Volume 86, Number 2, IN PROGRESS

Review
Roos J. Jutten*, Louisa Thompson*, Sietske A.M. Sikkes, Paul Maruff, José Luis Molinuevo, Henrik Zetterberg, Jessica Alber, David Faust, Serge Gauthier, Michael Gold, John Harrison, Athene K.W. Lee, Peter J. Snyder (Handling Associate Editor: Katherine Gifford) *These authors contributed equally to this work.
A Neuropsychological Perspective on Defining Cognitive Impairment in the Clinical Study of Alzheimer’s Disease: Towards a More Continuous Approach
Abstract: The global fight against Alzheimer’s disease (AD) poses unique challenges for the field of neuropsychology. Along with the increased focus on early detection of AD pathophysiology, characterizing the earliest clinical stage of the disease has become a priority. We believe this is an important time for neuropsychology to consider how our approach to the characterization of cognitive impairment can be improved to detect subtle cognitive changes during early-stage AD. The present article aims to provide a critical examination of how we define and measure cognitive status in the context of aging and AD. First, we discuss pitfalls of current methods for defining cognitive impairment within the context of research shifting to earlier (pre)symptomatic disease stages. Next, we introduce a shift towards a more continuous approach for identifying early markers of cognitive decline and characterizing progression and discuss how this may be facilitated by novel assessment approaches. Finally, we summarize potential implications and challenges of characterizing cognitive status using a continuous approach.

Short Communication
Alexandre Morin, Thibaut Pressat-Laffouilhere, Marie Sarazin, Julien Lagarde, Carole Roue-Jagot, Pauline Olivieri, Claire Paquet, Emmanuel Cognat, Julien Dumurgier, Florence Pasquier, Thibaut Lebouvier, Matthieu Ceccaldi, Olivier Godefroy, Olivier Martinaud, Julien Grosjean, Aline Zarea, David Maltête, David Wallon
Telemedicine in French Memory Clinics During the COVID-19 Pandemic
Abstract: This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March-May 2020). The objective was to evaluate the effect of a telemedicine consultation on treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer’s disease. A control group of patients referred March-May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of -4% (p=0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.

Short Communication
Noreen Khan, Nelda Garcia, Roshanak Mehdipanah, Emily M. Briceño, Steven G. Heeringa, Deborah A. Levine, Xavier F. Gonzales, Kenneth M. Langa, Ruth Longoria, Lewis B. Morgenstern
Lack of Any Caregiving for Those with Dementia
Abstract:Older adults with significant cognitive impairment require help with activities of daily living. The BASIC-Cognitive Project, set in Nueces County, Texas, is a community-based study examining trends in cognition among Mexican Americans and non-Hispanic Whites. Using cross-sectional data from a cohort study, we found that at least 7% of individuals aged 65 and older with a Montreal Cognitive Assessment (MoCA) score of < 20 (or < 15 for telephone MoCA), did not receive any caregiving help. This conservative estimate highlights an important community need for those with significant cognitive impairment and has implications regarding safety and care for older adults.

Zhiyuan Yang, Xiaoning Sheng, Ruomeng Qin, Haifeng Chen, Pengfei Shao, Hengheng Xu, Weina Yao, Hui Zhao, Yun Xu, Feng Bai
Cognitive Improvement via Left Angular Gyrus-Navigated Repetitive Transcranial Magnetic Stimulation Inducing the Neuroplasticity of Thalamic System in Amnesic Mild Cognitive Impairment Patients
Abstract: Background: Stimulating superficial brain regions highly associated with the hippocampus by repetitive transcranial magnetic stimulation (rTMS) may improve memory of Alzheimer’s disease (AD) spectrum patients. Objective: We recruited 16 amnesic mild cognitive impairment (aMCI) and 6 AD patients in the study. All the patients were stimulated to the left angular gyrus, which was confirmed a strong link to the hippocampus through neuroimaging studies, by the neuro-navigated rTMS for four weeks. Methods: Automated fiber quantification using diffusion tensor imaging metrics and graph theory analysis on functional network were employed to detect the neuroplasticity of brain networks. Results: After neuro-navigated rTMS intervention, the episodic memory of aMCI patients and Montreal Cognitive Assessment score of two groups were significantly improved. Increased FA values of right anterior thalamic radiation among aMCI patients, while decreased functional network properties of thalamus subregions were observed, whereas similar changes not found in AD patients. It is worth noting that the improvement of cognition was associated with the neuroplasticity of thalamic system. Conclusion: We speculated that the rTMS intervention targeting left angular gyrus may be served as a strategy to improve cognitive impairment at the early stage of AD patients, supporting by the neuroplasticity of thalamic system.

