bluuebunny/crossref_metadata_2025 huggingface dataset:
Is there a relationship between periodontitis and Alzheimer's disease? Systematic review and comparative analysis
Authors: Torrealba‐García Daniela , Garcia‐Morales Pilar , Torrealba Eduardo , Cejudo Juan Carlos , Silvestre‐Rangil Javier
Published: December 2021

Background

Alzheimer’s disease is a neurodegenerative disease with unknown cause, being the first cause of dementia affecting 24 million people, which is set to double by 2040. Periodontitis is a multifactorial, inflammatory and chronic disease that causes the loss of the tooth’s support system; being the number one cause of tooth loss in adults. Both diseases are highly prevalent, making them an important public health issue. New studies have shown that there might be a relation between them.

Method

Systematic review and comparative analysis of studies through a bibliographic search that included clinical trials, case‐control and cohort studies in humans, with objective tests for the diagnosis of both diseases. Excluding: descriptive studies or studies that didn’t focus on Alzheimer’s; studies that didn’t diagnose periodontitis clinically; sigle case studies; based on patients with syndromes; or evaluated exclusively the quality of life of the patients. From the 473 articles found only 9 fulfilled the inclusion and exclusion criteria.

Result

Out of the 9 articles selected, 7 found a statistically significant difference between people with Alzheimer’s and without it in relation to periodontitis (Choi S et al, Ide M et al, de Suza T et al, Martande SS et al, Holmer J et al, Cestari JA at al, Aragón F et al). Chen CK et al didn’t find a statistical significance at the beginning (p=0.0547) but did in the 10 years follow‐up (p=0.00264). Tiisanoja A et al didn’t find a statistic significance (RR=1.54; IC=0.52‐4.56). However, when subjecting the article’s results to CI for the proportion analysis we discovered that only one study found this difference significant out of the 6 included.

Conclusion

The most common oral problems in patients with Alzheimer’s were gingivitis, periodontitis, tooth loss, candidiasis, calculus. Although there seems to be a relationship between the two, further studies with larger populations and a better screening process for participants, are needed in order to truly assess whether there is a causal relationship between the two pathologies or not. One of the greatest limitations we encountered was the lack of homogeneity between the studies statistical tools, making it impossible to do a meta‐analysis.
Impact of Alzheimer’s disease and related disorders neuropathology on neuropsychiatric symptoms during life
Authors: Devanand Davangere P , Lee Seonjoo , Huey Edward D. , Goldberg Terry E.
Published: December 2021

Background

There is limited information on the impact of specific neuropathologies on neuropsychiatric symptoms (NPS). We evaluated the impact of neuropathologically defined subtypes of Alzheimer’s Disease and Related Dementias (ADRD) on neuropsychiatric symptoms (NPS) during life.

Method

The study design used a direct and unbiased approach that did not consider clinical diagnoses and included all brains with neuropathological diagnoses in the V.10 collection of the National Alzheimer’s Coordinating Center (NACC) database that also had Neuropsychiatric Interview‐Questionnaire (NPI‐Q) data collected during life. Data from 1,808 patients from 39 sites were examined. We utilized pairwise, ordinal and multiple logistic regression analyses to assess the effects of 8 neuropathological diagnoses on 12 domains in the Neuropsychiatric Inventory Questionnaire (NPI‐Q), correcting for multiple statistical comparisons. For NPS, average NPI‐Q domain scores during annual follow‐ups was the primary measure and NPI‐Q domain ever present/always absent was the secondary measure.

Result

The neuropathological diagnosis of Alzheimer’s disease (AD) using ABC criteria showed moderate associations with increased delusions, agitation/aggression and hallucinations. Cerebral amyloid angiopathy showed associations with NPS that were similar to AD. Lewy Body Disease (LBD) showed increased hallucinations. Infarcts/lacunes and microinfarcts showed weak associations with mood and motivational symptoms. Frontotemporal Dementia (FTD) was associated with marked increase in apathy and significantly decreased psychotic features and agitation. Hippocampal sclerosis was associated with less depression and increased apathy and disinhibition; these associations persisted after controlling for vascular neuropathology and FTD. In multiple regression analyses that controlled for other neuropathologies, the main findings were not altered.

Conclusion

The associations of ADRD neuropathologies with specific NPS support current diagnostic criteria for behavioral symptoms in specific disorders. The findings on apathy and disinhibition in hippocampal sclerosis are novel and unique, and may explain inconsistent findings for depression treatment in dementia. Further investigation is needed to clarify the impact of hippocampal sclerosis on medial temporal lobe function and NPS, which may help eventually with diagnosis and clinical management.
The APP669‐711/Aβ1‐40 ratio as a plasma biomarker specific for the brain Aβ deposition in APP/PS1 mouse
Authors: Kaneko Naoki , Matsuzaki Masaya , Yokoyama Miyabishara , Korenaga Akihito , Sekiya Sadanori , Iwamoto Shinichi , Tanaka Koichi , Tomita Taisuke
Published: December 2021

Background

We have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). However, the significance of these peptide ratios in an APP/PS1 mouse model of Alzheimer's disease has been unclear. In this study, we investigated the levels of Aβ‐related peptides including APP669‐711 in plasma samples from the model mouse.

