Sanaz , Ruiz Mara Ramirez , Obisesan Thomas O. , Ntekim Oyonumo , Mwendwa Denée T. , Ngwa Julius S. , Campbell Alfonso L. ,   for the Alzhemer's Disease Neuroimaging Initiative
Published: December 2021

Background

Accumulating evidence suggests that α‐synuclein is associated with poor cognitive functioning and plays a role in the pathophysiology of AD. High accumulation of α‐synuclein eventually leads to neuronal death and the initiation of inflammatory cascades. Prior research suggests inflammation plays a role in the development and acceleration of cognitive decline. Moreover, recent studies suggest VEGF may be involved in the development of AD. Therefore, this study examined whether α‐synuclein in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also determined whether this relationship was influenced by elevated levels of pro‐inflammatory cytokines TNFα, IL‐6, soluble IL‐6 receptor along with VEGF.

Method

Using a cross‐sectional Alzheimer’s Disease Neuroimaging Initiative (ADNI; n= 148) sample, we examined the relationship between CSF measured α‐synuclein and participants' performance on MMSE and ADAS‐Cog 13 at baseline. Mediation analyses while adjusting for age, education, APOEe4, and GDS scores were utilized.

Result

Participants in the current sample were largely males (58.3%), Caucasian (95.5%), average education of 15.5 (SD = 2.97) years and average age 74.4 (SD = 7.51). We observed that higher accumulation of α‐synuclein was associated with lower performance on the MMSE (β =‐.41, SE=1.54, p<.001). This relationship was also mediated by VEGF (β =.27, SE=2.15, p=.025) and IL‐6r (β =.22, SE=1.66, p<.026). In addition, α‐synuclein was associated with poorer performance on the ADAS‐Cog 13 (β =0.34, p=.005) and mediated by VEGF (β =‐.19, SE=4.13, p=.025) after adjusting for age, education, APOEe4, and depressive symptoms.

Conclusion

Our findings suggest that α‐synuclein can be used as an additional biomarker for poor cognitive functioning. VEGF and IL‐6 soluble receptors were significant mediators in the relationship between α‐synuclein and cognitive functioning. However, this study observed that pro‐inflammatory cytokines TNFα and IL‐6 did not mediate this relationship. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.
Memory decline is not normal, healthy brain aging
Authors: Pardo Jose V. , Nyabwari Shantal M. , Lee Joel T ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

Background

It is generally accepted that memory decline is a cardinal feature of aging even in those who are healthy and cognitively intact. However, recent work indicates that as many as 1/4 cognitively unimpaired older adults have significant amyloid deposits and as many as 8% meet the biological definition of Alzheimer's disease (AD; i.e., A+T+; Therriault et al. 10.1212/WNL.0000000000011416). Therefore, studies of cognitive aging before the advent of AD biomarkers may have included a significant number of older adults with preclinical AD skewing findings toward abnormal values.

Method

Baseline data from cognitively intact older adults with subthreshold whole‐brain amyloid (A‐) were downloaded from the ADNI website (LONI: http://adni.loni.usc.edu/). The scores from the Logical Memory I & II tests (recall of items for story presented verbally; immediate and delayed) were selected because these place minimal demands on executive function that can also become impaired with age. These volunteers (N = 155) were 59–93 years old (mean age 74 years, SD 6.6; 77 females). The relationship between memory and age was tested for significance.

Result

There was no significant correlation between age and immediate or delayed scores on the Logical Memory Test (r ∼ 0.1; d.f. 153).

Conclusion

Even into ninety years of age, older adults show cross sectionally no relationship between age and logical memory. However, age‐related deficits may surface in neuropsychological tests that are more demanding or that tax multiple brain systems such as executive functions. The lack of correlation of age with memory converges with recent studies, both cross‐sectional and longitudinal, examining other cohorts of cognitively intact, amyloid‐negative, older adults with more comprehensive testing of memory (Lim et. al. 2018: 10.1001/jamaneurol.2017.4325; Tomassen et al., 2020: 10.1002/alz.045112; Pelkmans et al. 2021: 10.1002/acn3.51273). Support: VA Merit I01CX000501; NIH ADNI U19 AG024904.
BIOFACE: A prospective study of risk factors, cognition and biomarkers in a cohort of individuals with early‐onset mild cognitive impairment at Fundació ACE
Authors: Antonio Ester Esteban‐De , Pérez‐Cordón Alba , Gil Silvia , Cano Amanda , Orellana Adelina , Alegret Montserrat , Espinosa Ana , Alarcón‐Martín Emilio , Valero Sergi , Martínez Joan , Montrreal Laura , de Rojas Itziar , Sotolongo‐Grau Oscar , Martín Elvira , Vivas Assumpta , Chiari Marta Gómez , Tejero Miguel Angel , Tarraga Lluis , Ruiz Agustin , Marquié Marta , Boada Mercè ,   BIOFACE Study Group
Published: December 2021