Yoo Hyun Um, Sheng-Min Wang, Dong Woo Kang, Nak-Young Kim, Hyun Kook Lim
Subcortical and Cerebellar Neural Correlates of Prodromal Alzheimer’s Disease with Prolonged Sleep Latency
Abstract: Background: Despite the important associations among sleep, Alzheimer’s disease (AD), subcortical structures, and the cerebellum, structural and functional magnetic resonance imaging (MRI) with regard to these regions and sleep on patients in AD trajectory are scarce. Objective: This study aimed to evaluate the influence of prolonged sleep latency on the structural and functional alterations in the subcortical and cerebellar neural correlates in amyloid-β positive amnestic mild cognitive impairment patients (Aβ+aMCI). Methods: A total of 60 patients with aMCI who were identified as amyloid positive ([18F] flutemetamol +) were recruited in the study, 24 patients with normal sleep latency (aMCI-n) and 36 patients prolonged sleep latency (aMCI-p). Cortical thickness and volumes between the two groups were compared. Volumetric analyses were implemented on the brainstem, thalamus, and hippocampus. Subcortical and cerebellar resting state functional connectivity (FC) differences were measured between the both groups through seed-to-voxel analysis. Additionally, group x Aβ interactive effects on FC values were tested with a general linear model. Result: There was a significantly decreased brainstem volume in aMCI-p subjects. We observed a significant reduction of the locus coeruleus (LC) FC with frontal, temporal, insular cortices, hippocampus, and left thalamic FC with occipital cortex. Moreover, the LC FC with occipital cortex and left hippocampal FC with frontal cortex were increased in aMCI-p subjects. In addition, there was a statistically significant group by regional standardized uptake value ratio interactions discovered in cerebro-cerebellar networks. Conclusion: The aforementioned findings suggest that prolonged sleep latency may be a detrimental factor in compromising structural and functional correlates of subcortical structures and the cerebellum, which may accelerate AD pathophysiology.

Knut Engedal, Linda Gjøra, Jūratė Šaltytė Benth, Jørgen Wagle, Thale Kinne Rønqvist, Geir Selbæk (Handling Associate Editor: Anne Fink)
The Montreal Cognitive Assessment: Normative Data from a Large, Population-Based Sample of Cognitive Healthy Older Adults in Norway—The HUNT Study
Abstract: Background: Several studies have found that normative scores on the Montreal Cognitive Assessment Scale (MoCA) vary depending on the person’s education and age. The evidence for different normative scores between sexes is poor. Objective: The main aim of the study was to determine normative scores on the MoCA for Norwegian older adults stratified by educational level, age, and sex. In addition, we aimed to explore sex differences in greater detail. Methods: From two population-based studies in Norway, we included 4,780 people age 70 years and older. People with a diagnosis of dementia or mild cognitive impairment, a history of stroke, and depression were excluded. Trained health personnel tested the participants with the MoCA. Results: The mean MoCA score varied between 22 and 27 and was highest among women 70–74 years with education >13 years and lowest among men age 85 and older with education 10 years. Education, age, and sex were significant predictors of MoCA scores. Conclusion: In the present study of cognitively healthy Norwegian adults 70 years and older, we found that the normative score on the MoCA varied between 22 and 27 depending on a person’s education, age, and sex. We suggest that normative scores should be determined taking these three variables into consideration.

Lan Gao*, Dieu Nguyen*, Marj Moodie *These authors contributed equally to this work.
Economic Burden of Dementia Caused by Cardiovascular Disease in Australia
Abstract: Background: The established link between cardiovascular disease (CVD) and dementia may provide new insights into dementia prevention. Objective: It aims to quantify the burden of dementia attributable to people with CVD. Methods: A Markov microsimulation model was developed to simulate the lifetime cost and quality-adjusted life-years (QALYs) related to people with and without CVD in Australia. A de-novo systematic review was undertaken to identify all evidence around the association between CVD [i.e., stroke, myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF)] and the risk of developing dementia. Incremental costs and QALY losses were estimated for people by type of CVD compared to the general Australian population without CVD. Results: Of the comprehensive literature search, 19 observational studies were included in the qualitative synthesis. Patients who had CVD incurred both higher healthcare costs over their lifetime (ranging from $73,131 for patients with AF to $127,396 for patients with HF) and fewer QALYs gains (from -1.099 for patients with MI to -5.163 for patients with stroke), compared to people who did not have CVD. The total incremental economic burden of dementia from patients aged 65 years and over with CVD was $6.45 billion (stroke), $11.89 billion (AF), $17.57 billion (MI), or $7.95 billion (HF) over their remaining life expectancy. Conclusion: The results highlighted the importance of CVD prevention to reduce the CVD burden and decrease the prevalence of dementia. Interventions that target patients with dementia risk factors like CVD may prove to be effective and cost-effective strategies.

