Pages 3-18
Review
Efthalia Angelopoulou, Sokratis G Papageorgiou
Telemedicine in Alzheimer’s disease and other dementias: Where we are?
Abstract: The prevalence and global health burden of dementia including Alzheimer’s disease (AD) is rising, while patients living in remote and underserved areas face significant challenges in reaching specialized care. Telemedicine offers a valuable solution in bridging this widening gap, by providing equal and timely access to tertiary-specialized centers. Accumulating evidence highlights that most parts of the remote neuropsychological and neurological evaluation are feasible, with patients, healthcare professionals and caregivers being generally satisfied with this means of care. Herein, we provide an updated overview of the available evidence on the use of telemedicine for patients with cognitive disorders, focusing on the different applications and settings, the remote, video-based neurological and neuropsychological assessment, current recommendations, non-pharmacological interventions, as well as legal and ethical considerations. Based on the literature review and our three-year experience in the “Specialized Outpatient Clinic of Memory, Dementia and Parkinson’s disease through the National Telemedicine Network” in the Aiginition University Hospital of Athens, we propose a brief guide for assessing patients with cognitive impairment via telemedicine and suggest future research directions for the more effective and appropriate use of telemedicine in dementia assessment and care.
Pages 19-37
Review
Siyuan Su, Ruihan Huang, Yongsheng Liu
The effects of transcranial direct current stimulation on global cognition in patients with Alzheimer’s disease: an update meta-analysis
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disease. At present, there are currently no drugs that can cure AD. Objective: A number of empirical studies have shown that transcranial direct current stimulation (tDCS) may be used to treat cognitive abnormalities in patients with AD. We will through meta-analysis reviews tDCS overall research on the effects of cognitive function in patients with AD. Methods: Systematic searches were performed in the PubMed, Embase, and Cochrane Library databases from their creation until 8 March 2024. Using a fixed effect model and random effect model to evaluate the average difference between the treatment group and control group (MD) and its 95% confidence interval (CI). Result: The study included 10 randomized controlled trials (Nactive=165, Nsham=167). The results of the overall analysis showed that tDCS did not significantly improve the overall cognitive function (SMD=0.17; 95%CI=-0.05, 0.39; p=0.14; I²=51%). Quality of life of AD patients after treatment was also evaluated, but no improvement was seen. Subgroup analysis showed no significant improvement in global cognitive function after tDCS treatment. The sensitivity analysis to confirm the reliability of the data, risk assessment did not find any high-risk projects. Conclusions: The tDCS treatment did not improve cognitive function in patients with AD. Further empirical research in the future will help to explore new schemes for tDCS to improve cognitive function of patients.
Pages 38-55
Review
Delia Righi, Carlo Manco, Matteo Pardini, Angela Stufano, Valentina Schino, Virginia Pelagotti, Federico Massa, Nicola De Stefano, Domenico Plantone
Investigating interleukin-8 in Alzheimer’s disease: A comprehensive review
Abstract: Several studies indicate that the development of Alzheimer's disease (AD) has strong interactions with immune mechanisms within the brain, indicating a close association between inflammation in the central nervous system and the progression of neurodegeneration. Despite considerable progress in understanding the inflammatory aspects of AD, several of them remain unresolved. Pro-inflammatory cytokines and microglia are pivotal components in the inflammatory cascade. Among these, the role of interleukin-8 (IL-8) in neurodegeneration seems complex and multifaceted, involving inflammation, neurotoxicity, blood-brain barrier disruption, and oxidative stress, and is still poorly characterized. We conducted a review to describe the evidence of IL-8 involvement in AD. IL-8 is a cytokine known for its proinflammatory properties and typically produced by macrophages, predominantly functions as a chemotactic signal for attracting neutrophils to inflamed sites in the bloodstream. Interestingly, IL-8 is also present in the brain, where it is primarily released by microglia in response to inflammatory signals. This review aims to provide a comprehensive overview of the structure, function, and regulatory mechanisms of IL-8 relevant to AD pathology.
Pages 56-67
Review
Xuhua Xu*, Zhiya Chen*, Feng Gao (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
The relationship between postoperative cognitive dysfunction and cerebral small vessel disease: A comprehensive review
Abstract: Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and cerebral small vessel disease (CSVD) has been suggested as a potential risk factor. This review examines the relationship between POCD and CSVD from epidemiological, pathophysiological, and clinical perspectives, while also considering the role of Alzheimer's disease (AD) pathology. We conducted a comprehensive literature search of major databases, supplemented by reference list checking, to ensure a thorough review of studies published between 2000 and 2023 on the relationship between POCD and CSVD. Epidemiological studies have shown that POCD and CSVD are associated in terms of common risk factors, including advanced age, vascular comorbidities, impaired baseline cognitive function, and certain population characteristics. Animal studies have revealed that CSVD and POCD share similar neuropathological changes, including abnormal cerebral hypoperfusion, inflammatory responses, and blood-brain barrier disruption. Furthermore, recent research suggests a complex interplay between CSVD, AD pathology, and POCD, with potential synergistic effects on cognitive decline. Neuroimaging studies have further demonstrated that preoperative CSVD burden and postoperative CSVD progression are associated with the development of POCD, and the presence of both CSVD and AD markers may increase the risk of cognitive decline. The association between CSVD and POCD has important implications for the perioperative management of elderly patients, including preoperative assessment, choice of anesthesia and surgical methods, intraoperative management, postoperative care, and long-term follow-up. A better understanding of the relationship between CSVD and POCD will guide evidence-based strategies to prevent and manage this debilitating complication in the aging population.