Method

We prepared plasma samples from young (2 months of age) and old (23–25 months of age) APP/PS1 mice expressing both APP bearing the Swedish mutation and PSEN1 harboring ΔE9 mutation, and cultured supernatants of HEK293 cells. Mouse plasma samples and cultured supernatants were measured by IP‐MALDI‐MS.

Result

Human APP669‐711 was detected in cultured supernatant of HEK293 cells overexpressing human wild‐type APP but not human APP with the Swedish mutation. This result indicated that two amino acid substitutions (i.e., Swedish mutation) near the APP669 site inhibited the APP669 cleavage and the production of APP669‐711 from the transgene of APP/PS1 mice. Then we focused on mouse endogenous murine Aβ‐related peptides in the evaluation of plasma biomarker for the amyloid deposition in the brains of APP/PS1 mice. The analysis of APP/PS1 mouse plasma showed that murine APP669‐711/Aβ1‐42 and APP669‐711/Aβ1‐40 ratios were increased in old mice with plaques compared to young mice without them. However, the murine Aβ1‐40/Aβ1‐42 ratio was not changed between old and young mice.

Conclusion

These results suggested that the APP669‐711/Aβ1‐42 ratio is a common biomarker for the amyloid plaque pathology in humans and APP/PS1 mice. Also, we revealed the possibility that the APP669‐711/Aβ1‐40 ratio is a biomarker specific for the brain Aβ deposition in APP/PS1 mice. These biomarkers can be useful tools to study lifestyle intervention and drug development for the prevention of amyloid deposition using the model mouse.
Higher coffee consumption is associated with slower cognitive decline and Aβ‐amyloid accumulation over 126 months: Data from the AIBL study
Authors: Gardener Samantha L , Rainey‐Smith Stephanie R , Villemagne Victor LL , Fripp Jurgen , Dore Vincent , Bourgeat Pierrick , Taddei Kevin , Masters Colin L , Maruff Paul T , Rowe Christopher C , Ames David , Martins Ralph N ,   AIBL Research Group
Published: December 2021

Background

Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data available in cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning these associations.

Method

The aim of the current study was to investigate the relationship between self‐reported baseline coffee intake (mean = 280 ± 323 g/day) and cognitive decline assessed using a comprehensive neuropsychological battery, over 126 months, in 227 cognitively normal individuals from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study. We also sought to investigate the relationship between coffee intake and cerebral Aβ‐amyloid accumulation and brain volumes in a subset of individuals (n=60; and n=51, respectively) over 126 months.

Result

Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown to reliably measure the first signs of cognitive decline in at‐risk cognitively normal populations) over 126 months. Higher baseline coffee consumption was also associated with slower Aβ‐amyloid accumulation over 126 months, and lower risk of transitioning from ‘negative’ Aβ‐amyloid status to ‘moderate’, and ‘very high’ Aβ‐amyloid burden over the same time period. There were no associations between coffee intake and atrophy in total grey matter, white matter, or hippocampal volume.

Conclusion

Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption reducing cognitive decline potentially by slowing cerebral Aβ‐amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ‐amyloid‐mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate how coffee intake could be incorporated as one modifiable lifestyle factor aimed at delaying AD onset.
The diagnostic significance of the chemokine CXCL12 in Alzheimer's disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Borawska Renata , Dulewicz Maciej , Doroszkiewicz Julia , Slowik Agnieszka
Published: December 2021

Background

A complex relationship between the stromal cell‐derived factor 1 (CXCL12) and dementia, including mild cognitive impairment (MCI) and Alzheimer's disease (AD) has been described in the literature. The chemokine CXCL12 regulates many functions of bone marrow‐derived stem cells and has been implicated in neurogenesis as well as with the recruitment of brain resident and non‐resident circulating cells towards sites of a lesion in the central nervous system. It has been suggested that dysregulation of the CXCL12/CXCR4 signaling pathway is involved in the pathologic process of cognitive impairment. Moreover, significantly changed expressions of the CXCL12 and CXCR4 were observed in AD patients' brains compared to the normal brain tissues of the healthy non‐demented subjects. The purpose of the study was to evaluate the concentration of the CXCL12 in patients with early stage of dementia (MCI) and compare it with classical biomarkers for AD.