Wen-Yih Isaac Tseng*, Yung-Chin Hsu*, Te-Wei Kao *These authors contributed equally to this work.
Brain Age Difference at Baseline Predicts Clinical Dementia Rating Change in Approximately Two Years
Abstract: Background: The Clinical Dementia Rating (CDR) has been widely used to assess dementia severity, but it is limited in predicting dementia progression, thus unable to advise preventive measures to those who are at high risk. Objective: Predicted age difference (PAD) was proposed to predict CDR change. Methods: All diffusion magnetic resonance imaging and CDR scores were obtained from the OASIS-3 databank. A brain age model was trained by a machine learning algorithm using the imaging data of 258 cognitively healthy adults. Two diffusion indices, i.e., mean diffusivity and fractional anisotropy, over the whole brain white matter were extracted to serve as the features for model training. The validated brain age model was applied to a longitudinal cohort of 217 participants who had CDR = 0 (CDR0), 0.5 (CDR0.5), and 1 (CDR1) at baseline. Participants were grouped according to different baseline CDR and their subsequent CDR in approximately 2 years of follow-up. PAD was compared between different groups with multiple comparison correction. Results: PADs were significantly different among participants with different baseline CDRs. PAD in participants with relatively stable CDR0.5 was significantly smaller than PAD in participants who had CDR0.5 at baseline but converted to CDR1 in the follow-up. Similarly, participants with relatively stable CDR0 had significantly smaller PAD than those who were CDR0 at baseline but converted to CDR0.5 in the follow-up. Conclusion: Our results imply that PAD might be a potential imaging biomarker for predicting CDR outcomes in patients with CDR0 or CDR0.5.

Seon Young Park, Jiyeon Han, Seon Hwa Kim, Hye Won Suk, Jee Eun Park, Dong Young Lee
Impact of Long-Term Exposure to Air Pollution on Cognitive Decline in Older Adults Without Dementia
Abstract: Background: Air pollution control is necessary to decrease the burden on older adults with cognitive impairment, especially in low- and middle-income countries (LMICs). Objective: This study retrospectively examined the effect of cumulative exposure to air pollution, including NO2, SO2, CO, fine particulate matter (PM)10, PM2.5, and O3, on cognitive function in older individuals. Methods: Community-dwelling older adults who underwent the Mini-Mental State Examination (MMSE) from 2007 to 2018 were included in the analyses. We excluded older individuals diagnosed with dementia at baseline, while those who had completed more than two MMSE tests were included in the longitudinal analyses. Baseline MMSE and changes in MMSE scores were analyzed according to 5-year average concentrations of the district-level air pollutants, after controlling for covariates associated with cognitive decline in older adults. Results: In total, 884,053 (74.3 ± 7.1 years; 64.1% females) and 398,889 (72.3 ± 6.4 years; 67.0% females) older individuals were included in the cross-sectional and longitudinal analyses, respectively. Older individuals exposed to higher levels of NO2, SO2, CO, and PM10 showed lower baseline MMSE scores. During follow-up, exposure to higher levels of NO2, SO2, CO, and PM10 was associated with greater decreases in MMSE scores in older individuals; for O3, the opposite pattern was observed. Conclusion: Our findings suggest that exposure to high levels of air pollutants can worsen the cognitive performance of older adults without dementia. Efforts to reduce air pollution in LMICs that have similar levels of pollutants to South Korea are necessary to reduce the burden on older adults with cognitive impairment.

Alberto Benussi*, Andrea Pilotto*, Valentina Cantoni, Elisabetta Ferrari, Barbara Borroni, Alessandro Padovani *These authors contributed equally to this work.
Neurophysiological Correlates of Motor and Cognitive Dysfunction in Prodromal and Overt Dementia with Lewy Bodies
Abstract: Background: The neurophysiological correlates of cognitive and motor symptoms in prodromal and overt dementia with Lewy bodies (DLB) are still to be elucidated. Objective: To evaluate if cognitive and motor features of patients with prodromal and overt DLB are associated with the impairment of specific neurotransmitter circuits, evaluated in vivo with transcranial magnetic stimulation (TMS). Methods: Fifty-one patients with DLB (twenty-five prodromal; twenty-six with dementia) underwent neuropsychological and clinical evaluation, with twenty-five patients having at least one follow-up evaluation. All patients were assessed with TMS at baseline, with protocols assessing cholinergic circuits (short latency afferent inhibition, SAI), GABAergic circuits (short interval intracortical inhibition, SICI), and glutamatergic circuits (intracortical facilitation, ICF). Results: Compared to HC, SICI, ICF, and SAI resulted significantly impaired in both prodromal and overt DLB, with the latter showing a reduced SICI and SAI also compared to prodromal DLB. There was a significant correlation between motor deficits, evaluated with the UPDRS-III, and the impairment of GABAergic (SICI) (r=0.729, p < 0.001) and glutamatergic (ICF) (r-0.608, p < 0.001) circuits; global cognition, evaluated with the Mini-Mental State Examination, correlated with the impairment of cholinergic (SAI) circuits (r=−0.738, p < 0.001). Worsening of cognitive functions at follow-up was associated with reduced cholinergic functions at baseline (R2=0.53%, p < 0.001). Conclusion: These results suggest that motor and cognitive dysfunctions in prodromal and overt DLB depend on specific and independent neurotransmitter circuits.