Pages 68-80
Systematic Review
Vanessa Daudt Santos, Adriana Coelho Costa, Nelson Carvas Junior, François Jean Delaere, Sebàstien Serlet, Marcia Cristina Nascimento Dourado
Virtual reality interventions and their effects on the cognition of individuals with Alzheimer’s disease: A systematic review and meta-analysis
Abstract: Background: Dementia due to Alzheimer's disease (AD) is the most prevalent neurocognitive disorder in the world and impacts the individual's cognitive functions and functionality in the early stages of the condition. Virtual reality (VR) interventions can assist in non-pharmacological treatment in a more ecological way, positively impacting cognitive abilities. However, there are few studies on VR exclusively involving people with AD in randomized controlled trials. Objective: To evaluate the effects of VR intervention on the cognitive functions of people with AD. Methods: A systematically conducted search was carried out in MEDLINE, EMBASE, BVS, Web of Science, and Scopus. Eligible studies were randomized controlled trials comparing the efficacy of VR and traditional cognitive interventions in people with AD. Methodologic quality was assessed with the Cochrane risk of bias tool, and outcomes were calculated as risk ratios (for dichotomous outcomes) and mean differences (for continuous outcomes) with 95% confidence interval. Results: A total of three randomized controlled trials with 75 participants were included. An improvement in the performance of the VR group was observed in memory, especially when comparing the usual treatment [MD = 0.99; CI95%: 0.33; 1.66; I2 = 0%]. VR has little or no effect on participants' executive function [MD = 1.36; 95%CI: -1.12; 3.85; I2 = 0%] compared to the usual treatment Conclusions: Our study results cautiously suggest, despite the small number of participants, that VR intervention may be a suitable memory treatment for individuals diagnosed with AD.
Pages 81-91
Systematic Review
Daniel Kjaergaard, Anja Hviid Simonsen, Gunhild Waldemar, T. Rune Nielsen
Ethnic and racial influences on blood biomarkers for Alzheimer’s disease: A systematic review
Abstract: Background: Little is known about confounding factors influencing Alzheimer’s disease (AD) blood biomarker concentrations. Objective: The objective of this systematic review was to explore the available evidence for the influences of ethnicity and race on AD blood biomarker concentrations. Methods: We conducted a comprehensive systematic search in PubMed and Web of Science databases spanning from inception until 15 June 2023. We included studies that utilized plasma or serum biomarkers (amyloid-β [Aβ], total tau [t-tau], phosphorylated tau [p-tau], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]), compared individuals with AD to healthy controls, and included a minimum of two ethnic or racial groups for comparison. A total of 10 studies were included in the qualitative synthesis. All studies were conducted in the US. Results: Seven studies reported differences in blood biomarker concentrations between ethnic or racial groups. However, after adjusting for medical conditions and social determinants of health, the differences became non-significant in two of the studies. The included studies differed in their included covariates and their statistical approaches, which complicated the interpretation of the observed differences. Conclusions: The available evidence suggests that ethnicity and race may influence blood biomarker concentrations. However, it remains unclear to what extent these differences are mediated by differences in social determinants of health and medical conditions. Future studies are needed to explore ethnic and racial differences in blood biomarkers, including studies in diverse samples outside the US.
Pages 92-107
Systematic Review
Camila Cristine Gomes Nazareth, Ana Carolina Aparecida Marcondes Scalli, Marcos Paulo Braz de Oliveira, Antonio Felipe Souza Gomes, Sonia Brito-Costa, Guilherme Eustáquio Furtado, Natália Oiring de Castro Cezar
Differences in lean mass and sarcopenia between individuals with Alzheimer's disease and those without dementia: A systematic review and meta-analysis of observational studies
Abstract: Background: Studies have observed that individuals with Alzheimer's disease (AD) tend to have lower lean mass and higher rates of sarcopenia. Objective: This review aims to assess differences in lean mass, sarcopenia, and its components between individuals with AD and those without dementia (WD). Methods: Searches were conducted in the Medline, Web of Science, Embase, Scopus and Latin American and Caribbean Health Scientific Literature. Observational studies comparing lean mass, sarcopenia, and its components in the populations of interest were included. We used the Joanna Briggs Institute (JBI) scale to assess methodological quality. Mean differences (MD) and standardized mean differences were calculated for the meta-analyses. Results: Four studies with 2,035 individuals found that those with AD had significantly lower upper and lower limb lean mass, and skeletal muscle mass index compared to WD individuals. AD individuals also had a higher sarcopenia prevalence (41.33% versus 20.66%) and significant reductions in handgrip strength, lower limb muscle strength, and gait speed compared to WD individuals. The JBI scale analysis showed high agreement among the studies (k=1.00, p=0.046). Conclusions: Individuals with AD have lower lean mass, higher rates of sarcopenia, and reduced muscle function compared to those without dementia. While the results suggest the need for early screening programs and integrated therapeutic interventions to improve clinical outcomes and quality of life for individuals with AD, it is important to consider that biases inherent in observational studies may compromise the quality of the evidence. Therefore, further research, preferably clinical trials, is needed to confirm these associations.