Method

The study group included 34 subjects: 18 patients with AD and 16 controls without cognitive impairments. The cerebrospinal fluid (CSF) concentrations of tested proteins were measured with the use of ELISA method.

Result

The CSF concentrations of CXCL12 were elevated in AD patients in comparison to non‐demented controls. The increased levels of CXCL12 correlated with all CSF biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, Tau, pTau181), age and MMSE in the whole study group. Moreover, significant negative correlation between CXCL12 and MMSE in AD and control group was observed.

Conclusion

It was established that CXCL12 might play role in the development of AD, although the question, whether this protein can be useful in diagnostic of dementia requires further examination on larger study group. Acknowledgment: The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Factors associated with levels of plasma markers of amyloid pathology and neurodegeneration in a population‐based sample
Authors: Syrjanen Jeremy A. , Campbell Michelle R. , Algeciras‐Schimnich Alicia , Vemuri Prashanthi , Graff‐Radford Jonathan , Machulda Mary M. , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Mielke Michelle M.
Published: December 2021

Background

Blood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect these plasma marker levels for accurate clinical interpretation. Herein we examined factors associated with plasma Ab42, Ab40, neurofilament light (NfL), total tau (T‐tau), and the ratio of Ab42 to Ab40 (Ab42/40).

Method

The plasma markers were measured for 996 participants (859 cognitively unimpaired [CU], 133 mild cognitive impairment [MCI], 4 dementia) from the Mayo Clinic Study of Aging (MCSA), aged 51 to 95 years. The Quanterix Simoa® HD‐1 analyzer was employed to measure the plasma markers using the Simoa® Neurology 3‐Plex A (N3PA) (T‐tau, Ab42, Ab40) (catalog #101995) and the Simoa® NF‐light (catalog #103180). All other data was collected during in‐person MCSA visits or abstracted from the medical record. Statistical significance was determined using an alpha level of 0.05.

Result

Among CU, all of the plasma markers showed correlation with age. T‐tau (Spearman’s rho = 0.113, p<0.001) showed the weakest correlation and NfL (rho = 0.695, p<0.001) had the strongest. Women had higher levels of T‐tau (Median women: 2.782 vs. 2.390, p<0.001) and lower Ab42/40 (0.033 vs. 0.035, p=0.024) compared to men. In linear regression models predicting z‐scored plasma markers and adjusted for age and sex, several statistically significant predictors were found. For example, higher Charlson comorbidity index and chronic kidney disease were associated with higher levels of all markers; slower gait speed was associated with higher levels for all but Ab42/40 where no relationship was seen. A higher BMI was associated with higher levels of Ab42, Ab40, and T‐tau whereas NfL tended to be lower with increased BMI. Among participants with MCI or dementia, the relationship between gait speed or chronic kidney disease with NfL and T‐tau strengthened considerably.

Conclusion

Multiple variables affect plasma markers of amyloid pathology and neurodegeneration among CU in the general population. Some relationships differed among MCI and dementia participants. Incorporating this information is critical for accurate interpretation of the marker levels and for the development of reference ranges.
Precognize pilot study: A visuomotor ability‐based novel screening method for Alzheimer’s disease?
Authors: Berente Dalida Borbala , Kamondi Anita , Horvath Andras Attila
Published: December 2021

Background

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In the early stages, cognitive decline starts with the involvement of episodic memory. Latest results suggest that impairment in visuomotor function also appears in the initial stages of the disease which may have diagnostic potential.

Method

52 AD patients underwent neuropsychological evaluation including Addenbrooke Cognitive Examination (ACE). The patients were then divided into three groups based on disease duration in years (y) (1:≤2y N=15; 2: 2‐4y N=26, 3:≥4y N=11). Cognitive subscores were analyzed with group comparisons and Spearman analysis was applied on ACE subscores and disease duration. Based on these results, our group developed an electronic test battery (Precognize). It is based on the trail‐making test and used for detecting and analyzing mouse movements. To test the accuracy of our tool, we examined control participants (N=24) and patients (N=9) suffering from mild cognitive impairment or AD. They were examined with structural MRI and neuropsychology as well. Spearman’s rho was used to test correlation between the neuropsychology, cortical volumes derived from MRI and precognize data.

Result

Significant difference was found between disease duration and ACE subscores (visuospatial χ2=28,36 p<0,001; memory f=12,05 p<0,001). Visuospatial score showed strong negative correlation with disease duration (r:‐0.73; p<0.001). We also found significant difference in mouse movements between the control and affected group (p=0,019). Prominent correlation was presented between ACE visuospatial subscores and mousemove parameters (r= ‐0,39 p=0,037). Furthermore, significant negative correlation was demonstrated between precognize results and the cortical volume of both hemispheres (p=0,006; r= ‐0,59).