Sandra Cardoso, Dina Silva, Luísa Alves, Manuela Guerreiro, Alexandre de Mendonça
The Outcome of Patients with Amyloid-Negative Amnestic Mild Cognitive Impairment
Abstract: Background: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer’s disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear. Objective: To know the etiology and prognosis of amyloid-negative aMCI. Methods: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments. Results: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease. Conclusion: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised.

Els D. Bakker, Ingrid S. van Maurik, Arenda Mank, Marissa D. Zwan, Lisa Waterink, Susanne van den Buuse, Jennifer R. van den Broeke, Freek Gillissen, Marleen van de Beek, Evelien Lemstra, Karlijn A. van den Bosch, Mardou van Leeuwenstijn, Femke H. Bouwman, Philip Scheltens, Wiesje M. van der Flier
Psychosocial Effects of COVID-19 Measures on (Pre-)Dementia Patients During Second Lockdown
Abstract: Background: The COVID-19 pandemic poses enormous social challenges, especially during lockdown. People with cognitive decline and their caregivers are particularly at risk of lockdown consequences. Objective: To investigate psychosocial effects in (pre-)dementia patients and caregivers during second lockdown and compare effects between first and second lockdown. Methods: We included n=511 (pre-)dementia patients and n=826 caregivers from the Amsterdam Dementia Cohort and via Alzheimer Nederland. All respondents completed a self-designed survey on psychosocial effects of COVID-19. We examined relations between experienced support and psychosocial and behavioral symptoms using logistic regression. In a subset of patients and caregivers we compared responses between first and second lockdown using generalized estimating equation. Results: The majority of patients (≥58%) and caregivers (≥60%) reported that family and friends, hobbies, and music helped them cope. Support from family and friends was strongly related to less negative feelings in patients (loneliness: OR=0.3[0.1-0.6]) and caregivers (loneliness: OR=0.2[0.1-0.3]; depression: OR=0.4[0.2-0.5]; anxiety: OR=0.4[0.3-0.6]; uncertainty: OR=0.3[0.2-0.5]; fatigue: OR=0.3[0.2-0.4]; stress: OR=0.3[0.2-0.5]). In second lockdown, less psychosocial and behavioral symptoms were reported compared to first lockdown (patients; e.g., anxiety: 22% versus 13%, p=0.007; apathy: 27% versus 8%, p<0.001, caregivers; e.g., anxiety: 23% versus 16%, p=0.033; patient’s behavioral problems: 50% versus 35%, p<0.001). Patients experienced more support (e.g., family and friends: 52% versus 93%, p<0.001; neighbors: 28% versus 66%, p<0.001). Conclusion: During second lockdown, patients and caregivers adapted to challenges posed by lockdown, as psychosocial and behavioral effects decreased, while patients experienced more social support compared to first lockdown. Support from family and friends is a major protective factor for negative outcomes in patients and caregivers.

Kelly Ceyzériat, Benjamin B. Tournier, Philippe Millet, Giovanna Dipasquale, Nikolaos Koutsouvelis, Giovanni B. Frisoni, Valentina Garibotto, Thomas Zilli
Low-Dose Radiation Therapy Reduces Amyloid Load in Young 3xTg-AD Mice
Abstract: Background: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer’s disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood. Objective: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated. Methods: The whole brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA. Results: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aβ42 aggregated forms (-71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed. Conclusion: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies.