Pages 108-112
Short Communication
Angelina Sutin, Martina Luchetti, Yannick Stephan, Antonio Terracciano
Meaning in life and neurobiomarkers of brain health in the UK Biobank
Abstract: This study examines meaning in life and four neurobiomarkers implicated in dementia risk: amyloid-β 42 to 40 ratio, phosphorylated tau-181, neurofilament light, and glial fibrillary acidic protein. Adults without dementia (N=1,150; Mage=59.89) from the UK Biobank reported their meaning in life; neurobiomarkers were assayed twice. Meaning in life was unrelated to the biomarkers at either assessment (βs range -0.03-0.02). No association was moderated by age. These findings do not support the hypothesis that meaning in life is associated with neurobiomarkers in adults without dementia. The relation between meaning and cognition may be through other pathways, such as resilience to neuropathology.
Pages 113-126
Matthew G Engel, Sushma Narayan, Min-Hui Cui, Craig A Branch, Xusheng Zhang, Samuel E Gandy, Michelle Ehrlich, Derek M Huffman
Intranasal Long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD mice
Abstract: Background: Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer’s disease (AD). Objective: Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice. Methods: Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n=19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed. Results: In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis. Conclusions: LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.
Pages 127-132
Matthew Lee Smith, Ashley D. Wilson, Janice Knebl, Robin C Hilsabeck, Kristen Reuter, Alyssa Aguirre, Barbara Harty, Chung Lin Kew, Shinduk Lee, Marcia G Ory
Utilization and perceived usefulness of monitoring technology for family caregivers of people living with Alzheimer’s disease and related dementias
Abstract: Background: Caregivers of people living with dementia (PLWD) often experience burden based on their care recipients’ symptoms of wandering, disorientation, and agitation. Objective: To examine the utilization and perceived value of technology-based solutions for caregiving among caregivers of PLWD. Methods: In collaboration with three Texas sites, PLWD and family caregiver dyads were recruited from clinical and community sites to assess the feasibility of a caregiving technology. PLWDs were asked to wear a GPS-based wearable device, which was paired with caregivers’ smartphone application, that enabled location monitoring and was equipped with call functions. After three months, researchers called caregivers to ask about their utilization of the “system” (i.e., wearable paired with smartphone application) and the perceived value of this technology. Forty-one caregivers completed follow-up telephone interviews. Results: About 70% of caregivers reported their care recipient wore the wearable device daily, and 39.1% used the smartphone application daily. Approximately 31% of caregivers reported daily use of the tracking feature, 30.8% reported daily use of the “safe zone” feature (i.e., geo-fencing), and 17.1% reported daily use of the two-way calling feature. About 39% of caregivers were extremely satisfied with the “system,” 43.6% found it extremely easy to use, and 46.2% found it extremely useful for caregiving. On average, caregivers with higher baseline Zarit Burden Interview scores found the “system” to be more useful with their caregiving (f=5.97, p=0.006) and were more satisfied with the “system” (f=3.75, p=0.034). Conclusions: Findings suggest caregiver burden may drive the perceived usefulness of, and satisfaction with, technology-based solutions.
Pages 133-148
Louis J Kolling, Michael S Chimenti, Catherine A Marcinkiewcz (Handling Associate Editor: Ganesh M. Babulal)
Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer’s disease
Abstract: Background: Persons with Alzheimer’s disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate. Objective: We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology. Methods: The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest. Results: We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA Map2k3os. Conclusions: Map2k3os may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.