Background

The diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) is based on either cerebrospinal fluid (CSF) or neuroimaging biomarkers (Albert et al, 2011). Currently, several non‐invasive and cheaper blood‐based biomarkers are being investigated, including neuronal‐derived plasma exosomes (NPEs) (Winston et al, 2016). The role of neuroinflammation, oxidative stress and early vascular changes, prior to the onset of amyloidosis, has been described in the pathogenesis of AD (Iturria‐Medina et al, 2016) and vascular‐related proteins can be traced in plasma and NPEs using proteomics. However, these changes have not been studied in early onset MCI (EOMCI), that is, when symptoms begin under the age of 65 (Rossor et al, 2010).

Objective

To describe the rationale, study design and baseline characteristics of the BIOFACE cohort, a two‐year prospective observational study on EOMCI conducted at Fundació ACE in Barcelona, Spain. The study goal is to characterize different clinical, neuropsychological and biomarker phenotypes and to investigate CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.

Method

Participants underwent neurological and neuropsychological batteries and multimodal biomarkers including brain MRI, APOE genotyping, plasma and NPEs, saliva, CSF, non‐invasive arterial peripheral testing, anthropometrics and neuro‐ophthalmological examinations. In the final visit, participants will undergo brain MRI, lumbar puncture and blood extraction for NPEs.

Result

Ninety‐seven patients with EOMCI were recruited. Most participants were women (59.8%). Mean age at symptom onset was 57 years; mean MMSE score was 28 with a mean of 12.13 years of education. First degree and presenile family history of dementia was present in 60.8% and 15.5%, respectively. Depressive and anxiety disorders, along with vascular risk factors, were the most frequent comorbidities. Syndromic diagnoses were established: possible amnestic MCI (n=32), possible non‐amnestic MCI (n=33), probable amnestic MCI (n=16) and probable non amnestic MCI (n=16). CSF biomarkers (ATN classification): A+ (n=15), A‐T/N+ (n=13), A‐T‐N‐ (n=57).

Conclusion

BIOFACE is a two‐year observational study of cognition and biomarkers that will shed light on the physiopathology and the potential utility of plasma proteomics and NPEs as non‐invasive early diagnostic and prognostic biomarkers in individuals with early onset MCI.
Neuropsychiatric symptoms in patients with possible vascular cognitive impairment: Does sex matter?
Authors: Exalto Lieza G. , Boomsma Jooske , Sep Yoni C.P. , Leeuwis Anna E. , Prins Niels D. , Scheltens Philip , Biessels Geert Jan , van der Flier Wiesje M ,   TRACE‐VCI study group
Published: December 2021

Background

Emerging evidence shows sex differences in manifestations of neuropsychiatric symptoms (NPS) in memory clinic patients. NPS are common in patients with vascular cognitive impairment (VCI) affecting quality of life and caregiver burden, however sex differences are largely unknown. We aimed first to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and second to investigate the association between different NPS and substantial cognitive decline stratified by sex.

Method

We included 737 memory clinic patients (age 68.1±8.4; 45% female) from the prospective TRACE‐VCI cohort study with possible VCI; cognitive complaints and vascular brain injury (moderate/severe white matter hyperintensities (n = 398), microbleeds (n = 317), lacunar (n = 167) and non‐lacunar (n = 85) infarct(s), macrobleeds (n = 14)). Dementia was diagnosed in 405 and MCI in 197 patients. NPS were measured using the 12‐item Neuropsychiatric Inventory (NPI) and dichotomized as present ≥1. Substantial cognitive decline was defined as change of CDR ≥1 or institutionalization (available for n=571 without advanced dementia at baseline). The association between NPS and cognitive decline was assessed with Cox proportional hazard models in females and males separate, adjusted for other NPS, age and clinical diagnosis.

Result

We found no difference in age nor distribution of clinical diagnoses between the sexes. Males more often presented with agitation (29% versus 17%) and irritability (58% versus 46%), while females more often presented with anxiety (32% versus 25%, all p<0.05), the other 9 NPS (delusions, hallucinations, aggression, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, sleep/night‐time disturbances and appetite and eating abnormalities) did not differ between the sexes. During follow‐up, occurrence of substantial cognitive decline was comparable between males (14%) and females (15%). In males, substantial cognitive decline was higher in the presence of apathy (HR 2.5, 95%CI;1.2‐5.4) and aberrant motor behavior (HR 2.2, 95%CI;1.1‐4.6) and lower in the presence of appetite and eating abnormalities (HR 0.4, 95%CI;0.2‐0.9). In females, none of the NPS were associated with substantial cognitive decline.

Conclusion

Pattern and predictive value of NPS differs by sex in memory clinic patients with VCI. Acknowledgment of these differences could direct interventions.
Longitudinal changes of multiple CSF phosphorylated tau sites in dominantly inherited Alzheimer disease
Authors: Barthelemy Nicolas R. , Li Yan , Sato Chihiro , Horie Kanta , McDade Eric
Published: December 2021

Background

Recent analyses of tau phosphorylation in cerebrospinal fluid (CSF) from dominantly inherited Alzheimer disease (DIAD) patients have pinpointed early modification of phosphorylated tau (p‐tau) at 217 (pT217) occurring simultaneously with emergence of amyloid plaques. This has opened new perspective in diagnosing AD pathology at preclinical stages using ptau in CSF and plasma. Tau is phosphorylated at many sites in brain and a subset of them is detectable in CSF. To date, we have investigated four p‐tau sites and demonstrated the modifications of pT217, pT181 and pT205 start respectively 21, 19 and 13 years before estimated year to symptom onset (EYO) when pS202 remained unchanged. We extend the list of monitored ptau sites in the DIAN cohort to ten tau residues.

Method

589 CSF samples from 370 participants in DIAD families were analyzed by tau immunopurification and multiplex‐targeted mass spectrometry using nanoLC‐Q‐LTQ‐Orbitrap instrument. We measured phosphorylation occupancy and ptau level at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231. For each ptau, we calculated area under curve (AUC) of receiver operating characteristic (ROC) to detect amyloidosis as measured by PiB‐PET. We determined phosphorylation amount and rate of change over the course of the disease based on EYO.

Result

The most to least sensitive phosphorylated sites for detecting amyloidosis in mutation carriers were T217, T181, T153, T111, T231, S208 and T205 with AUC ranging from 0.96 to 0.87. T175, S199 and S202 were not significantly modified. For the newly investigated sites pT111, pT153, pS208 and T231, we found significant hyperphosphorylation compared to non‐carriers at EYOs ranging from ‐22 to ‐19 years. Longitudinal analyses of pT153, pS208 and pT231 demonstrated a decreasing of the phosphorylation after symptoms as previously observed for pT217 and pT181. Separately, pT111 continued to increase after onset.

Conclusion

This study corroborates the distinct response of tau residues to hyperphosphorylation over AD process. We confirm pT217 is the earliest abnormally modified phosphorylated site in AD amongst the 10 sites investigated in CSF. Our results support the use of pT153, pT111 pT231 and pS208 as additional ptau biomarkers for the diagnosis of asymptomatic AD.
A novel PU.1 inhibitor for the treatment of Alzheimer’s disease
Authors: Ralvenius William T , Tsai Li‐Huei , Woolf Hannah , Cam Hugh , Mungenast Alison
Published: December 2021

Background

In 2015, we identified the microglia‐specific transcription factor PU.1, encoded for by SPI1, as a master regulator of neuroinflammation in a mouse model of Alzheimer’s Disease and in human brain tissue from deceased Alzheimer’s Disease patients1. In 2017, a GWAS SNP that delays onset of Alzheimer’s Disease, was shown to reduce PU.1 expression levels2. Here, we describe a high‐throughput screen for small molecules that inhibit PU.1 activity. Our goal is to develop novel agents that can rein in the abnormal neuroimmune response associated with Alzheimer’s dementia.

Method

We used a stable immortalized mouse microglia (BV2) reporter line that expresses luciferase in a PU.1‐dependent manner. We screened a total of 58’100 molecules from 3 separate chemical libraries and obtained 264 hits. We further validated these hits using multiple assays in human stem cell derived microglia. Finally, we administered our top hit (A11) to transgenic mouse models of Alzheimer’s Disease.

Result

A11 exhibits anti‐inflammatory effects at a concentration of 20 nM in activated microglia, as assessed by RTqPCR and ELISA for IL1β, morphological analyses and lipid accumulation quantification. In mice, A11 preferentially distributed to brain tissues after systemic (intraperitoneal) application and reached a peak concentration at 4 hours. When dosing mice that develop severe neurodegeneration (CK‐p25 transgenic mice), we found a reduction of microglial proliferation, astrogliosis and retention of p25‐positive neurons in the hippocampus. No abnormalities were seen in the treated control littermates.

Conclusion

Our novel PU.1 inhibitor (A11) shows nanomolar potency and efficacy in multiple assays and cell lines. Mouse experiments demonstrate suitability for systemic application. Administration of A11 in CK‐p25 transgenic mice show an amelioration of neurodegeneration‐associated hallmarks, such as microglial and astrocytic activation and loss of p25‐positive neurons. References: (1) Gjoneska,E, A R Pfenning, H Mathys, G Quon, A Kundaje, L H Tsai and M Kellis. 2015. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nat. 518(7539)365‐9. (2) Huang,K L, E Marcora, A A Pimenova, A F Di Narzo et al. 2017. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci. 20(8) 1052‐1061.
Asian cohort for Alzheimer’s disease (ACAD) data collection: Rationale, design and validation
Authors: Chow Tiffany W , Reyes‐Dumeyer Dolly , Gu Yian , Li Clara , Tee Boon Lead , Lee Haeok , Park Van Ta , Lieu Kevin , Lu Anna T , Peavy Guerry M , Hsiung Ging‐Yuek Robin , Vogel Briana , Ho Pei‐chuan , Yu W. Haung , Choi Yun‐Beom , Jun Gyungah R , Henderson Victor W , Chow Tiffany H , Mayeux Richard , Wang Li‐San ,   The Asian Cohort for Alzheimer's Disease Study
Published: December 2021

Background

As the first large Alzheimer’s Disease (AD) genetics cohort for Asians in the United States and Canada, the Asian Cohort for Alzheimer’s Disease (ACAD) has adapted existing instruments to collect data on sex, genetics, medical history, and lifestyle risk factors. We hypothesize that any and all of these factors impact AD risk differently for Asians. Initially ACAD focuses on US and Canadian participants of Chinese, Korean, and Vietnamese ancestry.

Method

ACAD’s Clinical Workgroup reviewed commonly used dementia research questionnaires, including the NACC Uniform Data Set, Religious Order Study, and NIA‐Late‐Onset AD to select, and in some cases adapt, questions that are most appropriate for ACAD. A combination of AD clinical researchers and community outreach specialists reviewed the data collection packet, administration procedures, and consensus diagnosis process for cultural sensitivity without sacrificing scientific rigor to gather non‐genetic and lifestyle risk factor data.

Result

We designed the ACAD Data Collection Packet (DCP) to create a friendly dialogue with participants through a socio‐culturally and linguistically sensitive 3‐part process. The DCP consists of some instruments already validated in Chinese, Vietnamese and Korean languages to screen for cognitive impairment (Cognitive Abilities Screening Instrument (CASI) and Modified Mini‐Mental State (3MS)). Part A collects origins, Mediterranean diet compliance, and Clinical Dementia Rating scores. The self‐administered Part B uses an adaptation of the Rush Cognitive Activity Questionnaire on early‐life enrichment. Part C structures the collection of medical history and cognitive testing with CASI vs 3MS, the Common Objects Memory Test, Category (not Letter) Fluency, and the 15‐item Clock Drawing Task. This assessment is designed to be administered either remotely or face to face.

Conclusion

Over the next year, we will pilot the ACAD Data Collection Packet, to set a community standard for dementia screening among Asian Americans and Canadians that can support data harmonization across epidemiological studies. While ACAD translation accommodates Chinese, Korean, and Vietnamese at this stage, we look forward to implementing additional major Asian languages.
Causal mediation analysis with longitudinal data: Relationships among sleep quality, diabetes, and subjective memory in older adults
Authors: Park Sang‐Mi , Lee Chang Dae
Published: December 2021

Background

Low quality sleep or lack of sleep is related to both lower levels of quality of life and negative health problems such as cognitive decline or diabetes in older adults. Although the associations among sleep quality, cognitive function, and diabetes were reported in previous studies, the mechanisms of association and their causal link is unclear. The aim of this study was to explore the mechanism between quality of sleep and cognitive decline by examining the mediation model of quality of sleep, diabetes, and subjective memory.

Method

The longitudinal panel data from the National Health and Aging Trends Study (NHATS) which was released to the public for research was used for this study. Research hypothesis was that diabetes in the third wave mediates the association between sleep quality in the first wave and subjective memory in the fifth wave among consecutive five years of wave. Presence of diabetes was used as a mediation variable. Sleep quality was measured with three questions about frequency of difficulties in falling asleep or maintaining a good sleep at night within the last month. Subjective memory was measured by one question with a five‐point‐Likert scale. Causal mediation analysis was conducted using CAUSALMED procedure in SAS 9.4.

Result

Except for the cases which contained missing data, data from 3,238 older adults above the age of 65 was used for final analysis. After controlling for diabetes, education, subjective memory, economic well‐being, depression, medication, age, smoking history in the first wave, the total effect of higher sleep quality on better subjective memory was .011 (p=.036). However, indirect effect of sleep quality mediated by diabetes was not statistically significant (estimate = ‐.0003, p=.641). The percentage due to interaction effect of sleep quality and diabetes was not statistically significant as well (estimate = ‐31.269, p=.295).

Conclusion

Although both sleep quality and diabetes were reported to be important predictors of dementia in previous studies, the result did not support the mediation effect of diabetes between sleep quality and subjective cognitive decline. Further study to discover the mediation effect of predictors of dementia is needed for better understanding of the cognitive decline mechanism in older adults.
Differences between neurodegenerative disorders in conversational turn‐taking
Authors: Pressman Peter S. , Matthewson Gordon , Lemieux Eric , Levenson Robert W
Published: December 2021

Background

A smooth turn‐taking transition from one person to the next is an expected part of many conversations. Turn‐taking combines high temporal coordination between participants with the remarkable complexity and open‐endedness of the language and paralanguage that fills the turns. Turn‐taking may therefore serve as a naturally occurring marker of disorders that disrupt executive functioning, ability to interpret nonverbal cues, as well as social drive and motivation.

Methods

Couples consisting of a healthy control and a person with a neurodegenerative condition were instructed to discuss a mutually selected topic of continuing disagreement in their relationship. Each conversation lasted between 10 to 15 minutes. Manual labeling of speakers, non‐speech vocalizations and background noise was then performed using Praat. Statistical analysis was then performed on numerous conversational metrics, including both count and duration of gaps, interruptions, and pauses throughout the conversations.

Results

Overall differences were found in number of times someone took the floor, interrupted the partner, and number of perfect exchanges. Compared to Alzheimer’s disease (AD), the semantic variant of primary progressive aphasia (svPPA) and progressive supranuclear palsy had more interruptions. Behavioral variant frontotemporal dementia had fewer perfect exchanges (< 0.1 second between speakers without interruption) than AD.

Conclusion

Floor exchanges, specifically numbers of interruptions and “perfect exchanges,” may be useful in distinguishing atypical AD from other dementia types. Next steps include comparing patients with neurodegenerative conditions against normal controls and correlating data with imaging and neuropsychiatric testing.
Gut microbiome alterations in Alzheimer’s patients from Kazakhstan
Authors: Askarova Sholpan , Kaiyrlykyzy Aiym , Kozhakhmetov Samat , Babenko Dmitriy , Olzhayev Farkhad , Kushugulova Almagul
Published: December 2021

Background

Recent studies strongly suggest that gut microbiome is capable of influencing brain functions and contribute to the development of Alzheimer’s disease (AD). However, only few studies have characterized the human gut microbiome communities associated with AD. Moreover, reported changes in the gut microbiomes in AD patients from different countries are not similar. Therefore, more research is needed in order to reveal the relationships existing between human microbiomes and AD in different ethnic populations. Here, we report the first pilot case‐control study of diversity and composition of gut microbiomes isolated from the patients diagnosed with AD in comparison with healthy seniors from the Central Asian region.

Method

Microbial DNA was isolated from fecal samples of the patients with confirmed AD (n=11) and healthy age‐ and gender‐matched individuals (n=13). The composition of gut microbiomes were characterized by 16S ribosomal RNA MiSeq sequencing. Data analysis was performed using less operational taxonomic units scripts (LotuS) and R (v4.03).

Result

Our results demonstrated that gut microbiota of AD individuals had overall higher α‐diversity compared to healthy controls, although this difference was not significant. The absence of statistical power might be explained by a low sample size. However, we have found significant differences of bacterial abundance at class, order and genus levels. At class level the amount of Bacilli was depleted in AD group; at order level, the relative abundance of Oscillospirales increased, while the abundance of Lactobacillales decreased in AD patients. Among bacterial genera, microbiomes of AD participants were characterized by a preponderance of unknown_Prevotellaceae and unknown_Ruminococcaceae. Linear discriminant analysis (LDA) has revealed that the relative abundances of Eubacterium coprostanoligenes group, Rikenellaceae RC9 gut group, Bacilli RF39, Oscillospirales UCG‐011 were significantly different in AD patients compared to healthy participants.

Conclusion

Studying the gut microbiome alterations in AD patients is of considerable interest. By focusing on the mechanism of interactions between human microbiota and the brain, we can uncover new pathophysiological pathways leading to the onset and progression of AD, evaluate the contributions of environment and lifestyle to the increase in prevalence of dementia and develop practical recommendations for the prevention and treatment of this severe pathology.
Mild behavioral impairment: Prevalence, clinical profile, and prognosis in a memory clinic cohort in Singapore
Authors: Kan Cheuk Ni , Cano Jemellee , Chan Victoria , Ismail Zahinoor , Zhao Xuhao , Chen Christopher , Xu Xin
Published: December 2021

Background

Mild behavioral impairment (MBI) is characterized as later‐life emergent and persistent neuropsychiatric symptoms (NPS) that are suggestive of early manifestations of Alzheimer’s Disease (AD) and dementia. This study aims to investigate the prevalence, clinical correlates, cognitive trajectories, and dementia risk of MBI in a clinical cohort.

Method

In a Singaporean longitudinal cohort, 309 dementia‐free participants (mean age=71.6 [SD=7.8], 52% females) underwent annual neuropsychological, neuropsychiatric, and clinical assessments for up to four years. The diagnosis of MBI was ascertained using neuropsychiatric inventory assessments at two time‐points. Global and domain‐specific cognitive Z‐scores were calculated from a comprehensive neuropsychological battery, and Clinical Dementia Rating sum‐of‐boxes (CDR‐SoB) scores were used to assess disease progression.

Result

A total of 72 (23.3%) participants had MBI. Cross‐sectionally, MBI patients performed poorer in global cognition (β=‐0.27 [‐0.51–0.03], p=0.026), particularly in memory (β=‐0.56 [‐0.79–0.33], p<0.001), executive function (β=‐0.33 [‐0.62–0.03], p=0.030), and visuomotor speed (β=‐0.20 [‐0.39–0.02], p=0.031) domains. On follow‐up, MBI patients showed faster decline in global cognition (β=‐0.19 [‐0.27–0.11], p<0.001) (Fig. 1) and faster increment in CDR‐SoB (β=0.96 [0.74‐1.19], p<0.001) (Fig. 2) as compared to non‐MBI elderly, regardless of cognitive status. On follow‐up, 40.3% (n=29) of MBI patients progressed to dementia, compared with 8% (n=19) of non‐MBI elderly. MBI diagnosis was associated with a significantly higher risk of dementia (Hazard Ratio=6.28 [3.51‐11.23], p<0.001) (Fig. 3).

Conclusion

MBI may be an early neurobehavioral marker of cognitive decline leading to dementia. Incorporating MBI evaluations into clinical assessments may identify high risk patients for dementia who may benefit from intervention.