Alissa Bernstein Sideman, Rachel Chalmer, Emmeline Ayers, Richard Gershon, Joe Verghese, Michael Wolf, Asif Ansari, Marina Arvanitis, Nhat Bui, Pei Chen, Anna Chodos, Roderick Corriveau, Laura Curtis, Amy R. Ehrlich, Sarah E. Tomaszewski Farias, Collette Goode, Laura Hill-Sakurai, Cindy J. Nowinski, Mukund Premkumar, Katherine P. Rankin, Christine S. Ritchie, Elena Tsoy, Erica Weiss, Katherine L. Possin
Lessons from Detecting Cognitive Impairment Including Dementia (DetectCID) in Primary Care
Abstract: Background: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up. Objective: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation. Methods: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis. Results: We identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations. Conclusion: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

Sungyang Jo*, E-Nae Cheong*, Nayoung Kim, Jungsu S. Oh, Woo Hyun Shim, Hyung-Ji Kim, Sun Ju Lee, Yoojin Lee, Minyoung Oh, Jae Seung Kim, Bum Joon Kim, Jee Hoon Roh, Sang Joon Kim, Jae-Hong Lee (Handling Associate Editor: Yi-Cheng Zhu) *These authors contributed equally to this work.
Role of White Matter Abnormalities in the Relationship Between Microbleed Burden and Cognitive Impairment in Cerebral Amyloid Angiopathy
Abstract: Background: Cerebral amyloid angiopathy (CAA) often presents as cognitive impairment, but the mechanism of cognitive decline is unclear. Recent studies showed that number of microbleeds were associated with cognitive decline. Objective: We aimed to investigate how microbleeds contribute to cognitive impairment in association with white matter tract abnormalities or cortical thickness in CAA. Methods: This retrospective comparative study involved patients with probable CAA according to the Boston criteria (Aβ+ CAA) and patients with Alzheimer’s disease (Aβ+ AD), all of whom showed severe amyloid deposition on amyloid PET. Using mediation analysis, we investigated how FA or cortical thickness mediates the correlation between the number of lobar microbleeds and cognition. Results: We analyzed 30 patients with Aβ+ CAA (age 72.2 ± 7.6, female 53.3%) and 30 patients with Aβ+ AD (age 71.5 ± 7.6, female 53.3%). The two groups showed similar degrees of cortical amyloid deposition in AD-related regions. The Aβ+ CAA group had significantly lower FA values in the clusters of the posterior area than did the Aβ+ AD group (family-wise error-corrected p<0.05). The correlation between the number of lobar microbleeds and visuospatial function was indirectly mediated by white matter tract abnormality of right posterior thalamic radiation (PTR) and tapetum, while lobar microbleeds and language function was indirectly mediated by the abnormality of left PTR and sagittal stratum. Cortical thickness did not mediate the association between lobar microbleeds and cognition. Conclusion: This result supports the hypothesis that microbleeds burden leads to white matter tract damage and subsequent cognitive decline in CAA.

Wan-Ting Chen, Nai-Fang Chi, Hao-Min Cheng, Yu-Ting Ko, Shao-Yuan Chuang, Wen-Harn Pan, Chen-Huan Chen, Chih-Ping Chung, Pei-Ning Wang
Associations Between Cerebral Vasoreactivity and Cognitive Function in the Middle-Aged Non-Demented Population
Abstract: Background: Increasing evidence shows early vascular dysregulation in the pathophysiology of Alzheimer’s disease (AD) in elderly population. Objective: We wondered about the relationship between vascular health and cognitive performance in middle-aged adults. The present study aims to evaluate whether and which brain vascular hemodynamic parameters are associated with cognitive functions in a middle-aged, non-demented population. Methods: We recruited 490 middle-aged community-based participants (30–60 years). Transcranial color-coded sonography was used to measure cerebral vascular hemodynamics, including mean flow velocity, pulsatility index, and breath-holding index (BHI) in the middle cerebral arteries (MCAs). Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA). A multivariate linear regression model was used to determine the association between the MoCA scores and each intracranial hemodynamic parameter. Results: In 369 participants (median age 52 years [IQR 47-56], 48.8% men) with robust acoustic windows, the factors related to poorer MoCA scores were older age, less education extent, and the habitats of cigarette smoking or alcohol consumption. Multivariate analyses did not show a significant association between any intracranial hemodynamic parameters in both MCAs and MoCA scores in the total study population. Left MCA BHI was found to be significantly and independently correlated with the MoCA scores only in people aged 55–60 years (n=111, B=0.70, 95% confidence interval, 0.13–1.26, p=0.017), however, not in people younger than 55 years. Conclusion: Our results emphasize the role of neurovascular abnormalities in the early pathophysiology of cognitive impairment and suggest cerebral vasoreactivity as the earliest detectable cognition-associated hemodynamic parameter.