Pages 149-158
Yuka Misu, Kota Tsutsumimoto, Yuto Kiuchi, Kazuhei Nishimoto, Tomoka Ohata, Hiroyuki Shimada
Coexistence of somatic and psychological symptoms of depression among community-dwelling older adults is associated with the incidence of dementia
Abstract: Background: Depression in old age is associated with the incidence of dementia. However, whether a combination of somatic and psychological symptoms influences the risk of dementia has not been fully investigated. Objective: We aimed to determine the association between the combination of psychological and somatic symptoms of depression and the incidence of dementia. Methods: This prospective cohort study included 2,111 community-dwelling older adults (median age=73 years, interquartile range=68–78 years, 39.5% male). Participants were evaluated for 5 years from baseline to assess the incidence of dementia. Somatic symptoms were defined as the presence of one or more symptoms of fatigue, weight loss, sleep disturbances, and abnormal appetite. Psychological symptoms were assessed using the 15-item Geriatric Depression Scale. Participants were stratified into four groups based on the presence or absence of somatic and psychological symptoms. A Cox proportional hazards model was used to examine the associations with the incidence of dementia, adjusted for potential confounders. Results: The hazard ratios for the incidence of dementia in the somatic (HR 1.42, 95% CI: 0.96–2.09) and psychological symptoms-only groups (HR 1.47, 95% CI: 0.83–2.59) were not significantly different; however, they were significantly higher in the coexistent group than in the normal group (HR 1.91, 95% CI: 1.24–2.94). Conclusions: The coexistence of somatic and psychological symptoms of depression increases the risk of dementia. Therefore, interventions should consider both somatic and psychological symptoms to prevent or delay dementia.
Pages 159-166
Zorian Radomyslsky, Sara Kivity, Yaniv Alon, Mor Saban
Ensuring continuity of care in times of crisis: A longitudinal analysis of dementia care delivery during armed conflict
Abstract: Background: Individuals with dementia are particularly vulnerable during emergency situations due to challenges with cognition, mobility, and daily functioning. However, little is known about how disruptive events may specifically impact the health of those with dementia. Objective: To evaluate changes in health outcomes for individuals with and without dementia surrounding the Israel-Gaza war in October 2023. Specifically, we analyzed and compared changes in mental health status, medication adherence, healthcare service utilization, and associated costs between individuals with dementia (Study Group) and those without dementia (Control Group) during the period surrounding the Israel-Gaza war in October 2023. Method: A prospective cohort study compared outcomes between individuals with dementia (Study Group, n=24,178) and without (Control Group, n=250,652) before and after the crisis onset. The conflict precipitously threw national systems into disarray, recruited healthcare personnel to the war effort, and disrupted supply chains. Results: Compared to baseline, analysis revealed alterations in patterns of dementia diagnoses, healthcare service utilization, medication adherence, and associated costs during the crisis period for both groups. However, the Study Group experienced comparatively larger declines. Conclusions: Findings provide insights into how humanitarian emergencies, through disruption of health systems and care networks, differentially impact continuity of dementia care. This underscores the need for tailored crisis response strategies to address the heightened vulnerabilities of patients with dementia.
Pages 167-179
Jianmin Zeng, Ziyun Gao, Xiong Xiong, Xingrong Hou, Huihui Qin, Yong Liu, Howard Bowman, Craig Ritchie, John T O’Brien, Li Su
The effects of two Alzheimer’s disease related genes APOE and MAPT in healthy young adults: An attentional blink study
Abstract: Background: Genetic risk factors start to affect the brain and behavior in Alzheimer’s disease (AD) before clinical symptoms occur. Although AD is mainly associated with memory deficits, attention and executive dysfunctions can present at the early presymptomatic stages in middle age for those with non-modifiable risks. Objective: Here, we investigated whether known risk genes for AD already affected attention in young adulthood. Methods: A total of 392 healthy young adults aged around 20 years underwent genetic testing for risks of dementia (APOE and MAPT) and performed a computerized cognitive test for temporal attention called the Attentional Blink (AB) task, in which patients with dementia tested in previous studies often showed reduced performance. Here, the AB task was analyzed using repeated-measurements analysis of variance for the ability of visual perception, attention deployment and temporal memory encoding/binding performance. Results: The results showed that all participants exhibited AB effects. Importantly, genetic risk factors had statistically significant influence on temporal attention depending on sex in healthy young adults. APOE4 status was associated with enhanced attention deployment in males but not females, while MAPT AA carriers had poorer performance in AB but only in females. No genetic effects were found for visual perception and temporal memory binding errors between high and low risk groups. Conclusions: We provided evidence that both APOE and MAPT start to affect attentional function as early as young adulthood. Furthermore, unlike previous findings in older people, these genes had a differential effect for males and females in young adults.