Conclusion

Testing of visuospatial abilities might hold important screening potential in the early identification of cognitive decline. Electronic algorithms could be able to test large populations without the mandatory need for qualified stuff and prominent financial background. Our test battery seems promising in the screening of dementia since the extracted data correlate well with the results of neuropsychology and structural neuroimaging.
Total sugar intake and cognition in community‐dwelling older adults
Authors: Ford Christopher N , Agarwal Puja , Beck Todd , Evans Denis A , Bennett David A
Published: December 2021

Background

Impaired glucose metabolism has been implicated in the progression of Alzheimer’s disease. Data from the Rush Memory and Aging Project was used to examine the relationship between sugar intake and cognition.

Method

Data were included from 837 respondents in the Rush Memory and Aging Project with complete food frequency questionnaire data consisting of 144 items. Cognition was assessed using a battery of 19 cognitive tests. Missing data were imputed using multiple imputation with chained equations. Linear random effects regression models were used to examine the relationship between total calorie‐adjusted quintile of sugar intake and global cognition, working memory, semantic memory, episodic memory, perceptual orientation and perceptual speed. Linear random effect models included race/ethnicity, age, sex, and time interactions for education (years), total energy (kilocalories/day), alcohol intake (grams/week), high‐density lipoprotein cholesterol (HDL‐C) and a continuous base term for time. Cox proportional hazards models were used to examine the relationship between total sugar intake and hazard of Alzheimer’s dementia, and to explore potential effect measure modification and confounding by race/ethnicity, age, sex, HDL‐C, total energy, alcohol intake, education and history of diabetes and hypertension. Variables were considered confounders if their inclusion resulted in >10% change in the crude hazard ratio. Effect measure modification was examined by including a time interaction term in Cox models and a performing a Wald test.

Result

In adjusted linear random effect models (Table 1) continuous quintile of sugar intake was inversely related to global cognition (β=‐0.0073; SE=0.0019; p=<0.001), episodic memory (β=‐0.0078; SE=0.0026; p=0.0026), semantic memory (β=‐0.0096; SE=0.0023; p=<0.001), working memory (β=‐0.0056; SE=0.0023; p=0.015) and perceptual speed (β=‐0.0090; SE=0.0025; p<0.001). There were 200 cases of Alzheimer’s dementia over 5,098 person years of follow‐up (IR: 39.2 cases per 1,000 person‐years). In crude Cox proportional hazards models (Table 2), those in the fifth quintile of total sugar intake were 1.84 (95% CI: 1.18; 2.87) as likely to develop Alzheimer’s dementia as those in the first quintile. A significant linear trend relationship was observed (p=0.006).

Conclusion

There is some evidence to suggest that total sugar intake may adversely affect cognitive function over time, and it may increase risk of Alzheimer’s dementia.
Populacional epidemiological study of dementia in the city of Londrina, Paraná, Brazil
Authors: Nakakogue Lindsey Mitie , Bersi Lília Maria Machado , Lepre Rafael Perusso
Published: December 2021

Background

Understanding the population context of dementias allows us to prepare socio‐economic and public policies aimed at broad and early care of the elderly population, in order to enhance health care, concerning the prevention and treatment of these diseases. The objective of the study is to obtain an estimate of the prevalence of dementia in Londrina ‐ PR, through the sample of two specialized service centers, as well as qualitative analysis of variants, such as subtype of dementias, gender, age, education, comorbidities, life habits, degree of dementia (CDR) and drugs used for its treatment, with the purpose of correlating them to gather information on potential risk factors for the development of dementia and, therefore, to be able to perform early diagnoses and proper interventions.

Method

A collection of 1469 electronic medical records were undertaken and analyzed manually from patients who consulted with previous diagnosis or who were diagnosed with dementia in 2019. When the exclusion criteria were applied, a total of 658 patients remained.

Result

The prevalence found in the ambulatory clinics of PUC‐PR and in the Municipal Polyclinic of Londrina are, respectively, 11.18% and 60.80%. It was detected that 60.8% of the diagnoses were in the female sex, with only 39.2% in the male sex. And there was a peak of diagnoses in patients who were 80‐89 years old. It was also observed 82% of cases of Alzheimer's Disease (AD), 7.1% of Mixed Dementia (MD), 5.8% of Vascular Dementia (VD), 3.4% of Lewy's Body Dementia and 1.7% of Parkinson's Disease. No correlation of dependence was identified between the development of dementia and the level of education (p > 0.05). In comorbidities, previous strokes were a risk factor for AD, VD and MD. A higher CDR was observed in older age groups. Greater use of donepezil and memantine was observed in AD and greater use of galantamine in DV.

Conclusion

It has been concluded that additional studies are needed to prove the potential risk factors for dementias, so that an early approach and prevention of this disease can be invested in, improving care even more.
Subjective cognitive and motoric complaints as predictors of motoric cognitive risk syndrome
Authors: Ayers Emmeline , Verghese Joe
Published: December 2021

Background

Motoric cognitive risk syndrome (MCR) is a pre‐dementia syndrome characterized by the presence of slow gait and cognitive complaints in non‐demented patients. Self‐reported subjective cognitive complaints (SCCs) have been shown to be harbingers of future cognitive decline. Likewise, subjective motoric complaints (SMC) are common with aging, and predict risk for future gait decline. Subjective complaints might have utility in screening and remote assessments. Our objective was to examine the validity of a subjective definition of MCR (presence of subjective motoric AND cognitive complaints) for predicting incident MCR defined using objective gait speed.

Methods

Five SMC and 8 SCC questions (independent of the SCCs used in the objective MCR definition) were assessed in a sample of 501 non‐demented community‐dwelling adults age 65 and older. Cox proportional hazard models adjusted for age, sex, education, comorbidities and a test of global cognitive function were used to examine the association between subjective MCR (presence of SMC and SCC) and risk of incident objective MCR (defined as slow gait 1 standard deviation below age and sex means and SCC).

Results

At baseline, 360 participants (71.1%) reported one or more subjective motoric complaints and 368 (72.7%) reported one or more SCCs. Two‐hundred seventy‐nine participants (55.1%) reported the presence of one or more of both SMC and SCCs (subjective MCR). Participants with subjective MCR were older (77.9 vs. 74.9) and more often female (61.4% vs. 48.4%) than those without subjective MCR. Of the 501 participants, 38 developed objective MCR over a median follow‐up 2.5 years. Subjective MCR was associated with increased risk of developing objective MCR (adjusted hazard ratio (aHR): 3.88, 95% Confidence Interval (CI): 1.58‐9.51). When subjective MCR was defined as the presence of 2 or more SMC and SCC, the association with objective MCR was stronger (aHR: 4.78, 95% CI: 2.45‐9.33).

Conclusions

Subjectively defined MCR is associated with increased risk of incident MCR. Remote identification of people at high‐risk for MCR has potential for clinical and research applications especially given the social isolation imposed by the Covid‐19 pandemic.
Racial differences in cognitive resilience to parental history of AD and cognitive impairment: The Offspring study
Authors: Manly Jennifer J , Avila Justina F , Vonk Jet MJ , Rentería Miguel Arce , Turney Indira C , Lao Patrick J , Seblova Dominika , Martinez Michelle N , Gutierrez Jose , Mayeux Richard , Schupf Nicole , Brickman Adam M
Published: December 2021

Background

The effect of family history on risk of developing late‐onset AD differs across race/ethnicity; however, the mechanisms underlying AD risk or resilience through heritability of genetic, environmental, and health factors are not well understood. Few large‐scale cohort studies have prospectively‐collected data of both parental and offspring generations and most intergenerational AD research is performed among volunteer‐based, well‐educated, White parents and offspring. We examined whether the association of midlife cognitive function with parental dementia status differs across race and ethnicity.

Method

Cognitive function was assessed in non‐Latinx White (n=66), non‐Latinx Black (n=181), Latinx English speaking (n=224), and Latinx Spanish speaking (n=362) people age 27 to 91 (mean age=56.5). Participants were offspring of participants in WHICAP, a community‐based sample of Medicare‐eligible residents of Washington Heights aged 65 and older. Of the 833 offspring, 610 families were represented, of which 176 (29%) parents were demented. We examined the association of parental dementia status on offspring measures of memory, attention, working memory, fluency, and processing speed, after adjusting for offspring age, sex/gender, parental education, and family relatedness, and tested for interactions between parental dementia status and racial/ethnic group. Next, we used multiple‐group analyses determined whether parental baseline memory performance predicted offspring cognitive test scores, adjusting for covariates.

Result

Offspring of WHICAP parents with dementia obtained lower scores on measures of memory, working memory, and attention, but processing speed and language were not affected by parental dementia status. Overall, offspring whose parents had poor memory had lower cognitive function across multiple domains (Figure 1); however, parental memory had a stronger impact on offspring memory, working memory, and fluency in non‐Latinx White and English speaking Latinx participants, compared with non‐Latinx Black and Spanish speaking Latinx participants.

Conclusion

This intergenerational study demonstrated that in middle age, offspring of parents with dementia have poorer cognitive function than offspring of parents without dementia, independent of parental SES; however, the strength of this relationship differed by race, ethnicity, and language. Results suggest that social and biological variables that confer familial risk and resilience may differ based on contextual factors that are patterned by racial and linguistic background.
The influence of race on intraprocedural complication and side effect rates of lumbar punctures
Authors: Eierman Allison C. , Cole Aleshia , Van Hulle Carol A. , Ma Yue , Lazar Karen K. , Carlsson Cynthia M. , Chin Nathaniel A. , Asthana Sanjay , Blazel Hanna , Bendlin Barbara B. , Okonkwo Ozioma C. , Edwards Dorothy Farrar , Wahoske Michelle L. , Johnson Sterling C. , Gleason Carey E.
Published: December 2021

Background

A lumbar puncture (LP) is required to study cerebrospinal fluid (CSF) based biomarkers in preclinical Alzheimer’s Disease (AD). However, participants are often reluctant to undergo an LP due to fear. Insufficient data on the experiences of participants from underrepresented groups may contribute to their greater reluctance to agree to LP procedures, impacting diversity in AD studies. This analysis explores racial differences in intra‐procedural and post‐procedural complications rates.

Methods

870 LP procedures were performed on 606 participants in the Wisconsin Alzheimer's Disease Research Center, using a standardized technique with 24 or 25 gauge atraumatic needles. Up to 22 milliliters of CSF was obtained using gentle syringe aspiration of fluid. The clinician performing the procedure documented any intraprocedural complications experienced, including: headache, pain, vasovagal response, and radiculopathy. A follow‐up phone call the next day was used to assess any side effects following the procedure. Statistical analysis was performed using IBM‐SPSS version 27. Chi‐square tests were performed to compare complication rates between non‐Hispanic white, African American, and American Indian participants. Logistic regression analysis helped determine if BMI and waist‐to‐hip ratio also influenced complication rates.

Results

Sample characteristics are shown in Table 1. LP success rates varied significantly by race (11.370, p=0.001). 90% of White, 77.5% of African American, and 66.6% of American Indian participants had a successful LP (Table 2); 61.1% of White, 48.8% of African American, and 52.4% of American Indian participants experienced zero complications (Figure 1). African American and American Indian participants experienced higher rates of total intraprocedural complications (9.642, p=0.022; 0.975, p=0.807 respectively). There was a significant group difference in reports of pain and headache during the procedure. However, few participants experienced any post‐procedural side effects. Overall, 5.5% experienced a headache and 8.5% experienced low back pain and no significant differences were seen between racial groups.

Conclusion

LPs are relatively safe with limited intraprocedural complications and few post‐procedural side effects. These results can help re‐evaluate potential disparities, alter LP procedures, and provide accurate information to potential participants to increase recruitment and study diversity.
Sex differences in the association between smoking status and increased incidence of Alzheimer’s dementia
Authors: Aslanyan Vahan , Ortega Nancy E , Mack Wendy J , Pa Judy
Published: December 2021

Background

Growing evidence indicates that smoking, a late life risk factor for Alzheimer’s dementia (AD), is significantly associated with increased prevalence of AD. However, the relationship between sex, smoking, and incident AD has not been well explored. The current study examined the relationship between sex, smoking status, and time to clinical diagnosis of AD.

Method

387 participants from UK Biobank were included in the study (mean±SE age=67.7±1.5 years, 50.9% female). Participants were over the age of 65 at their baseline visit and subsequently developed AD. Participant smoking status was determined from a baseline lifestyle questionnaire (8.5% current smoker, 45.7% previous smoker). Cox proportional‐hazard models were used to test the association between smoking and conversion. An interaction term and stratification by sex were used to assess the moderating role of sex in the association. Baseline age, APOE‐e4 status, sex, and Townsend deprivation index were included in the analyses.

Result

Median time to conversion was 6.39 years (interquartile range (IQR): 2.75) among never‐smoker participants, 6.36 years (IQR: 2.5) among previous smokers, while current smokers had a median time to conversion of 5.56 years (IQR: 2.59). Never‐smoker men had a shorter median time to conversion than never‐smoker women (6.20 (2.55) vs 6.57 (2.96) years). Current smoker men had a shorter median time to conversion than current smoker women (5.41 (2.69) vs 5.81 (1.87)). Previous smoker men, however, had a longer median time to conversion than previous smoker women (6.47 (2.46) vs 6.0 (2.58)). The hazard ratio (HR) for the current smokers relative to never‐smokers was 1.52 (confidence interval (CI): (1.03, 2.24), p=0.04), indicating that smoking increases the risk of conversion to AD by 52%. Smoking status and sex interaction (HR=0.65, CI: (0.42,0.99), p=0.05) revealed a significant difference between previous smoker men (HR=0.73, CI: (0.53,1), p=0.06) and previous smoker women (HR=1.11, CI: (0.83,1.5), p=0.48). Cessation of smoking had an opposing effect on the relative risk between men (reduced by 27%) and women (increased by 11%).

Conclusion

Current smoking status is associated with increased incidence of AD and differs by sex. Further analyses are needed to understand the causal mechanisms by sex underlying these associations.
Sex differences in survival in younger‐onset dementia
Authors: Loi Samantha M , Tsoukra Paraskevi , Chen Ben , Wibawa Pierre , Eratne Dhamidhu , Kelso Wendy , Farrand Sarah , Goh Anita M Y , Walterfang Mark , Velakoulis Dennis
Published: December 2021

Background

There is limited information about survival and mortality in younger‐onset dementia (YOD), including the role of sex differences. In older‐onset Alzheimer’s disease (AD), the risk of AD appears to be higher in women, despite longer life expectancy, and a recent mortality study suggested that women’s older age at death may explain sex‐related differences in death rates from AD and dementia (1). There have also been reports that women have more atrophy and amyloid burden in YOD (2). We sought to further explore this in YOD.

Method

Neuropsychiatry inpatients with a diagnosis of dementia or cognitive impairment (excluding those who had a diagnosis of Huntington’s disease) between 1992‐2014 were submitted to the Australian National Death Index. Kaplan Meier curves were used to estimate median survival and standardized mortality ratios (SMRs) were used to compare deaths in people with YOD with population norms.

Results

468 inpatients were included in the study, of whom n=330 of them (74.5%) had a YOD. 65% of them (n=215) had died. The mean age of death was 64 years old (SD=10.4). Median survival for the different dementias were: AD – 11.2 years, frontotemporal dementia (FTD) – 10.7 years, “other dementia” – 14.8 years and vascular dementia – 12.3 years. There were no differences in the proportions of people who had died according to dementia type, p=0.438 but median survival for men and women was significant, with men – 13.6 years, compared to women 10.9 years, p=0.02. SMRs were also higher for FTD (SMR=8.1) and for women, compared to men, particularly with women+FTD (SMR=12.2).

Conclusion

This study highlights that sex differences also exist in YOD. Differences such as increased cognitive reserve in men and sex‐related bias in identifying dementia in younger people are possible explanations but further investigation is warranted.

References: 1. Buckley R. et al. 2019. To what extent does age at death account for sex differences in rates of mortality from AD? Am J Epidemiology. 188: 1213‐1223. 2. Groh J. et al. 2020. Sex‐associated differences in pathology burden in early‐onset AD. Alzheimer’s Dement. 16 (supp. 5): e046532
Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy
Authors: Vacher Michael , Porter Tenielle , Milicic Lidija , Dore Vincent , Bourgeat Pierrick , Villemagne Victor L.L. , Doecke James D. , Laws Simon M. , Heng Julian Ik‐Tsen
Published: December 2021

Background

Neurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.

Method

From a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.

Result

At baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 (<20KB KATNB1) and ventricular volume (p = 2.13e‐4, β = 5.8). In the longitudinal analyses, we found that rs1142749, a marker located near TUBB4B, was consistently associated with accelerated rate of change in grey matter (p = 9.2e‐4, β = 0.034), hippocampal (p = 2.9e‐3, β = 0.025) and ventricular volume (p = 2.1e‐3, β = ‐0.028). Further, we observed that the strength and effects of these associations were exacerbated in Ab+ individuals but were absent in Ab negative sub‐population. Another noticeable link was identified between rs2555172 (DCHS1) and hippocampal volume change (p = 1.4e‐3, β = ‐0.024). The identified associations were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons.

Conclusion

The results support the hypothesis that genes associated with neurodevelopmental processes and signalling mechanisms are relevant to Alzheimer’s Disease. The identified associations suggest that mutations in key neurodevelopment genes could be linked to accelerated atrophy in specific areas of the brain.
Effect of cognitive reserve and amyloid deposition on sleep‐dependent cognition in older adults
Authors: Ourry Valentin , Rehel Stéphane , André Claire , Gonneaud Julie , Moulinet Inès , Kuhn Elizabeth , Touron Edelweiss , Landeau Brigitte , Mézenge Florence , Paly Léo , Delarue Marion , De la Sayette Vincent , Chetelat Gaël , Rauchs Géraldine ,   the Medit‐Ageing Research Group
Published: December 2021

Background

Sleep, especially slow wave sleep (SWS), favors efficient cognitive functioning. This effect may be impaired in aging, but might be modulated by cognitive reserve. Indeed, a study reported that highly educated older adults were able to better tolerate the negative effects of subjective sleep disturbances on verbal fluency scores. Growing evidence also suggests that sleep may favor amyloid clearance. In this context, we investigated the effect of cognitive reserve and amyloid deposition on the links between SWS and cognitive performance in older adults.

Methods

Baseline data of 135 cognitively unimpaired older adults (mean age ± SD: 69.3 ± 3.8 y) from the Age‐Well cohort were analysed. Participants underwent a neuropsychological assessment, a polysomnography, and a florbetapir PET scan to measure amyloid deposition. Cognitive reserve was estimated using a socio‐behavioral proxy, the Lifetime of Experiences Questionnaire. We conducted linear regressions between SWS (% of total sleep time) and 1) executive functions and 2) episodic memory composite scores. Standardized residuals were extracted so that higher values reflect a better cognition than expected (i.e., greater cognitive resilience). Then, we performed linear regressions with these residuals as dependent variables and cognitive reserve or amyloid deposition as independent variables. Analyses were repeated with age, sex and the apnea‐hypopnea index as covariates.

Results

SWS (%) was positively associated with executive functions (p=0.021) and episodic memory (p=0.017) composite scores (Figure 1). For both cognitive domains, higher residuals were associated with better cognitive reserve and lower amyloid deposition (p<0.05) (Figure 2). All links with cognitive reserve remained significant after controlling for the covariates (p<0.05), while those with amyloid deposition were close to the significance threshold (p=0.085 and p=0.054 for executive functions and episodic memory respectively).

Conclusions

Individuals with higher cognitive reserve or, to a lesser extent, lower amyloid deposition, were able to better tolerate the effects of low amounts of SWS on executive and episodic memory performance. Cognitive reserve may help maintaining cognitive performance even when sleep is disrupted (i.e., cognitive resilience to sleep changes), while amyloid deposition would increase the vulnerability to poor sleep quality. These findings are important to understand the factors promoting successful aging.
Atrophy in dopaminergic pathways is associated with emergence of delusions in patients with Alzheimer’s disease
Authors: Manca Riccardo , Valera‐Bermejo Jose Manuel , Venneri Annalena ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

Background

People with advanced Alzheimer’s disease (AD) may present with delusions that are associated with worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study aimed to investigate whether differences in cognitive and grey matter (GM) volume decline can be detected in the year before symptom onset between patients with AD who will and will not develop delusions.

Method

Two samples of patients with AD, 63 who will (AD‐D) and 63 who will not develop delusions (AD‐ND) over a year as recorded by means of the NPI, were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and matched for diagnosis, cognitive status, age, education, sex, handedness and APOE genotype. Sixty‐three additional matched healthy controls (HC) were selected. Group‐by‐time models were used to compare cognitive and clinical data across groups, as well as GM maps by means of VBM. Change in NPI scores was used as covariate. Post hoc analyses were performed to investigate AD‐D vs AD‐ND differences in volume decline in areas found to be more atrophic in the AD‐D group and in brainstem nuclei connected to these areas.

Result

No neurocognitive differences were observed between patient groups either prior to or at symptom onset. When the two patient groups were compared to HC, the AD‐ND showed no greater atrophy over time while greater atrophy in the left caudate was observed in the AD‐D group. Post hoc analyses revealed greater GM loss in the AD‐D group in both caudate bodies and dopaminergic nuclei (i.e. the substantia nigra and the ventral tegmental area), but not in serotoninergic nuclei.

Conclusion

Patients with AD who will develop delusion showed faster neurodegeneration prior to symptom onset in dopaminergic systems, especially in the nigrostriatal pathway. Therefore, alterations in dopamine neurotransmission due to AD‐related pathology may explain the emergence of delusional thoughts in this population, consistently with the dopaminergic hypothesis of positive symptoms in schizophrenia.
Graduation study design: Evaluation of once‐weekly subcutaneous administration of gantenerumab on brain amyloid load
Authors: Boess Frank , Sakaoka Shunsuke , Abi‐Saab Danielle , Scelsi Marzia Antonella , Delmar Paul , Hofmann Carsten , Klein Gregory , Baudler Monika , Doody Rachelle , Kerchner Geoffrey A
Published: December 2021

Background

Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Aβ), is a potential disease‐modifying treatment for early Alzheimer’s disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post‐hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to a target dose of up to 1200 mg confirmed significant Aβ removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of gantenerumab in early AD, using a 1020 mg/month regimen at target dose (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). These studies maximise exposure with a single titration scheme and target dose regardless of APOE genotype over more than two years of treatment. The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (Q1W) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous Q1W administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience.

Methods

In this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg every 4 weeks (Q4W), followed by 255 mg Q4W and Q2W for 12 weeks each, and a target dose of 255 mg Q1W. This target dose is equivalent to the 1020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a Q1W dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography (PET). Secondary objectives include the assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, cognitive and functional assessments.

Result

Results to come.

Conclusion

The GRADUATION study will determine the effect of once‐weekly administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home.

References: (1) Ostrowitzki et al., 2017; Alzheimers Res Ther. 9:95. (2) Klein et al., 2019; Alzheimers Res Ther. 11:101.