Ling Ni* Wenshan Sun*, Dan Yang, Lili Huang, Pengfei Shao, Chong Wang, Yun Xu *These authors contributed equally to this work.
The Cerebrovascular Reactivity-Adjusted Spontaneous Brain Activity Abnormalities in White Matter Hyperintensities Related Cognitive Impairment: A Resting-State Functional MRI Study
Abstract: Background: The BOLD signal is regulated by neuronal activity and vascular physiology. The evolution pattern of brain activities after modulating the vascular factors in white matter hyperintensities (WMHs) related cognitive impairment (CI) was unknown. Objective: To explore the “pure” low-frequency fluctuation (ALFF) alterations after adjusting the cerebrovascular reactivity (CVR) factor. Methods: In this study, 111 WMHs subjects including 55 with CI (WMH-CI) and 56 without CI (WMH-no-CI), and 72 normal controls (NCs) underwent resting-state fMRI. The CVR and ALFF maps were derived using BOLD data. A voxel-wise Pearson analysis was performed to detect the relationship between CVR and ALFF maps. The ANCOVA analysis with and without CVR as a covariate was conducted to explore the effect of CVR on ALFF analysis. Correlation between the ALFF alterations and cognitive performance was conducted in WMH-CI subjects. The receiver operating characteristic curve was constructed to assess the diagnostic performance of ALFF indexes to determine the occurrence of CI. Results: There was a significant widespread correlation between the CVR and ALFF maps. The ALFF alterations between the WMH groups and NC group with CVR as covariate were more than those without CVR as covariate. WMH-CI subjects showed further ALFF alterations when compared with WMH-no-CI subjects. The abnormal ALFF values were significantly associated with poor performance. The combination of inferior frontal gyrus and middle frontal gyrus to PCC provided an incremental contribution to the occurrence of CI. Conclusion: More areas with abnormal ALFF values which were specific to the WMHs related cognitive dysfunction were detected when considering the impact of CVR.

Jens Bohlken, Oliver Peters, Karel Kostev
Association Between Ginkgo biloba Extract Prescriptions and dementia Incidence in Outpatients with Mild Cognitive Impairment in Germany: A Retrospective Cohort Study
Abstract: Background: Clinical trials have demonstrated a significant effectiveness of Ginkgo biloba therapy versus placebo in patients with dementia. Objective: The present study aims to analyze the impact of Ginkgo biloba drug prescriptions on dementia incidence in patients with mild cognitive impairment (MCI) in a real-world setting. Methods: This retrospective study was based on the IQVIA Disease Analyzer database and included patients aged 65 or older with a first diagnosis of MCI from January 2000 to December 2019. Each patient was followed for up to 20 years after MCI diagnosis until February 2021. Date of the first diagnosis of dementia or loss to follow-up, whichever occurred first, was noted. To estimate the association between Ginkgo biloba prescriptions during the follow-up and dementia incidence, a multivariable Cox regression analysis was performed, adjusted for age, sex, health insurance, documented co-diagnoses, and prescription of cholinesterase inhibitors. Results: Overall, 24,483 MCI patients (mean age: 77.0 years, 56.3% women) were included. It was found that >2 prescriptions of Ginkgo biloba were significantly associated with a reduced dementia incidence (HR: 0.71 (95% CI: 0.55–0.91), p=0.007), as compared with no Ginkgo biloba prescription. The effect of receiving >3 Ginkgo biloba prescriptions was even stronger, with an HR of 0.64 (95% CI: 0.48–0.86), p=0.003), while for >4 prescriptions the HR was 0.58 (95% CI: 0.41–0.82) (p=0.002). Conclusion: All-cause dementia incidence decreased with higher numbers of Ginkgo biloba prescriptions in MCI patients.

Angie A. Diaz Baquero, Manuel A. Franco-Martín, Esther Parra Vidales, José Miguel Toribio-Guzmán, Yolanda Bueno-Aguado, Fernando Martínez Abad, María V. Perea Bartolomé, Aysan Mahmoudi Asl, Henriëtte G. van der Roest
The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment
Abstract: Background: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia. Objective: The objective was to evaluate the effectiveness of the cognitive rehabilitation program “GRADIOR” in people with mild cognitive impairment and mild dementia. Method: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0: baseline, T1: at 4 months, T2: at 12 months were compared within and between-groups. Results: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage's Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between “time and group” for MMSE (F=8.971; p=0.03; η2=0.019) and the GDS (F=3.414; p=0.04; η2=0.041), as well as small effect sizes for TMT-A-time (F=1.641; p=0.21; η2=0.021) and TMT-A-mistakes (F=0.908; p=0.41; η2=0.019). Conclusion: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788).