Pages 180-193
Victoria C Merritt, Rui Zhang, Richard Sherva, Monica T Ly, David Marra, Matthew S Panizzon, Debby W Tsuang, Richard L Hauger, The MVP Cognitive Decline and Dementia During Aging Working Group, VA Million Veteran Program, Mark W Logue
Curation and validation of electronic medical record-based dementia diagnoses in the VA Million Veteran Program
Abstract: Background: The age distribution and diversity of the VA Million Veteran Program (MVP) cohort make it a valuable resource for studying the genetics of Alzheimer’s disease (AD) and related dementias (ADRD). Objective: We present and evaluate the performance of several International Classification of Diseases (ICD) code-based classification algorithms for AD, ADRD, and dementia for use in MVP genetic studies and other studies using VA electronic medical record (EMR) data. These were benchmarked relative to existing ICD algorithms and AD-medication-identified cases. Methods: We used chart review of n=103 MVP participants to evaluate diagnostic utility of the algorithms. Suitability for genetic studies was examined by assessing association with APOE ε4, the strongest genetic AD risk factor, in a large MVP cohort (n=286K). Results: The newly developed MVP-ADRD algorithm performed well, comparable to the existing PheCode dementia algorithm (Phe-Dementia) in terms of sensitivity (0.95 and 0.95) and specificity (0.65 and 0.70). The strongest APOE ε4 associations were observed in cases identified using MVP-ADRD and Phe-Dementia augmented with medication-identified cases (MVP-ADRD or medication, p=3.6 x10-290; Phe-Dementia or medication, p=1.4 x10-290). Performance was improved when cases were restricted to those with onset age 60. Conclusions: We found that our MVP-developed ICD-based algorithms had good performance in chart review and generated strong genetic signals, especially after inclusion of medication-identified cases. Ultimately, our MVP-derived algorithms are likely to have good performance in the broader VA, and their performance may also be suitable for use in other large-scale EMR-based biobanks in the absence of definitive biomarkers such as amyloid-PET and cerebrospinal fluid biomarkers.
Pages 194-207
Giulia Bechi Gabrielli*, Fabrizia D'Antonio*, Antonella Di Vita, Roberta Margiotta, Massimiliano Panigutti, Maddalena Boccia, Laura Piccardi, Liana Palermo, Emanuela Salati, Micaela Sepe Monti, Giuseppina Talarico, Giuseppe Bruno, Cecilia Guariglia *These authors contributed equally to this work
Mind’s eye in the Alzheimer’s disease spectrum continuum
Abstract: Background: Visual mental imagery (VMI) is the ability to represent stimuli in the mind without sensory visual input. Previous studies have shown alterations in VMI in Alzheimer's disease (AD). However, VMI has not been investigated in the AD prodromal stage, mild cognitive impairment (MCI). Objective: We investigated VMI ability in mild AD and MCI patients, hypothesizing that VMI ability could be compromised since early disease stage. Methods: We enrolled 14 patients with mild AD, 19 amnestic MCI (aMCI), and 23 healthy control subjects (HC), matched for sex, age, and education. VMI assessment included: 1) the O’clock test that allows disentangling the possible role of visuo-perceptual difficulties in the VMI task’s performance; 2) a modified version of The Complete Visual Mental Imagery Battery (CVMIB), including tasks evaluating the different VMI processes (generation, maintenance, inspection and transformation). Results: Results indicated that AD patients performed worse than HC in both perceptual and imaginal tasks of the O’clock test and in all CVMIB’s tasks but maintenance. On the contrary, aMCI patients showed difficulties in the generation process and in the imaginal task of the O’clock test. Conclusions: Visual images generation, inspection and transformation processes are impaired in mild AD. Moreover, the generation process is selectively impaired in aMCI patients, suggesting that VMI deficits are already present in the prodromal stage of AD.
Pages 208-217
Ruihan Wan*, Jingnan Tu*, Jiahui Gao, Lei Cao, Lin Zhang, Jia Huang, Zhizhen Liu *These authors contributed equally to this work.
Mediation effect of neuropsychological factors on the relationship between social networks and mild cognitive impairment in older adults
Abstract: Background: Although links between social networks and mild cognitive impairment (MCI) have been suggested. The pathway between social networks and MCI from the Person-Environment-Occupation (PEO) model perspective among older adults remains inconclusive. Objective: To examine the relationship between social networks and MCI, and further identify whether neuropsychological factors mediate the relationship. Methods: 1,036 participants aged 55 to 75 years were recruited from two districts of Fuzhou, China, from December 2020 to December 2022. Data were obtained via a face-to-face neuropsychological scale assessment. Social networks and cognitive function were assessed by the Lubben Social Network Scale and the Montreal Cognitive Assessment, respectively. The Mediation model and structural equation model (SEM) pathway analysis were used to examine the direct and indirect effects of social networks on MCI via neuropsychological factors. Results: Data from 580 participants were analyzed (year: 65.16±5.38). Regression analysis indicated that higher levels of social networks and psychological resilience were positively correlated with improved cognitive function, even after adjusting for demographic data. Increased depressive symptoms and poor sleep quality were linked to cognitive decline. Support from family members had a greater impact than support from friends in reducing the risk of developing MCI. The SEM model supported the hypothesis that significant indirect effects of social networks on MCI via psychological resilience, depressive tendencies, and sleep quality. Conclusions: The effects of social networks on MCI are mediated by psychological resilience, depressive tendencies, and sleep quality.
