bluuebunny/crossref_metadata_2025 huggingface dataset:
A normative study of the Italian version of the CERAD neuropsychological battery in young‐old and old‐old participating in population‐based studies
Authors: Lucca Ugo , Tettamanti Mauro , Riva Emma , Mandelli Sara , Forloni Gianluigi , Galbussera Alessia A.
Published: June 2023

Background

Prevalence of dementia increases with increasing age. Although cognitive assessment is central to the diagnosis of dementia, normative data on neuropsychological tests in non‐selected elderly populations are limited and those available in the oldest‐old rare. Objectives: To report the distribution of scores and normative data on CERAD neuropsychological test battery in a large elderly population including a sizeable number of very old individuals participating in population‐based studies.

Method

Subjects included in the analyses were non‐demented participants in three Italian population‐based studies (Monzino‐80 plus, Varese Province, Lombardy; Heath and Anemia, Biella municipality, Piedmont; and Moltrasio, Como province, Lombardy) and in the first normative study on CERAD battery (Lugli 2002). Participants fulfilling DSM‐IV criteria for dementia were excluded. Tests were administered and scored by specifically trained psychologists following standardized criteria, the same in all four studies. The Italian version of CERAD showed high test‐retest reliability (r = 0.89). Multivariable linear regression models were fitted to investigate the association of age (in years), sex, and education (years of schooling) with performance on CERAD tests.

Result

The total population consisted of 2,501 individuals (mean age: 83 years; women: 64%; average education: 6.8 years; institutionalized: 69 [3%]), 802 of whom were young‐old (65‐79 years of age) and 1,699 old‐old (80+ years: 1,155 octogenarians, 470 nonagenarians, and 74 centenarians). The Table shows the distribution of scores (means, SDs, and 5th percentiles) on each test by the whole population as well as by each age class. Better performance on all tests was significantly associated with lower age and higher education; women scored significantly better than men on Word List Learning and Recall, and men better than women on short‐Boston Naming Test and Constructional Praxis Copy and Recall. Refusal to continue and fatigue were the main reasons put forward by elderly participants for not completing the test battery.

Conclusion

The present study provides normative data on a neuropsychological test battery commonly utilized in the diagnosis of dementia in a large, non‐selected population of young‐old and old‐old. Performance on CERAD test battery declines with increasing age and lower years of education; performance on some tests were also influenced by sex.
Polypharmacy as a risk factor for dementia: Scottish population‐based longitudinal record linkage study of 1 225 894 people
Authors: Stirland Lucy E , Russ Tom C , Ritchie Craig W. , Muniz‐Terrera Graciela
Published: June 2023

Background

Polypharmacy, the concurrent use of multiple medicines, is increasing. Population‐wide studies of its association with dementia are lacking. We examined this relationship longitudinally, at a national level.

Method

We used National Health Service community prescribing data from all adults in Scotland aged ≥50 years who received at least one drug in the first quarter of 2009. These data were linked to death records, including cause of death. We used Cox proportional hazards models to assess associations between the number of unique medicines dispensed in one quarter and mortality with any subtype of dementia over 8.5 years, in the whole sample and stratified by age.

Result

The sample contained 1,225,894 people aged ≥50 years (mean age 67.4 (SD = 10.8) years, 56.1% female, 3.8% care home residents). The mean number of drugs dispensed at baseline was 5.0 (SD = 3.7). Over 8.5 years, there were 336,244 deaths, of which 58,358 had any subtype of dementia on the death certificate.

Among the whole sample, the hazard ratio (HR) for dementia mortality with each additional medicine was 1.027 (95% CI 1.024‐1.028). In people aged 50‐64 years, the HR was 1.075 (1.061‐1.089); for 65‐79 year‐olds, HR = 1.043 (1.040‐1.047) and for those aged ≥80 years, HR = 1.009 (1.006‐1.012). All models were adjusted for baseline age, gender, care home residence status and deprivation index based on postcode.

Conclusion

There was higher mortality with dementia as the number of dispensed medicines increased. Age‐stratified analyses showed that the association was stronger in younger age groups, perhaps reflecting that younger people taking medication for more comorbidities had an increased risk of dying with dementia. These analyses did not allow adjustment for multimorbidity or the consideration of individual drug classes.
White matter hyperintensities in the corpus callosum are associated with beta‐amyloid, neurodegeneration and cognitive performance
Authors: D'Elia Ylenia , Cassing Vilana , Gaubert Malo , Dell'Orco Andrea , Garnier‐Crussard Antoine , Lange Catharina , Dyrba Martin , Ziegler Gabriel , Duering Marco , Teipel Stefan , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Laske Christoph , Heneka Michael T. , Wagner Michael , Spottke Annika , Jessen Frank , Duzel Emrah , Wirth Miranka ,   Delcode Study Group
Published: June 2023

Background

WMH in the corpus callosum (CC), as previously related to AD pathology(1) and lower cognition in AD patients(2), are suggested to play an important role in AD. The Aim of this study was to substantiate the associations between WMH location, biomarkers of AD pathophysiology, and cognitive performance in the DELCODE study.

Method

429 participants were included (HC: 126, SCD: 165, MCI: 87, AD: 51). WMH volumes were segmented from FLAIR images. WMH volumes were adjusted for total intracranial volume and log‐transformed. Beta‐Amyloid and total Tau (Aß42 and tTau, measured in CSF) and neurodegeneration (ND, measured by hippocampal volume) were log‐transformed and used as surrogate markers for AD pathophysiology. Cognitive performance was assessed by a global cognitive composite.

Path modelling, adjusted for age, sex and education, was performed to estimate direct and indirect associations between regional WMH volumes (in the CC splenium, body, genu and the frontal lobe as possible control region), AD biomarkers and cognition.

Results

The correlation matrix (Figure 1) showed the highest correlation of Aß42 and tTau with WMH volume the splenium CC.

Greater WMH volume in the splenium CC was directly associated with lower global cognition (Figure 2a, ß = ‐0.10, p = 0.01) and indirectly through Aß42 (ß = ‐0.10, p = 0.001) and ND (Figure 2b, ß = ‐0.05, p = 0.001). The same indirect association was statistically significant regarding tTau (ß = ‐0.03, p < 0.001). Model outcomes were similar for the body and genu of the CC.

For frontal WMH volume, the direct association with global cognition was not statistically significant (ß = ‐0.002, p = 0.96), only through indirect associations with Aß42 (ß = ‐0.05, p = 0.003) and ND (ß = ‐0.02, p = 0.05).

Conclusion

WMH in the CC are associated with lower cognitive performance through direct and indirect associations with Aß42 and neurodegeneration. Similar associations were seen for frontal WMH. However, a direct association between frontal WMH volume and cognition was not noticed, when considering AD biomarkers. Our study substantiates the clinical relevance and impact of WMH in the CC, in particular the splenium, in AD.

1)Gaubert et al.,2021

2)Garnier‐Crussard et al.,2021
Five year dementia registry in Thailand: Regional distribution, etiologies, and outcome of dementia
Authors: Senanarong Vorapun , Rattanabannakit Chatchawan , Hunnangkul Saowalak , Wongkom Natthamon , Likitjaroen Yuttachai , Witoonpanich Pirada , Phanthumchinda Kammant
Published: June 2023

Background

There is a lack of epidemiological knowledge about whether individuals with dementia receive the same quality of diagnostics and treatment.

Method

We explored the ICD10 National Health Security Office (NHSO) in‐patient record of dementia in Thailand. We analyzed the prevalence, etiologies, regional distribution, and outcome of dementia in Thailand during 2015‐2019.

We reviewed a cross‐sectional cohort study based on data from the NHSO.

Result

Studied in‐patients diagnosed with dementia between 2015 and 2019 (n = 29,895; 40,981 visits) 17,058(57.1%) were female. 3,665(12.3%); 11,638(38.9%); 8,845(29.6%); 1,814(6.1%); 1,418(4.7%); and 2,515(8.4%) were in the northern, central, northeast, eastern, western, and southern part of Thailand respectively. Among 29,895 dementia cases, 15.4%, 18.7%, 20.2%, 24.1%, and 21.6% were prevalence cases in 2015, 2016, 2017, 2018, and 2019 (registered up to 30th September where was the end of fiscal year) respectively. 16.1% were single, 68.5% were married, 6.6% were divorced, and 8.9% had other marital status. 85% aged 65 and over. Mean age of these cohort was 75.42(sd = 11.97) years old. The etiologies registered as dementia were as followed: 9.3% had AD, 0.2% had bvFTD, 9.3% ha VaD, 2.1% had other degenerative dementia, 77.4% ha unspecified dementia, and 1.8% had cognitive impairment due to metabolic and physiological condition. During these 5 years, 59.3% were dead. Mean duration of admission were 9.84(sd = 19.84) days. Mean cost of expense during admission were 31,521.79(sd = 80,647.68) Baht.

Conclusion

The dementia registry offers the surrogate clinical best practice and patient outcomes. The importance and significance in having dementia data cannot be undervalued.
Effect of social isolation and loneliness on functional abilities mediated by cognition (E‐cog) in Mexican older adults during the first wave of COVID‐19 pandemic
Authors: Durón Dafne Estefania , Aguilar‐Navarro Sara Gloria , Gutiérrez Lidia Antonia , Quiroz Yakeel T. , Mimenza Alberto , Avila Jose Alberto
Published: June 2023

Background

Loneliness and social isolation are known risk factors for cognitive decline; their effect in older adults (OA) after COVID‐19 lockdown is emerging.

Objective

To establish an association between loneliness with functional abilities mediated by cognition in Mexican OA during the first wave of the COVID‐19 pandemic.

Method

Cross‐sectional study derived from the cohort “The impact of COVID 19 on well‐being, cognition, and discrimination among older adults in the United States and Latin America”, which included 308 older adults recruited between March‐August 2020 whose cognition‐mediated functional abilities were determined with the Everyday Cognition Scale (E‐Cog) questionnaire. The presence of loneliness (The De Jong Gierveld Loneliness Scale) was a binomial variable. Univariate linear regression models were constructed to determine the association between loneliness, and E‐Cog (Ln) scores, which were later adjusted for potentially confounding variables like age and education. In addition, participants were categorized into tertiles of the global E‐Cog score with the following ranges: Tertile 1 (T1): 37.46 ‐46; Tertile 2 (T2): 46.01‐58 and Tertile 3 (T3): 58.01 or more and were compared using ANCOVA. Satistical analyses were conducted using SPSS version 25.0 for MAC (Chicago, IL, USA), figures were made with RStudio (R version 4.1.0, RStudio, Inc., Boston, MA)

Result

The mean age was 65.4 ± 7.9 years and 75.7% were women. The mean E‐Cog was 57.4 (SD: ± 19.1). 84% of participants (n:259) had loneliness. Those with less perception of loneliness had a better performance on E‐Cog by tertiles. The univariate linear model showed a positive and statistically significant association between loneliness and E‐Cog, adjusted by age, sex and education level (β 0.41, 95% CI: 0.22‐0.38, p: <0.01). This model explained 16.1% of the variability of the E‐Cog score.

Conclusion

OA with self‐reported loneliness had the worst performance in functional abilities mediated by cognition. These data suggest the need for increased vigilance of those who have loneliness due to its potential deleterious effect on cognitive function.
Neutrophil count, serum cytokines, and cognitive function among dementia‐free older adults: a population‐based cohort study
Authors: Fa Wenxin , Liang Xiaoyan , Liu Keke , Wang Nan , Liu Cuicui , Tian Na , Zhu Min , Cong Lin , Wang Yongxiang , Hou Tingting , Qiu Chengxuan , Du Yifeng
Published: June 2023

Background

Previous research has suggested that neutrophils could release cytokines to be involved in low‐grade chronic inflammation, which might contribute to cognitive dysfunction. However, population‐based studies have not explored the relationship between neutrophils and cognitive function in older adults. Here, we examined the associations of absolute neutrophil count (ANC) with cognitive performance and cognitive decline among rural Chinese older adults and further explored the potential mediation role of serum cytokines in their associations.

Method

This population‐based longitudinal study included 1666 dementia‐free participants (age ≥60 years; 976, 58.58% women) in the substudy of MIND‐China who undertook the baseline examination in March‐September 2018; of these, 1087 were followed in November‐December 2019. At baseline, ANC was measured using a Mindray BC 6800 automated hematology analyzer. We used the neuropsychological test battery to assess global cognitive function, memory, attention, verbal fluency, and executive function. Serum IL‐6 and eotaxin3 concentrations were measured using Meso Scale Discovery (MSD). Data were analyzed using multivariable general linear models and mediation models.

Result

The cross‐sectional analysis of data at baseline (n = 1666) showed that ANC (range, 0.3 ‐ 24, 109/L) was significantly associated with a lower memory z‐score (multi‐adjusted β coefficient: ‐0.131; 95% CI: ‐0.254 ‐ ‐0.008), but not with attention, verbal fluency, and executive function. Mediating modeling analysis suggested that 22.35% and 10.33% of the association between ANC and memory function were mediated by serum IL‐6 and eotaxin3, respectively. The analysis of longitudinal data (n = 1087) suggested a nonlinear relationship between ANC and memory z‐score decline, with the fourth quartile of ANC (vs. the third quartile) being significantly associated with a multi‐adjusted β coefficient of 0.146 (95% CI: 0.009 ‐ 0.283) for decline in memory z‐score.

Conclusion

Higher ANC is associated with worse memory performance and faster cognitive decline in rural‐dwelling Chinese older adults, in which their association may be mediated partly by serum cytokines.
Association of kidney function with dementia and brain pathologies: A community‐based cohort study
Authors: Wang Jiao , Wang Shuqi , Dove Abigail , Guo Jie , Qi Xiuying , Bennett David A , Xu Weili
Published: June 2023

Background

Kidney function has been linked to cognitive function, but its relation to dementia and mechanisms underlying this relation remains unclear. We aimed to examine the association of impaired kidney function with dementia and brain pathologies.

Method

Within Rush Memory and Aging Project, 1380 dementia‐free subjects (75.22% female; mean age: 79.42±7.61 years) at baseline were followed for up to 22 years. Blood samples were taken at baseline and serum creatinine was measured to calculate estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula. Kidney function dichotomized as normal (eGFR ≥ 60 mL/min/1.73 m2) or impaired (eGFR <60 mL/min/1.73 m2). Dementia, including Alzheimer’s dementia, was diagnosed following international criteria. During the follow‐up, 469 participants died and underwent autopsies for neuropathological assessment (including Alzheimer’s disease [AD], vascular, and other brain pathologies). Data were analyzed using Cox regression, Laplace regression, and logistic regression.

Result

At baseline, 895 (64.86%) participants with normal kidney function and 485 (35.14%) with impaired. Over follow‐up (median [interquartile range]: 5 [2–9] years), 300 (21.74%) participants developed dementia, including 273 (19.78%) with Alzheimer’s dementia. In multi‐adjusted Cox regression, lower eGFR was does‐dependently associated with higher dementia risk (hazard ratio [HR] = 1.01, 95% confidence interval [CI]: 1.01–1.02, P = 0.003) and Alzheimer’s dementia risk (HR = 1.01, 95% CI: 1.00‐1.02, P = 0.002). Compared to normal kidney function, impaired kidney function was associated with a greater risk of dementia (HR = 1.49, 95% CI: 1.16–1.91) and Alzheimer’s dementia (HR = 1.45, 95% CI: 1.12–1.89). The median time to the development of dementia or Alzheimer’s dementia was 2.48 (95% CI: 0.36–3.03) or 2.56 (95% CI: 0.37–2.79) years shorter in people with impaired vs. normal kidney function, respectively. In brain pathology analysis, impaired kidney function was significantly related to higher burdens of cerebral amyloid angiopathy (odds ratio = 2.03, 95% CI: 1.23–3.35).

Conclusion

Impaired kidney function is associated with an increased risk of dementia and Alzheimer’s dementia. Vascular mechanisms may underlie this association.
Particularities of Cerebrovascular Changes in Patients with Dementia during Alzheimer’s Disease in Comparison with Distal Cerebral Atherosclerosis
Authors: Maksimovich Ivan V
Published: June 2023

Background

When studying the causes of dementia, there are certain difficulties in differentiating existing cerebrovascular changes. We present the features of cerebrovascular changes in Alzheimer’s disease (AD) and in distal forms of cerebral atherosclerosis.

Methods

The research included 935 patients, of whom: 93 people aged 34‐80 (mean age 67.5), 32 men (34.40%), 61 women (65.59%), suffered from AD. According to their dementia severity, the patients were subdivided: (TDR‐0) ‐ 10, (TDR‐1) ‐ 29, (TDR‐2) ‐ 36, (TDR‐3) ‐ 18;

• 842 people aged 29‐81 (mean age 74.5), 622 men (73.87%), 220 women (26.13%), with distal cerebral atherosclerosis and chronic cerebrovascular insufficiency. According to their dementia severity, the patients were subdivided: (CDR‐1) ‐ 284, (CDR‐2) ‐ 18.

• The examination plan included cerebral MRI, CT, scitrigraphy (SG), rheoencephalography (REG), cerebral multi‐gated angiography (MUGA).

Results

In patients with AD, changes in angioarchitectonics and microcirculation are manifested in:

• Absence of calcium salts deposits and atherosclerotic changes in intracerebral arteries;

• Increased tortuosity of the distal parts of the intracerebral arteries;

• Reduction of the capillary bed in the temporal and frontoparietal regions;

• Development of multiple large arteriovenous shunts with early venous discharge of arterial

blood in the same regions;

• Development of abnormal venous trunks in the same regions;

• Development of intracerebral stagnation of venous blood;

These changes are called “Dyscirculatory angiopathy of Alzheimer’s type” (DAAT).

In patients with distal cerebral atherosclerosis, changes in angioarchitectonics and microcirculation are manifested in:

• Multiple calcium salts deposition and atherosclerotic changes in the intracerebral arteries;

• Multiple disseminated contraction of the intracerebral capillary bed;

• Development of multiple small disseminated intracerebral arteriovenous shunts;

• Lack of pronounced intracerebral venous congestion.

Conclusions

Dyscirculatory angiopathy of Alzheimer’s type (DAAT), regardless of the severity of dementia, is an AD‐specific cerebrovascular and microcirculatory lesion of the brain not associated with atherosclerotic processes.

In patients with distal cerebral atherosclerosis, regardless of the severity of dementia, vascular disorders are of disseminated atherosclerotic character. Anatomically, the lesion of the capillary bed and the presence of arteriovenous shunts are of disseminated character, and there is no pronounced venous stasis. Timely detection of these changes is very important for diagnosis.
Novel residual neural network approach for analyzing amyloid PET scans: Associations with cerebrospinal fluid beta amyloid and episodic memory
Authors: Tagmazian Arina , Schwarz Claudia , Pitkänen Esa , Vuoksimaa Eero
Published: June 2023

Background

Diagnosing Alzheimer’s disease (AD) based on the biological definition depends on accurately determining amyloid‐β (Aβ) status. In this research, we aimed to create a deep learning model for predicting Aβ cerebral spinal fluid (CSF) measures directly from amyloid PET scans, and compare the result with AD clinical hallmarks.

Method

We developed a novel residual neural network (ResNet) model to predict CSF Aβ from amyloid PET scans and trained the model using 1,870 scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Episodic memory (EM) was measured with immediate and delayed recall in the Rey Auditory Verbal Learning Test (AVLTim/AVLTdel) and in Logical Memory (LMim/LMdel) subtest from the Wechsler Memory Scale. We investigated associations of predicted CSF values with EM measures and compared our model against the traditional approach of determining cortical amyloid with a standardized uptake value ratio (SUVR) measure. We used Pearson correlations to investigate the associations of cortical amyloid with CSF and AD clinical markers. Further, we looked at these correlations separately in different clinically defined groups (cognitively normal, mild cognitive impairment (MCI), and AD).

Result

ResNet accurately predicted Aβ CSF measures (r = 0.93, p<1e‐10). SUVR significantly correlated with clinical CSF (r←0.65, p<1e‐10) and with ResNet model predicted CSF (r←0.67, p<1e‐10). The predicted CSF is also significantly associated with EM (LMim and LMdel, r = 0.46; AVLTim, r = 0.40; AVLTdel, r = 0.34; p<1e‐10). Correlations in those with AD were generally weaker (SUVR, r←0.37; EM, 0.02<r<0.29) than in those with MCI (SUVR, r←0.70; EM, 0.27<r<0.43) or in cognitively healthy (SUVR, r←0.56; EM, 0.16<r<0.28).

Conclusion

We developed to our knowledge the first ResNet model, which predicts Aβ CSF measures with high accuracy. Predicted CSF values strongly correlate with clinical AD hallmarks. However, there are many questions that warrant further study, and we aim to investigate our model in relation to early prediction and diagnosis of AD, and in studying the discordance between biological and clinical AD classifications.
Thalamic‐insomnia phenotype in genetic E200K Creutzfeldt‐Jakob disease: A PET/MRI study
Authors: Chu Min , Chen Zhongyun , Xie Kexin , Ye Hong , Wu Liyong
Published: June 2023

Background

Insomnia and thalamic involvement are hallmarks of fatal familial insomnia; however, it was occasionally reported that genetic E200K Creutzfeldt‐Jakob disease (CJD) patients had also manifested thalamic‐insomnia phenotype. The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD by comprehensive neuroimage analysis.

Methods

Six genetic CJD patients carried Glu to Lys change at codon 200 (E200K) mutations on prion protein gene (PRNP), thirteen sporadic CJD (sCJD), and twenty‐two age‐ and sex‐matched normal controls were enrolled in the study. All participants completed hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI) examinations. The high signal was visually inspected on diffusion weighted imaging (DWI) sequence. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) and structural images were quantitively analyzed by statistically parameter mapping (SPM). Clinical and image characteristics are compared between genetic E200K CJD patients and sporadic CJD patients.

Results

There was no group difference in age (49.0±7.1 versus 55.0±4.9 versus 52.7±7.3, p = 0.193) and gender (3/3 versus 4/9 versus 11/11, p = 0.513) between genetic E200K CJD, sCJD, and normal controls. Insomnia was the main complaint in the genetic E200K CJD patients’ group (4/2 versus 1/12, p = 0.007). Hyperintensity, hypometabolism but not predominant atrophy of the thalamus was found by visual inspection in genetic E200K CJD patients. A decreased trend was found on gray matter volume (uncorrected p<0.0001) and metabolism (FWE corrected) of the thalamus in genetic E200K patients.

Conclusion

The clinical and image characteristics of genetic E200K CJD mimic fatal familial insomnia, manifested as a thalamic‐insomnia phenotype, indicating some specific underlying pathological changes might exist in E200K mutations. PET measurement is a sensitive approach to help identify the functional changes of the thalamus in prion disease.
Erythrocyte indices in creutzfeldt–jakob disease predict survival time
Authors: Kong Yu , Chen Zhongyun , Zhang Jing , Wu Liyong
Published: June 2023

Background

Creutzfeldt–Jakob disease (CJD) is a devastating neurodegenerative disease caused by propagation of abnormally folded prion proteins (PrPSc). Some fluid biomarkers have been reported to be associated with disease duration in CJD. Based on studies which have found that prion protein (PrPC) played a role in erythrocytic hematopoiesis, we evaluated the association between peripheral red blood cell indices and survival time in CJD.

Method

We retrospectively collected data on peripheral red blood cell indices, including red blood cell (RBC) count, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW), from 125 CJD patients. Cox proportional hazard models were generated to determine whether red cell indices correlated with survival time of patients with CJD.

Result

Of the 125 included participants, 70 (56%) were male, and the mean age at diagnosis (SD) was 60.3 (9.5) years. Hemoglobin levels (hazard ratio 1.710, 95% CI 1.124‐2.600, p = 0.012) and HCT (hazard ratio 1.689, 95% CI 1.112‐2.565, p = 0.014) were significantly associated with survival time after controlling for sex, age, and Barthel Index. Red blood cell count, MCV, MCH, MCHC, and RDW were not associated with survival time before or after adjusting for covariates.

Conclusion

Our study found that Hb and HCT were significantly associated with survival time in patients with CJD. These results may inform evaluation of the mechanisms of interaction between prion disease and hematopoiesis, and indicate that Hb and HCT may be potential prognostic biomarkers.
Predicting cognitive decline using neuropsychiatric symptoms in prodromal Lewy body disease
Authors: Wright Laura M , Donaghy Paul , Burn David , Taylor John‐Paul , O'Brien John T , Yarnall Alison J , Matthews Fiona E , Firbank Michael J , Thomas Alan J , Lawson Rachael A
Published: June 2023

Background

Neuropsychiatric symptoms (NPS) in Lewy body diseases, including dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) dementia, occur frequently and at an early stage in disease progression. Such symptoms are significantly associated with quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the relationship between NPS and cognitive decline.

Methods

Data from 217 participants were derived from three cohort studies. Patients diagnosed with either MCI with Lewy bodies (MCI‐LB, n = 67), PD‐MCI (n = 56) or Alzheimer’s disease (MCI‐AD, n = 39) and a group of healthy older adults (n = 55) completed comprehensive neuropsychological and neuropsychiatric assessment and were followed up longitudinally for a median of three years. NPS identified at baseline by the Neuropsychiatric Inventory (NPI) were included as predictors in linear regressions and linear mixed effects models to assess the relationship between NPS and performance on a range of cognitive tests both at baseline and longitudinally.

Results

At baseline, NPS were most prevalent and severe among the MCI‐LB group (49% with NPI score >4 in at least one symptom) and least prevalent in controls (7% with NPI score >4). Total NPI score was not related to baseline cognitive function in any domain in any group. Greater baseline total NPI score was associated with steeper rates of decline among PD‐MCI patients on a measure of processing speed (p = .01). Among healthy adults, only sleep disturbance was associated with steeper rates of decline on global cognition (p = .005). None of the patient groups showed any association between individual NPS and decline on a measure of global cognitive function.

Conclusions

The lack of a significant relationship found between NPS and either global cognitive function or decline in global cognition seen among MCI patients suggests that at this prodromal stage of disease, NPS appear to be of limited clinical impact and indicates that the mechanisms of cognitive and neuropsychiatric symptoms may differ in early Lewy body disease. Future work will investigate these mechanisms using multimodal imaging data from this cohort.
Mortality across the Alzheimer’s disease clinical stages: An analysis using the U.S. National Alzheimer’s Coordinating Center Uniform Data Set
Authors: Crowell Valerie , Reyes Adriana , Gustavsson Anders , Gsteiger Sandro , Zhou Summera , Vassilaki Maria
Published: June 2023

Background

Understanding mortality risk across the Alzheimer’s disease (AD) clinical stages is essential for resource planning and estimating the value of disease modifying therapies (DMTs), which may slow progression. Such studies are lacking.

Method

The study used the Uniform Data Set of the National Alzheimer’s Coordinating Center (NACC) from September 1, 2005 to March 1, 2021 to assess mortality risk across the AD clinical stages. It included 12,414 participants aged ≥ 50 years, who contributed to the following stages: cognitively unimpaired (CU n = 11,458), incident prodromal AD (n = 937), and AD dementia (n = 745). AD etiology and stage were established based on clinical evaluation and cognitive, behavioral, and functional scores. Study centers report mortality for actively followed participants. Participants contributed observation time until all‐cause death, disease progression, discontinuation, loss to follow‐up, data cutoff or the last visit before a longer than 36‐month gap in visits or recorded scores.

Hazard ratios for each AD stage versus CU were estimated using Cox proportional hazards models. Least absolute shrinkage and selection operator facilitated final predictor selection.

Result

Participants’ mean age (SD) at study entry was 71.0 years (SD 9.2) (34.9% males). Participants with incident mild, moderate, and severe AD had increased mortality risk relative to CU after controlling for age, sex, education, apolipoprotein E ε4 genotype status, BMI, and residence type. Relative all‐cause mortality risk by AD stage decreased with increasing age; the HRs (95% CI) for mortality at 65 years of age were 6.7 (2.7‐16.9), 14.8 (8.8‐24.8), and 30.1 (16.7‐56.8) for mild, moderate and severe AD respectively; at 80 years of age, the corresponding HR (95% CI) were 2.4 (1.7‐3.3), 3.1 (2.4‐3.9), and 6.6 (4.8‐9.1). Male sex (HR = 1.75, 95% CI 1.52‐2.04) and residing in an institution (vs. private residence; HR = 3.11, 95% CI 2.28‐4.25) significantly increased relative all‐cause mortality risk.

Conclusion

Relative all‐cause mortality risk increases with AD severity, and more so at younger ages. Despite data limitations, findings are significant as efforts to delay disease, for instance with DMTs, could not only improve patient and caregiver quality of life and reduce costs, but also extend the lives of patients with AD.

NIA/NIH Grant U24 AG072122 funds the NACC database.
The associations of SNAP use and memory function among us older adults: Findings from the health and retirement study
Authors: Lu Peiyi , Kezios Katrina L , Lee Jongseong , Wimer Christopher T , Hazzouri Adina Zeki Al
Published: June 2023

Background

Studies on the health effect of Supplemental Nutrition Assistance Program (SNAP) on the cognitive health of older adults are scarce. In this study, we examined the associations of SNAP use and memory function trajectories among US older adults.

Method

Our sample included 3,555 SNAP‐eligible participants (aged 50+) from the 1996 Health and Retirement Study survey, among whom 559 were SNAP users and 2,996 were non‐users. SNAP eligibility was constructed based on household income and assets compared to the federal criterion. Memory function was assessed biennially from 1996 through 2016. To account for pre‐existing differences in characteristics and variations in survey attrition between SNAP users and non‐users, we modeled the probability of SNAP use and of attrition using pre‐SNAP exposure (i.e., 1994) demographic and health covariates. We then modeled trajectories of memory function across SNAP use using linear mixed effect models weighted by the inverse probability of treatment (i.e. SNAP use) and of attrition. We also cross‐examined the results in a propensity score (PS) matched sample (N = 1,050).

Result

SNAP users in 1996 had lower socioeconomic status and worse health at baseline than SNAP non‐users, and were more likely to be lost to follow‐up. Results using IP‐weights suggested SNAP users had worse memory scores at baseline but slower memory decline compared with non‐users (annual decline rate is ‐0.038 standard units [95%CI = ‐0.044, ‐0.033] for non‐users and ‐0.043 [95%CI = ‐0.046, ‐0.040] for users). Results from the PS‐matched sample also showed SNAP users had slower memory declines compared with non‐users (annual decline rate was ‐0.052 units [95%CI = ‐0.055, ‐0.050] for non‐users and ‐0.048 units [95%CI = ‐0.051, ‐0.046] for users).

Conclusion

After accounting for pre‐existing differences between eligible SNAP users and non‐users as well as differential loss to follow‐up, our findings suggested that SNAP participation is associated with slower memory decline among eligible older adults.
Consensus harmonization of brain‐secreted extracellular vesicles isolation and validation protocols for blood biomarker work in Alzheimer’s disease: An international overview
Authors: Badhwar AmanPreet , Hirschberg Yael , Sukreet Sonal , Udeh‐Momoh Chi T. , Iulita M. Florencia , Sandebring‐Matton Anna , Winston Charisse N. , Haqqani Arsalan S. ,   Exosome Working Group (EWG) of the Biofluid‐Based‐Biomarkers Professional Interest Area (BBB‐PIA) of the Alzheimer’s Association
Published: June 2023

Background

Isolation of brain‐secreted extracellular vesicles (BEVs) from blood, provides a novel, minimally invasive way to sample brain tissue in individuals along the Alzheimer’s disease (AD) continuum. BEVs in blood demonstrate enormous potential to serve as a novel AD biomarker discovery platform and treatment tool. However, at present, BEV isolation and validation protocols vary from center to center. Given the growing popularity of immunoprecipitation (IP)‐based BEV isolation methods, we assessed the brain‐specificity of reported cell‐surface and cargo proteins associated with this category of methods.

Method

We performed a systematic evaluation of BEV isolation and validation protocols from 34 published articles investigating biomarker potential of blood‐isolated BEVs in AD. Proteins used for polyethylene glycol‐based precipitation followed by IP‐capture BEV isolation, or as BEV biomarker candidates, were compiled. The proteins were categorized by brain specificity, abundance, extracellular accessibility and extracellular vesicles presence by examining their expression from publicly available datasets in over 60 human tissue types, including 13 central nervous system (CNS) regions and 48 peripheral tissues.

Result

We compiled 68 unique IP or biomarker protein candidates. Analyses demonstrated that of these, 22 had extracellular domains (that could be used for BEV isolation), 7 were membrane proteins lacking extracellular domains, and the remaining were intracellular proteins. Moreover, >50% of the compiled proteins were present in extracellular vesicle datasets, >20% were considered highly CNS specific, and ∼60% demonstrated moderate‐to‐high CNS abundance (Fig.1). Furthermore, in addition to confirming that some proteins widely used for IP‐based BEV isolation are CNS‐enriched (e.g., L1CAM, Fig. 1B), we also identified, at least, 5 additional proteins with higher CNS abundance and specificity, extracellular domains, and known to be present in extracellular vesicles.

Conclusion

Consensus harmonization of BEV isolation and validation protocols are essential steps in blood‐isolated BEV biomarker work in AD, and is advocated by the Alzheimer’s Association BBB‐PIA. This harmonization of BEV protocols is crucial, given the growing interest in developing minimally‐invasive AD biomarker discovery tools, and the increasing number of researchers worldwide conducting BEV biomarker work. Moreover, the additional proteins identified by the EWG‐BBB‐PIA will lead to better IP‐based BEV isolation from blood.
Using the clock drawing test to differentiate impairments in executive functioning between Alzheimer’s Dementia and Parkinson’s disease
Authors: Bakir Danah , Trivedi Mehul Alkesh , Ala Tom , Zec Ronald F , Kouzi Ahmed El , Agamah Alikem Miriam , Porter Nicholas , Unnam Pavani , Hascup Erin R. , Hollinshead Madison G. , Kohlrus Stephanie R.
Published: June 2023

Background

Previous studies suggest the usefulness of CDT in distinguishing between neurodegenerative diseases. The purpose of this study was to examine differences in CDT performance in individuals with AD and PD compared to normal controls.

Methods

Total of 194 participants. Four groups included in analysis: patients that met diagnostic criteria for late MCI/mild AD, moderate AD, PD with no cognitive impairment, and normal controls. All participants completed MMSE and CDT. MMSE score ≤ 23 considered moderate AD, MMSE score >24 considered mixed late MCI/mild AD, all PD patients had MMSE score >24.

Results

An ANOVA was used to examine group differences in CDT and MMSE scores. There was a significant main effect of group for both CDT and MMSE scores (p < 0.001). Moderate AD group had significantly lower MMSE scores compared to other groups (average MMSE score of 19.4 for moderate AD compared to 26.6 for mild AD, 26.9 for Parkinson’s, and 28.2 for controls). Post‐hoc t‐tests (Bonferroni corrected for multiple comparisons) showed moderate AD group had significantly higher error scores on CDT compared to controls (p<0.001). Moderate AD group also had significantly higher error score compared to both MCI/mild AD and PD patient groups (p<0.001). No statistical significance existed in error scores between MCI/mild AD group compared to controls (p = 0.134) or to Parkinson’s disease (p = 1.000). No statistical significance in CDT error scores between the Parkinson’s group compared to controls (p = 0.904). Findings suggest executive functioning may only begin to significantly decline in advanced stages of AD.

Conclusion

Our findings suggest that deficits in executive functions measured by CDT is impaired in moderate AD but relatively preserved in MCI/mild AD and PD with no cognitive impairment, which is consistent with previous studies. One limitation of the study is that we did not include a copy trial for the CDT, which may support that our findings are due to executive dysfunction rather than visuospatial deficits. Future directions include increasing sample sizes, including individuals with PD with cognitive impairment, and using novel digital versions of the CDT to different variables of the CDT such as time to start and complete, visuospatial coordination, and graphic size.
Proposal of new clinical diagnostic criteria for fatal familial insomnia
Authors: Chu Min , Xie Kexin , Chen Zhongyun , Zhang Jing , Ghorayeb Imad , Rupprecht Sven , Reder Anthony T , Garay Arturo , Honda Hiroyuki , Nagayama Masao , Shi Qi , Zhan Shuqin , Nan Haitian , Zhang Jiatang , Guan Hongzhi , Cui Li , Guo Yanjun , Wang Jiawei , Dong Xiaoping , Rosa‐Neto Pedro , Gauthier Serge , Wu Liyong
Published: June 2023

Background

Early and accurate diagnosis of fatal familial insomnia (FFI) is critical for effective screening; however, this rare disease remains difficult to recognize. This work aimed to propose a new diagnostic criterion for fatal familial insomnia (FFI) with optimal sensitivity, specificity, and likelihood ratio.

Methods

An international group of experts was established and 128 genetically confirmed FFI cases and 281 non‐FFI prion disease controls are enrolled in the validation process. The new criteria were proposed based on the following steps with 2‐round expert consultation: 1) Validation of the 2018 FFI criteria. 2) Diagnostic item selection according to statistical analysis and expert consensus. 3) Validation of the new criteria.

Results

The 2018 criteria for possible FFI had a sensitivity of 90.6%, specificity of 83.3%, the positive likelihood ratio (PLR) of 5.43, and negative likelihood ratio (NLR) of 0.11; the probable FFI criteria had a sensitivity of 83.6%, specificity of 92.9%, the PLR of 11.77, and NLR of 0.18. The new criteria included more specific and/or common clinical features, 2 exclusion items, and summarized a precise and flexible diagnostic hierarchy. The new criteria for possible FFI had a sensitivity of 92.2%, specificity of 96.1%, a PLR of 23.64, and NLR of 0.08, while the probable FFI criteria had a sensitivity of 90.6%, specificity of 98.2%, the PLR of 50.33, and NLR of 0.095.

Conclusion

A new clinical diagnostic criteria was proposed for FFI, which will be practical at the clinic for early recognition of FFI and differentiation from other prion diseases then help further referral and genetic test.
Optical coherence tomography in the diagnosis of primery neurodegenerative diseases
Authors: Makhnovich Ekaterina Vladimirovna , Bogolepova Anna Nicolaevna , Andreevna Kovalenko Ekaterina , Alekseevna Osinovskaya Nina
Published: June 2023

Background

The priority task of the world community of neurologists is the early diagnosis of dementia, which is associated with an increase in life expectancy of the population. Among all dementias, Alzheimer’s disease occupies a leading position. Existing criteria for Alzheimer’s disease do not allow a diagnosis at the stage of predementia. New predictors of cognitive deficits, as such a method, scientists hope for optical coherence tomography.

Method

90 patients were examined, divided into 3 groups: the first group ‐ patients with Alzheimer’s disease (AD), meeting the NINCDS ADRDA criteria, the second ‐ patients with vascular dementia (VD), meeting the NINDS‐AIREN criteria. According to the criteria, each group of BA and DM consisted of 21 (70%) women and 9 (30%) men, mean age 65 years [61; 67] ∖ 66 [60; 69] years respectively. The third group included patients with open‐angle glaucoma (POAG) ‐ 20 (66.7%) women and 10 (33.3%) men, mean age 70 years [62; 76] years.

Result

According to the results of OCT in the area of the optic disc, there were no statistically significant differences in the width of the neuroretinal rim between the groups. In the VAD group, the thickness of the peripapillary layer of nerve fibers in the upper and lower temporal quadrants was greater than in the DA and POAG groups. OCT in the macular region revealed a decrease in the thickness of the retina and the inner plexiform layer in the upper and lower quadrant of the peripheral region, as well as a decrease in the thickness of the nerve fibers, the ganglionic layer in the lower quadrant of the peripheral region in the OP and POAG groups compared with the VAD group.

Conclusion

Based on the data obtained, it can be concluded that in AD, degenerative changes in the retina are observed in the peripheral region, while in VD, the process is more pronounced in the foveal (central) region of the retina. In conclusion, it should be noted that a comprehensive ophthalmological examination can become one of the key and affordable methods for the early diagnosis of BA.
The cerebrospinal fluid Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) concentration in Alzheimer’s Disease (AD)
Authors: Doroszkiewicz Julia , Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Borawska Renata , Slowik Agnieszka , Mroczko Barbara
Published: June 2023

Background

Alzheimer Disease (AD) is a common neurodegenerative disorder which is the most widespread form of dementia in the world. The disease is characterized by amyloid‐β peptides, phosphorylated tau proteins and neuroinflammation. Because of late manifestation of the disease, it is pivotal to find new biomarkers that can help detect AD in the earliest phases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane endogenous glycoprotein involved in neuroinflammation. Recent studies have confirmed GPNMB presence in the microglia in AD patients brains, especially near amyloid‐β plaques, although the exact role of this protein in AD is still not fully known. Furthermore, it has been observed that GPNMB may negatively influence secretion of proinflammatory cytokines form macrophages making this glycoprotein possibly protective to neuroinflammation. Thus, the purpose of our research was to measure the concentration of GPNMB in cerebrospinal fluid of AD patients and non‐demented controls and compare with classical AD biomarkers.

Method

The concentrations of GPNMB was measured in cerebrospinal fluid (CSF) of 17 AD patients and 17 non‐demented controls using multiplexing method.

Result

GPNMB concentrations were significantly higher in AD patients in comparison to non‐demented controls. Moreover, increased CSF levels of GPNMB correlated positively with Tau, pTau181, age and negatively with Aβ‐42, Aβ‐42/Aβ‐40 ratio and MMSE in the whole study group.

Conclusion

Findings of our research suggest a potential role of GPNMB in pathology of AD. However, follow‐up studies on larger study group are needed.
WMH and biomarker heterogeneity of individuals on the amyloid pathway
Authors: Prosser Lloyd , Oxtoby Neil P , Cash David M , Malone Ian B , Carrasco Ferran Prados , Sudre Carole H , Barnes Jo
Published: June 2023

Background

Research studies of Alzheimer’s disease (AD) are increasingly using biomarker‐based criteria to define disease. One useful definition is amyloid positivity since it identifies those on a pathological pathway that likely results in AD. However, within amyloid positive individuals, there is substantial heterogeneity in terms of when biomarkers that measure different aspects of the disease become abnormal. Here we examine this heterogeneity amongst biomarkers that reflect various aspects of the disease process.

Method

CSF Amyloid positive individuals’ data from Alzheimer’s Disease Neuroimaging Initiative (ADNIGO/2/3) were used (n = 376). Demographics were compared across diagnostic group using linear regression and Fisher’s exact tests where appropriate, table 1. CSF phosphorylated tau (ptau), whole‐brain and hippocampal volume, Logical memory (LM) and Trails A and B, and white matter hyperintensity (WMH) volumes were used to derive data‐driven subtypes using the z‐score version of the SuStaIn algorithm. The algorithm produced subtypes with differing patterns of biomarker orderings. SuStaIn calculated z‐scores using 86 CSF amyloid negative, APOE e4 non‐carrier healthy controls, selected from ADNIGO/2/3. Proportions of APOE e4 carriers, and clinical diagnosis were compared between subtypes using Fisher’s exact test.

Result

359 individuals were grouped into three subtypes (figure 1); determined using cross‐validation. Subtype one (n = 136) had an initial event of WMH, followed by LM, trails A and B, and whole‐brain volume (hippocampal sparing). Subtype two (n = 115) had initial events of ptau, followed by LM and hippocampal volume (tau‐led). Subtype three (n = 108) had initial events of LM total, followed by ptau and hippocampal volume (tau‐late). 17 individuals were not subtyped, as their biomarker data showed no significant abnormalities and would suggest that they are not on an AD pathway.

There was a trend towards a higher proportion APOE e4 carriers in subtype one and three (p = .06). There was a significant difference in clinical diagnosis between subtypes (p < .001), with subtype one having a lower proportion of CNs and a higher proportion of MCIs than subtypes two and three (figure 1).

Conclusion

We found considerable heterogeneity in biomarker progression sequences in individuals with elevated amyloid.