Min-Chien Tu, Hsiao-Wen Chung, Yen-Hsuan Hsu, Jir-Jei Yang, Wen-Chau Wu
Stage-Dependent Cerebral Blood Flow and Leukoaraiosis Couplings in Subcortical Ischemic Vascular Disease and Alzheimer's Disease
Abstract: Background: Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD) have both been associated with white matter hyperintensities (WMHs) and altered cerebral blood flow (CBF) although the etiology of AD is still unclear. Objective: To test the hypothesis that CBF and WMHs have differential effects on cognition and that the relationship between CBF and WMHs changes with the subtypes and stages of dementia. Methods: Forty-two patients with SIVD, 50 patients with clinically-diagnosed AD, and 30 cognitively-normal subjects were included. Based on the Clinical Dementia Rating (CDR), the patients were dichotomized into early-stage (CDR = 0.5) and late-stage (CDR = 1 or 2) groups. CBF and WMH metrics were derived from magnetic resonance imaging and correlated with cognition. Results: Hierarchical linear regression revealed that CBF metrics had distinct contribution to global cognition, memory, and attention, whereas WMH metrics had distinct contribution to executive function (all p < 0.05). In SIVD, the WMHs in frontotemporal areas correlated with the CBF in bilateral thalami at the early stage; the correlation then became between the WMHs in basal ganglia and the CBF in frontotemporal areas at the late stage. A similar corticosubcortical coupling was observed in AD but involved fewer areas. Conclusion: A stage-dependent coupling between CBF and WMHs was identified in AD and SIVD, where the extent of cortical WMHs correlated with subcortical CBF for CDR = 0.5, whereas the extent of subcortical WMHs correlated with cortical CBF for CDR = 1-2.

Zili Zhu, Qingze Zeng, Ruiting Zhang, Xiao Luo, Kaicheng Li, Xiaopei Xu, Minming Zhang, Yunjun Yang, Peiyu Huang, for the Alzheimer’s Disease Neuroimaging Initiative
White Matter Free Water Outperforms Cerebral Small Vessel Disease Total Score in Predicting Cognitive Decline in Persons with Mild Cognitive Impairment
Abstract: Background: Vascular pathology is an important partner of Alzheimer’s disease (AD). Both total cerebral small vessel disease (CSVD) score and white matter free water (FW) are useful markers that could reflect cerebral vascular injury. Objective: We aim to investigate the efficacy of these two metrics in predicting cognitive declines in patients with mild cognitive impairment (MCI). Methods: We enrolled 126 MCI subjects with 3D T1-weighted images, fluid-attenuated inversion recovery images, T2* images, diffusion tensor imaging images, cerebrospinal fluid biomarkers and neuropsychological tests from the Alzheimer’s Disease Neuroimaging Initiative database. The total CSVD score and FW values were calculated. Simple and multiple linear regression analyses were applied to explore the association between vascular and cognitive impairments. Linear mixed effect models were constructed to investigate the efficacy of total CSVD score and FW on predicting cognitive decline. Results: FW was associated with baseline cognition and could predict the decline of executive and language functions in MCI subjects, while no association was found between total CSVD score and cognitive declines. Conclusion: FW is a promising imaging marker for investigating the effect of CSVD on AD progression.

Yen-Hsuan Hsu, Sheng-Min Huang, Shih-Yeh Lin, Jir-Jei Yang, Min-Chien Tu, Li-Wei Kuo
Prospective Memory and Default Mode Network Functional Connectivity in Normal and Pathological Aging
Abstract: Background: Prospective memory (PM), the ability to execute a previously formed intention given the proper circumstance, has been proven to be vulnerable to Alzheimer’s disease. Previous studies have indicated the involvement of the frontoparietal networks; however, it is proposed that PM may also be associated with other neural substrates that support stimulus-dependent spontaneous cognition. Objective: The present study aimed to examine the hypothesis that PM deficit in Alzheimer’s disease is related to altered functional connectivity (FC) within the default mode network (DMN). Methods: Thirty-four patients with very mild or mild dementia (17 with Alzheimer’s disease and 17 with subcortical ischemic vascular disease) and 22 cognitively-normal participants aged above 60 received a computerized PM task and resting-state functional magnetic resonance imaging study. Seed-based functional connectivity analysis was performed at group level within the DMN. Results: We found that the dementia groups showed worse PM performance and altered FC within the DMN as compared to the normal aging individuals. The FC between the medial prefrontal cortices and precuneus/posterior cingulate cortex was significantly correlated with PM in normal aging, while the FC between the right precuneus and bilateral inferior parietal lobules was correlated with PM in patients with Alzheimer’s disease. Conclusion: These findings support a potential role for the DMN in PM, and corroborate that PM deficit in Alzheimer’s disease was associated with altered FC within the posterior hubs of the DMN, with spatial patterning different from normal aging.