Pages 218-229
Aaron Lam, Angela L D’Rozario, Shawn Kong, Catriona Ireland, Loren Mowszowski, Haley M LaMonica, Craig L Phillips, Camilla M Hoyos, Ronald R Grunstein, Sharon L Naismith
Screening for obstructive sleep apnea in the memory clinic: A comparison of questionnaires, pulse oximetry, and polysomnography
Abstract: Background: Obstructive sleep apnea (OSA) is highly prevalent among older adults and has been associated with cognitive decline and dementia risk. The suitability of screening tools for detecting OSA in memory clinic settings is unclear. Objective: To evaluate the utility and validity of the STOP-Bang questionnaire (SBQ) and pulse oximeter as a screening tool, compared to gold-standard polysomnography (PSG) in older adults attending a memory clinic. Methods: Participants aged over 50 with new onset cognitive/mood concerns attended a memory clinic, then completed the SBQ, oximetry, and PSG. The SBQ and oximetry’s accuracy in detecting moderate-severe and severe OSA was evaluated using receiver operating curves. Intraclass correlation and Bland-Altman plots compared the oximeter’s adjusted oxygen desaturation index (ODI-Ox) and PSG’s apnea-hypopnea index (AHI-PSG). Results: Of 194 participants (mean age=65.6, 64 males) who completed PSG, 184 completed the SBQ, and 138 completed oximetry. SBQ demonstrated limited performance for moderate-severe OSA (sensitivity=52%, specificity=62%, AUC=0.600) and severe OSA (sensitivity=18%, specificity=87%, AUC=0.577). Oximetry was satisfactory for moderate-severe OSA (sensitivity=67%, specificity=73%, AUC=0.769) and severe OSA (sensitivity=50%, specificity=88%, AUC=0.730). The diagnostic performance was improved with new cut-offs at ODI-Ox≥11 for AHI-PSG≥15 and ODI-Ox≥20 for AHI-PSG≥30. Bland-Altman plots and intraclass correlation indicated acceptable agreement for oximetry. Conclusions: The findings suggest that while the SBQ may be unsuitable to detect moderate or severe OSA for older adults with cognitive impairment, oximetry may be a viable screening tool. Given OSA treatment can optimize sleep and may slow cognitive decline, routine screening for OSA should be part of memory clinic assessments.
Pages 230-242
Rubina Malik, Derek Beaton, Juweiriya Ahmed, Kwangsik Nho, Andrew J Saykin, Jian Wang, Robert A Hegele, Elizabeth Finger, Alzheimer’s Disease Neuroimaging Initiative
A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in mild cognitive impairment and Alzheimer’s disease
Abstract: Background: Apathy in patients with Alzheimer’s disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored. Objective: To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD. Methods: In a sample of individuals with AD (n=266), MCI (n=518), and cognitively normal controls (n=378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy. Results: An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups. Conclusions: The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.
Pages 243-255
Pilar M Ferraro*, Laura Filippi*, Marta Ponzano, Alessio Signori, Beatrice Orso, Federico Massa, Dario Arnaldi, Stefano Caneva, Lucia Argenti, Mattia Losa, Lorenzo Lombardo, Pietro Mattioli, Mauro Costagli, Lorenzo Gualco, Martina Pulze, Domenico Plantone, Andrea Brugnolo, Nicola Girtler, Andrea Diociasi, Sara Garbarino, Flavio Villani, Maria Pia Sormani, Antonio Uccelli, Luca Roccatagliata, Matteo Pardini; for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Clinical and biological underpinnings of longitudinal atrophy pattern progression in Alzheimer’s disease
Abstract: Background: Magnetic resonance imaging (MRI) has recently enabled to identify four distinct Alzheimer’s disease (AD) subtypes: hippocampal sparing (HpSp), typical AD (tAD), limbic predominant (Lp), and minimal atrophy (MinAtr). To date, however, the natural history of these subtypes, especially regarding the presence of subjects switching to other MRI patterns and their clinical and biological differences, remains poorly understood. Objective: To investigate the clinical and biological underpinnings of longitudinal atrophy pattern progression in AD. Methods: 251 AD patients (16 with significant memory concern, 66 with early mild cognitive impairment (MCI), 125 with late MCI, and 44 with AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were assigned to their baseline MRI atrophy subtype using Freesurfer-derived cortical:hippocampal volumes ratio. Switching to other MRI patterns was investigated on longitudinal scans, and patients were accordingly classified as “switching” and “stable”. Logistic regression models were applied to identify predictors of switching to other MRI patterns. Results: 40% of Lp, 26% of HpSp, and 35% of MinAtr cases switched to other MRI patterns, with tAD representing the destination subtype of all switching HpSp and Lp, and the majority of MinAtr. At baseline significant clinical, cognitive and biomarkers differences were observed across the four subtypes. Only clinical and cognitive variables, however, were significantly associated with switch to other MRI patterns. Conclusions: Our results suggest convergent directions of disease progression across atypical and typical AD forms, at least in a subset of AD subjects, and highlight the importance of deep-phenotyping approaches to understand AD heterogeneity.
Pages 256-267
Yaping Zhang, Yingqi Liao, Yifan Yan, Cheuk Ni Kan, Yi Zhou, Shenghao Fang, Jingkai Huang, Saima Hilal, Christopher LH Chen, Xin Xu
Associations of neurocognitive and neuropsychiatric patterns with brain structural biomarkers and dementia risk: A latent class analysis
Abstract: Background: Neurocognitive and neuropsychiatric symptoms are essential clinical manifestations of age-related cognitive impairment, yet their patterns of co-existence remain unclear through the cognitive continuum. Objective: To examine the associations of person-centered cluster-derived patterns, based on a comprehensive collection of domain-specific cognitive and neuropsychiatric assessments, with neuroimaging markers and dementia risk. Methods: 641 participants were included in the analysis from memory clinics in Singapore. Latent class analysis was applied to define clusters of individuals with different clinical patterns. The associations between identified clinical groups with neuroimaging markers of cerebrovascular diseases and neurodegeneration were analyzed using logistic regression models. Cox proportional hazard models were applied for incident dementia. Results: Three latent classes differing in neurocognitive and neuropsychiatric impairment were identified (Class 1 “memory impairment only”; Class 2 “global cognitive impairment”; Class 3 “global cognitive and neuropsychiatric impairment”). Compared with Class 1, Class 2 and 3 were associated with smaller brain volumes, moderate-to-severe cortical atrophy and medial temporal lobe atrophy, and the presence of all cerebrovascular lesions. Moreover, compared with Class 2, Class 3 had smaller brain volumes, moderate-to-severe cortical atrophy and presence of intracranial stenosis. Additionally, compared to Class 1, Class 2 (hazard ratio [HR] = 3.84, 95%CI 2.11-7.00), and Class 3 (HR = 6.92, 95%CI 2.84-16.83) showed an increased risk of incident dementia. Conclusions: Participants characterized by multi-domain cognitive impairment and co-occurrence of cognitive and neuropsychiatric impairment showed the highest risk of incident dementia, which may be attributed to both neurodegenerative and cerebrovascular pathologies.
Pages 268-281
Miriana Maria Bressan, Anna Maria Musso, Tommaso Bovi, Bruno Bonetti, Chiara Zucchella (Handling Associate Editor: Ileana De Anda-Duran)
Tele-neuropsychological multidomain assessment in Italian people with cognitive disorders: Reliability and user satisfaction
Abstract: Background: Tele-neuropsychology has already been employed in neurocognitive disorders, however, in Italy, the evidence of its psychometric quality and satisfaction is still limited. Objective: This study aimed to: (1) evaluate the reliability of a standardized battery of neuropsychological screening and domain-specific tests delivered at home via videoconference to a sample of Italian people with cognitive disorders, compared with traditional face-to-face administration; (2) assess the feasibility and satisfaction about remote administration. Methods: This crossover study enrolled patients with subjective cognitive disorder, mild neurocognitive disorder, or dementia. All participants performed a brief neuropsychological screening assessment in face-to-face or remote mode. People with milder cognitive disorders (Mini-Mental State Examination≥20) also performed an extended neuropsychological battery. After 15 days, each participant repeated the same assessment in the opposite mode. Finally, participants completed a satisfaction questionnaire. Results: 114 participants were initially enrolled in the study and 100 individuals performed both face-to-face and remote assessments (14 dropouts). All neuropsychological tests showed agreement between the two modes of administration, except for the Digit Span Forward (p=0.009) and oral-Symbol Digit Modalities Test (p<0.001). According to Lin's concordance correlation coefficient (LCCCs), tests also showed good or excellent reliability (LCCCs between 0.609 and 0.964); only the Digit Span Backward and the Stroop test showed moderate reliability (LCCCs =0.514 – 0.441, respectively). Among 100 participants, 65 patients answered the satisfaction questionnaire, declaring high satisfaction for the remote evaluation. Conclusions: Tele-neuropsychology seems to work with in-home assessments among Italian patients with cognitive disorders and seems to be acceptable to them.
Pages 282-292
Jianying Peng*, Xiaolong Li*, Jie Wang*, Fengping Li, Jianfeng Gao, Yan Deng, Benchao Li, Tingting Li, Yuanyuan Li, Sui Tang, Likang Lu, Peiyang Zhou, Shuang Rong *The authors contributed equally to this work.
Association between plant-based dietary patterns and cognitive function in middle-aged and older residents of China
Abstract: Background: Plant-based diets may protect against cognitive impairment; however, observational data have not been consistent. Objective：This study aimed to evaluate the association between plant-based dietary patterns and cognitive function. Methods: The study recruited 937 participants who were asked to complete food frequency questionnaires to assess the quality of their plant-based diets using the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Cognitive function evaluated using the Montreal Cognitive Assessment (MoCA) test. Logistic regression was used to explore the association between plant-based dietary patterns and the prevalence of mild cognitive impairment (MCI), while multiple linear regression was used to analyze the association between plant-based dietary patterns and cognitive scores. Results: The prevalence of MCI was 26% among the 937 participants. There was a significant association between higher uPDI scores and higher odds of MCI, with Quintile 4 compared with Quintile 1 showing an odds ratio of 2.21 (95% confidence interval 1.35, 3.60). Higher uPDI scores were associated with a lower total MoCA score and poorer performance in various cognitive domains. There were no significant associations between the PDI, the hPDI, and cognitive function. Consuming whole grains, nuts, and eggs once a week or more were associated with a lower risk of MCI, whereas frequently consumption of pickled vegetables was associated with an increased risk of MCI. Conclusions: Unhealthy plant-based diets were associated with cognitive impairment, while whole grains, nuts, and eggs may protect cognitive function; pickled vegetables are associated with cognitive impairment.
Pages 293-304
Haruto Shibata, Yuto Uchida, Hirohito Kan, Keita Sakurai, Yuta Madokoro, Sayaka Iwano, Sunil Kumar Maurya, Ángel Muñoz-González, Ilya Ardakani, Kentaro Yamada, Noriyuki Matsukawa
Deep-learning assessment of hippocampal magnetic susceptibility in Alzheimer’s disease
Abstract: Background: Quantitative susceptibility mapping (QSM) is pivotal for analyzing neurodegenerative diseases. However, accurate hippocampal segmentation remains a challenge. Objective: This study introduces a method for extracting hippocampal magnetic susceptibility values using a convolutional neural network (CNN) model referred to as 3D residual UNET. Methods: The model was pre-trained on whole QSM images and hippocampal segmentations from 3D T1-weighted images of 297 patients with Alzheimer’s disease and mild cognitive impairment. Fine-tuning was conducted through manually annotated hippocampal segmentations from the QSM images of 60 patients. The performance was assessed using the Dice similarity coefficient (DSC) and Pearson correlation coefficient. Results: The developed model was applied to another 98 patients, 49 with AD and 49 with mild cognitive impairment (MCI), and the correlation between the hippocampal magnetic susceptibility and volume was evaluated. The mean DSC for the hippocampal segmentation model was 0.716 ± 0.045. The correlation coefficient between the magnetic susceptibility values derived from manual segmentation and the CNN model was 0.983. The Pearson correlation coefficient between magnetic susceptibility and hippocampal volume from the CNN model was -0.252 (p = 0.012) on the left side and -0.311 (p = 0.002) on the right. Conclusions: The 3D residual UNET model enhances hippocampal analysis precision using QSM, which is capable of accurately extracting magnetic susceptibility.
Pages 305-315
Daniele Imperiale, Cristiana Atzori, Daniele Pio Angeloro, Amelia Murgioni, Alessia Bagatin, Valentina Secci, Andrea Calcagno, Marco Capobianco, Mario Coletti Moja, Eugenia Rota, Maria Roberta Bongioanni, Mara Rosso, Laura Godi, Massimo Barra, Marco De Mattei, Massimo Bonzanino, Delfina Ferrandi, Innocenzo Rainero, Leonardo Lopiano, Marco Bozzali
Real-life reliability of plasma pTau181, Aβ42/Aβ40, and pTau181/Aβ42 measured by Lumipulse G600II in predicting cerebrospinal fluid amyloid status
Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative dementia, with diagnosis traditionally reliant on clinical criteria. Cerebrospinal fluid (CSF) biomarkers like pTau181 and Aβ42/Aβ40 ratio significantly improve diagnostic accuracy but are invasive. Plasma biomarkers measured by automated assays offer a non-invasive alternative. Objective: To evaluate the diagnostic performance of plasma pTau181, Aβ42/Aβ40, and pTau181/Aβ42 ratios in predicting CSF amyloid status in a real-life clinical setting. Methods: Data from consecutive patients whose plasma and CSF samples sent to our laboratory between March and October 2022, were retrospectively analyzed. Plasma and CSF pTau181, Aβ42, and Aβ40 levels were measured using the Lumipulse G600II platform. CSF amyloid status was classified as amyloid-positive (A+) or amyloid-negative (A-) based on the Aβ42/Aβ40 ratio. Statistical analyses included Spearman correlation, receiver operating characteristic (ROC) curves, and multivariate logistic regression to evaluate biomarker performance. Results: Among 165 individuals (83 females), 29.1% were classified as A+. Significant correlations were found between plasma and CSF biomarkers, with the highest for the pTau181/Aβ42 ratio (ρ=0.620, p<0.0001). ROC analysis showed the pTau181/Aβ42 ratio had the highest diagnostic performance (AUC 0.818), followed by pTau181 (AUC 0.794) and Aβ42/Aβ40 (AUC 0.775). Combining plasma biomarkers in age-adjusted models improved diagnostic accuracy (AUC up to 0.846). Conclusions: Plasma biomarkers measured by the Lumipulse G600II platform show strong potential in predicting CSF amyloid status and possibly reduces the need for lumbar punctures. These findings support the potential use of plasma assays in the early diagnosis of AD. Anyway, further validations in larger multicenter cohorts are mandatory.