Martina Assogna, Caterina Motta, Sonia Bonnì, Ilaria Borghi, Elias P. Casula, Alessandro Martorana, Giacomo Koch (Handling Associate Editor: Marco Bozzali)
Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer’s Disease Patients
Abstract: Background: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer’s disease (AD) patients. Objective: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) classification and APOE genotype. Methods: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of Aβ amyloid deposition (A) and fibrillar tau (T), in four groups: A+/T– E4 (n=9), A+/T– E3 (n=18), A+/T+ E4 (n=21), and A+/T+ E3 (n=17). We applied intermittent theta burst stimulation over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination scores respect to the baseline. Results: A+/T- E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T- E3 and to A+/T+ patients independently from genotype (p<0.001). In addition, A+/T- E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (-0.5±2.12 versus -6.05±4.95; post-hoc p=0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p=0.028). No differences were found for SAI protocol (p>0.05). Conclusion: Our results suggest that APOE4 in patients with isolated amyloid pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Yuchao Dou*, Shuai Liu*, Yuqing Li, Hao Wu, Hui Chen, Yong Ji *These authors contributed equally to this work.
Plasma Cholesterol Levels as Potential Nutritional Biomarkers for Lewy Body Dementia
Abstract: Background: The relationship between cholesterol level and the risk of developing Alzheimer’s disease has been well established, but the relationship between cholesterol level and Lewy body dementia (LBD) is still not well known. Objective: The aim of this case-control study was to explore the association between blood cholesterol levels and LBD in Chinese older adults. Methods: A total of 65 patients with LBD and 110 older adult controls were enrolled during the study period. The levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were measured separately. The associations between LBD, blood cholesterol levels, and fasting glucose levels were assessed using multiple binary logistic regression analyses adjusted for multiple covariates. Results: Increased plasma LDL-C levels and lower HDL-C levels were independently associated with the risk of LBD in models adjusted for age, sex, education, alcohol use status, smoking status, and vascular disorders. Higher fasting glucose levels may be associated with the risk of LBD. Conclusion: The results of this study suggest that elevated levels of LDL-C and reduced levels of HDL-C were associated with LBD development and therefore are potential nutritional risk factors for LBD. Adjusting diet and individualized and effective cholesterol-lowering therapy in high-risk adults may aid in the prevention or management of LBD.

Milap A. Nowrangi, John D. Outen, Farah Naaz, Liuyi Chen, Arnold Bakker, Cynthia A. Munro, Vidyulata Kamath, George W. Rebok, Paul B. Rosenberg
Altered Angular Gyrus Resting State Functional Connectivity Associated with Financial Capacity in Mild Cognitive Impairment
Abstract: Background: Financial capacity (FC) is a complex ability commonly impaired in older individuals with cognitive impairment; however, the underlying neural mechanisms are not well understood. Objective: To assess resting state functional connectivity using functional magnetic resonance imaging (rs-fMRI) in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal older adults. Methods: rs-fMRI scans were obtained from individuals with MCI (N=17) and normal older adults (N=15). All participants completed the Financial Capacity Instrument Short Form (FCI-SF) and neuropsychological assessments. Based on previous findings, the left angular gyrus (lAG) was used as the seed region. Connectivity correlation coefficients were calculated for each seed-based connection that showed significantly altered connectivity. A Pearson’s correlation was calculated between the connectivity correlation values from relevant regions and FC and other cognitive measures. Results: A total of 26 brain regions showed significantly increased functional connectivity with the lAG. Of these regions, 14 were identified as relevant to higher-level cognitive function for analysis. Pearson’s correlations showed a significant negative correlation between the FCI-SF total score and increased connectivity between the IAG and the right temporal fusiform cortex (rTFC) (r = -0.455, p = 0.009). Conclusion: Results showed a significant correlation between FC and increased functional connectivity between the lAG and the rTFC in cognitively normal older adults compared to participants with MCI. These exploratory findings suggest that cognitive functions play important roles in FC as the functional connectivity between the lAG and rTFC was not associated with other tests of executive or visuospatial cognition.

Adi Shafir, Christine S. Ritchie, Sarah B. Garrett, Alissa Bernstein Sideman, Georges Naasan, Jennifer Merrilees, Eric Widera, Lynn Flint, Krista L. Harrison
“Captive by the Uncertainty”—Experiences with Anticipatory Guidance for People Living with Dementia and Their Caregivers at a Specialty Dementia Clinic
Abstract: Background: After a diagnosis of Alzheimer’s disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic. Objective: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic. Methods: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance. Results: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n=6/9); caregivers had a mean age of 67 and were primarily female (n=21/31). Participants felt they received incomplete or “hesitant” guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources. Conclusion: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision.