Volume 70, Number 2, 2019

Pages 315-320

Asangaedem Akpan, Maturin Tabue-Teguo, Bertrand Fougère
Neurocognitive Disorders: Importance of Early/Timely Detection in Daily Clinical Practice
Abstract: Neurocognitive disorders create important challenges for patients, their families, and clinicians who provide their health care. Early/timely detection in daily clinical practice allows for diagnosis and adequate treatment, psychosocial support, education, and engagement in shared decision-making related to health care, life planning, involvement in research, and financial matters. However, neurocognitive disorders, when present, are not detected or not diagnosed and not documented, in more than half of patients seen by primary care physicians. The aim of this paper is to highlight the strategies and the perspectives to improve the early/timely detection of neurocognitive disorders in daily clinical practice.

Pages 321-339

Youssef H. El-Hayek, Ryan E. Wiley, Charles P. Khoury, Ritesh P. Daya, Clive Ballard, Alison R. Evans, Michael Karran, José Luis Molinuevo, Matthew Norton, Alireza Atri
Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer’s Disease and Related Dementias and Strategic Implications for Stakeholders
Abstract: While it is generally understood that Alzheimer’s disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

Pages 341-358

Lilian Calderón-Garcidueñas, Angélica González-Maciel, Randy J. Kulesza, Luis Oscar González-González, Rafael Reynoso-Robles, Partha S. Mukherjee, Ricardo Torres-Jardón
Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer’s Disease in Urban Children and Young Adults
Abstract: Exposures to fine particulate matter (PM2.5) and ozone (O3) ≥ US EPA standards are associated with Alzheimer’s disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ε4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations.

Pages 359-368
Dominik Wolf, Florian U. Fischer, Andreas Fellgiebel, for the Alzheimer’s Disease Neuroimaging Initiative
Impact of Resilience on the Association Between Amyloid-β and Longitudinal Cognitive Decline in Cognitively Healthy Older Adults
Abstract: The present study aims at investigating if the association between amyloid-β and longitudinal cognitive decline in cognitively healthy elderly is modulated by resilience capacity. Resilience capacity was quantified by education, which is a common proxy of resilience and has been shown to be related to a wide range of behaviors promoting resilience. Analyses were conducted with longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). 276 cognitively healthy older individuals (≥56 years) were included in the study. Baseline amyloid pathology was quantified using CSF amyloid-β 1-42 measurements. Longitudinal cognitive decline was assessed using ADAS13, Clinical Dementia Rating – Sum of Boxes, and ADNI-Memory composite scores. Duration of follow-up was 10 years (mean follow-up: 2.6 years). Linear mixed effects models demonstrated stronger cognitive decline over time with increasing baseline amyloid. Subsequent mixed-effects analyses showed that this amyloid-related cognitive decline is stronger in individuals with lower resilience capacity (i.e., lower levels of education). Of note, this effect was not an artifact of differences in neurodegeneration patterns between individuals with lower and higher resilience. Results suggest that resilience capacity has high potential to counteract early amyloid pathology and to significantly slow cognitive decline.

Pages 369-386
Sarah C. Kelly, Erin C. McKay, John S. Beck, Timothy J. Collier, Anne M. Dorrance, Scott E. Counts
Locus Coeruleus Degeneration Induces Forebrain Vascular Pathology in a Transgenic Rat Model of Alzheimer’s Disease
Abstract: Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairment and Alzheimer’s disease (AD). The LC is the primary source of norepinephrine in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated norepinephrine signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease and AD. However, the extent to which LC projection system degeneration influences vascular pathology is not fully understood. To address this question in vivo, we stereotactically lesioned LC projection neurons innervating the PFC of six-month-old Tg344-19 AD rats using the noradrenergic immunotoxin, dopamine-β-hydroxylase IgG-saporin (DBH-sap), or an untargeted control IgG-saporin (IgG-sap). DBH-sap-lesioned animals performed significantly worse than IgG-sap animals on the Barnes maze task in measures of both spatial and working memory. DBH-sap-lesioned rats also displayed increased amyloid and inflammation pathology compared to IgG-sap controls. However, we also discovered prominent parenchymal albumin extravasation with DBH-sap lesions indicative of BBB breakdown. Moreover, microvessel wall-to-lumen ratios were increased in the PFC of DBH-sap compared to IgG-sap rats, suggesting that LC deafferentation results in vascular remodeling. Finally, we noted an early emergence of amyloid angiopathy in the DBH-sap-lesioned Tg344-19 AD rats. Taken together, these data indicate that LC projection system degeneration is a nexus lesion that compromises both vascular and neuronal function in cognitive brain areas during the prodromal stages of AD.

Pages 387-395
Marleen van de Beek, Inger van Steenoven, Inez H.G.B. Ramakers, Pauline Aalten, Huiberdina L. Koek, Marcel G.M. Olde Rikkert, Judith Manniën, Janne M. Papma, Frank Jan de Jong, Afina W. Lemstra, Wiesje M. van der Flier
Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer’s Disease
Abstract: Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer’s disease (AD) and controls. Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69±6), 68 AD patients (age 70±6), and 41 controls (age 70±5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: β±SE= -7.6±2.8, controls: β±SE= -7.9±3.0, p<0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (β±SE= 2.9±1.5, p<0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS β±SE= -1.8±0.3, EQ5D-utility β±SE= -3.7±0.4; DAD: VAS= 0.1±0.0, EQ5D-utility β±SE= 0.1±0.1, p<0.05). No associations between cognitive tests and QoL remained in the multivariate model. Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL.

Pages 397-410
Bin-Lu Sun*, Wei-Wei Li*, Jun Wang, Ya-Li Xu, Hao-Lun Sun, Ding-Yuan Tian, Yan-Jiang Wang, Xiu-Qing Yao (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Gut Microbiota Alteration and Its Time Course in a Tauopathy Mouse Model
Abstract: Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of paired helical filament-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

Pages 411-421
Teng-Hong Lian, Wan-Lin Zhu, Shao-Wu Li, Ya-Ou Liu, Peng Guo, Li-Jun Zuo, Yang Hu, Shu-Yang Yu, Li-Xia Li, Zhao Jin, Qiu-Jin Yu, Rui-Dan Wang, Wei Zhang
Clinical, Structural, and Neuropathological Features of Olfactory Dysfunction in Patients with Alzheimer’s Disease
Abstract: We explored changes in clinical features and neuropathological mechanisms underlying olfactory dysfunction (OD) in 60 patients with Alzheimer’s disease (AD). Olfactory function was evaluated using the Sniffin’ Sticks test and a threshold discrimination identification (TDI) score. Based on the TDI score, we divided patients according to the presence or absence of OD (AD-OD and AD-NOD, respectively). Cognitive and neuropsychiatric symptoms were evaluated by a series of rating scales. The volumes and cortical thickness of the thalamus, hippocampus, and amygdala were measured using structural magnetic resonance imaging. Neuropathological protein levels in cerebrospinal fluid were measured. The frequency of OD was 50%. TDI scores were lower in the AD-OD group than in the AD-NOD group (p < 0.001). Compared with the AD-NOD group, the AD-OD group showed greater cognitive function impairments (p < 0.001), and daily living activities were more severely compromised (p = 0.019). The AD-OD group had lower hippocampal and amygdala volumes (p = 0.025, p = 0.030, respectively) and a more pronounced reduction in cortical thickness (p = 0.010). The total tau level was lower in the AD-OD group than the AD-NOD group (p = 0.040). Lower Mini-Mental State Examination scores and thinner AD-signature cortices were associated with lower TDI scores (OR = 0.826, p < 0.001; OR = 1.433, p = 0.008). Overall, in AD patients, the impairments in olfactory discrimination and identification seem to be more correlated with cognitive levels. OD in AD may be an indicator of pathological cognitive decline and structural changes.

Pages 423-430
Fabrizia D’Antonio, Maria Ilenia De Bartolo, Gina Ferrazzano, Alessandro Trebbastoni, Sara Amicarelli, Alessandra Campanelli, Carlo de Lena, Alfredo Berardelli, Antonella Conte
Somatosensory Temporal Discrimination Threshold in Patients with Cognitive Disorders
Abstract: Background: The temporal processing of sensory information can be evaluated by testing the somatosensory temporal discrimination threshold (STDT), which is defined as the shortest interstimulus interval needed to recognize two sequential sensory stimuli as separate in time. The STDT requires the functional integrity of the basal ganglia and of the somatosensory cortex (S1). Although there is evidence that time processing is impaired in patients with Alzheimer’s disease (AD), no study has yet investigated STDT in patients with various degree of cognitive impairment. Objective: The aim of our study was to understand how cognition and attention deficits affect STDT values in patients with cognitive abnormalities. Methods: We enrolled 63 patients: 28 had mild-moderate AD, 16 had mild cognitive impairment (MCI), and the remaining 19 had subjective cognitive deficit (SCD). A group of 45 age-matched healthy subjects acted as controls. Paired tactile stimuli for STDT testing consisted of square­wave electrical pulses delivered with a constant current stimulator through surface electrodes over the distal phalanx of the index finger. Results: STDT values were higher in AD and MCI patients than in SCD subjects or healthy controls. Changes in the STDT in AD and MCI were similar in both conditions and did not correlate with disease severity. Conclusions: STDT alterations in AD and MCI may reflect a dysfunction of the dopaminergic system, which signals salient events and includes the striatum and the mesocortical and mesolimbic circuits.

Pages 431-440
Pilar Pérez-Ros, Laura Cubero-Plazas, Trinidad Mejías-Serrano, Cristina Cunha, Francisco M. Martínez-Arnau
Preferred Music Listening Intervention in Nursing Home Residents with Cognitive Impairment: A Randomized Intervention Study
Abstract Background: The current trend in addressing symptoms of dementia comprises non-pharmacological strategies such as music interventions for the management and improvement of cognitive function, memory, agitation, depression, or anxiety. Objective: To determine the impact of a preferred music listening group intervention upon the functional, cognitive, and emotional dimensions in nursing home residents. Methods: A randomized intervention study was carried out. The study was conducted from June to August 2015, and involved a preferred music listening group intervention lasting 60 minutes, 5 days/week during 8 weeks. A total of 119 adults aged ≥65 years, with annual permanent residence in the nursing home (Málaga, Spain) were included in the study. 47 (39.5%) subjects were randomized to the music group intervention. The nurses and physiotherapists were blinded to the assessments. Results: The sample had a mean age of 80.52 (SD7.44) years, with female predominance. The subjects presented dependency in Barthel, and cognitive impairment as determined by the MMSE. The Tinetti scores yielded fall risk and depression as evidenced by the Yesavage scale. The Cornell scores evidenced no depression in elderly people with dementia. Following the intervention, function improved significantly with a medium effect size, as did emotional state, with a large effect size. Cognitive function was seen to worsen in the control group, but remained stable in the intervention group, with a large effect size. Conclusions: A preferred music listening group intervention among elderly people in nursing homes is effective, resulting in improvements in functional and emotional condition.

Pages 441-451
Luciana Baroni, Chiara Bonetto, Gianluca Rizzo, Caterina Bertola, Livio Caberlotto, Giorgio Bazzerla
Association between Cognitive Impairment and Vitamin B12, Folate, and Homocysteine Status in Elderly Adults: A Retrospective Study
Abstract: Background: Cognitive disorders in old age have a serious impact on the health and social aspects of patients and their families. Objective: The scope of this paper is to explore the role of cobalamin and folate that has been linked to cognitive decline, not only as a deficiency state depending on malnutrition, but also a determinant in cognitive impairment. Methods: A 6-year observational, retrospective study was conducted by collecting the routine blood analyses and cognitive screening scores of patients aged 60 years or older, followed at our Centre for the Diagnosis and Treatment of Cognitive Disorders. Results: In a linear regression with a multi-vitamin model, higher folate concentrations were correlated with better cognitive performances through MMSE score, even after correction for sex, age, and years of education (beta=0.144, p=0.001). Estimated MMSE marginal means for folate versus homocysteine showed that folate deficiency was associated with worse cognitive performances, with a more severe cognitive impairment when hyperhomocysteinemia was present. Conclusion: The assessment of B-vitamin status among elderly adults can contribute to an economic and practical approach to the prevention and management of cognitive decline. Future studies focused to define optimal vitamin status are warranted.

Pages 453-463
Melanie Dani, Melanie Wood, Ruth Mizoguchi, Zhen Fan, Trudi Edginton, Rainer Hinz, Zarni Win, David James Brooks, Paul Edison
Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer’s Disease Subjects
Abstract: Background: Amyloid plaque and tau-containing neurofibrillary tangles are important features of Alzheimer’s disease (AD). However, the relationship between these processes is still debated. Objective: We aimed to investigate local and distant relationships between tau and amyloid deposition in the cortex in mild cognitive impairment (MCI) and AD using PET imaging. Methods: Seventy-nine subjects (51 controls, 13 amyloid-positive MCI subjects, and 15 amyloid positive AD subjects) underwent MRI and 18F-flutemetamol PET. All MCI/AD subjects and 8 healthy controls as well as 33 healthy control subjects from the ADNI dataset also had 18F-AV1451 PET. Regional and distant correlations were examined after sampling target-to-cerebellar ratio images. Biological parametric mapping was used to evaluate voxel level correlations locally. Results: We found multiple clusters of voxels with highly significant positive correlations throughout the association cortex in both MCI and AD subjects. Conclusion: The multiple clusters of positive correlations indicate that tau and amyloid may interact locally and be involved in disease progression. Our findings suggest that targeting both pathologies may be required.

Pages 465-473
Yumei Liu, Sophy J. Perdomo, Jaimie Ward, Eric D. Vidoni, Jason F. Sisante, Kiersten Kirkendoll, Jeffrey M. Burns, Sandra A. Billinger (Handling Associate Editor: Jack de la Torre)
Vascular Health Is Associated with Amyloid-β in Cognitively Normal Older Adults
Abstract: Background: Vascular health is closely related to Alzheimer’s disease (AD). Vascular function measured by flow mediated dilation (FMD) or pulsatility index (PI) can be used as marker of peripheral and central vascular health but is poorly characterized in those at risk for AD. Objective: To assess the relationship of peripheral and central vascular function with amyloid-β (Aβ) and white matter lesion burden among cognitively normal older adults. Methods: We enrolled participants 65 years of age and older. Using Doppler ultrasound, we assessed brachial artery FMD, and middle cerebral artery (PI). Global Aβ burden, quantified using [18F] Florbetapir PET imaging, and white matter lesion volume (WML) were used as measures of AD pathology and vascular brain injury. Results: After adjusting for age and cardiovascular risk factors, the data (n=83) showed a negative association between FMD and Aβ burden (β=-0.03, p<0.001). FMD at a cut-off of 4.45% had 88% specificity and 75% sensitivity to elevated Aβ (AUC=0.86, 95%CI: 0.77 - 0.95). FMD was not related to WML volume (p=0.8), and PI was unrelated to Aβ burden or WML volume (0>0.4). Conclusions: Among cognitively normal older adults, blunted peripheral vascular function, as measured by brachial artery FMD, is associated with Aβ burden. These findings provide support for further exploration into the pathophysiological relationship of vascular health and AD risk as measured by Aβ.

Pages 475-484
Sungmin Jun, Heeyoung Kim, Bum Soo Kim, Bong-Goo Yoo, Won Gu Lee; Alzheimer’s Disease Neuroimaging Initiative
Quantitative Brain Amyloid Measures Predict Time-to-Progression from Amnestic Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: This study was designed to investigate factors that predict progression from amnestic mild cognitive impairment (aMCI) to probable Alzheimer’s disease (AD). Objective: We studied the usefulness of quantitative assessment of amyloid burden measured by Florbetapir PET scan. Methods: The study cohort consisted of aMCI participants older than 65 and those with available Florbetapir PET scan at diagnosis from the ADNI database (http://adni.loni.usc.edu). To assess the prognostic impact of amyloid burden, a staging system based on the global SUVr of the PET scan was applied. We defined the stages as: stage I, negative amyloid scan; stage II, positive amyloid in 1st tertile; stage III, positive amyloid in 2nd tertile; and stage IV, positive amyloid in 3rd tertile. Results: Of 250 eligible aMCI subjects (age 74.1±5.4, female n=105), 71 (28.4%) were diagnosed with probable AD within 3 years. Higher amyloid stages showed faster cognitive decline by Kaplan-Meier analysis. In multivariate Cox analysis, with stage I as a reference, the hazard ratio (HR) increased as the stage increased: stage II (HR, 4.509; p=0.015), stage III (HR, 7.616; p=0.001), and stage IV (HR, 9.421; p<0.001). Along with amyloid stage, ApoE ε4 (HR, 1.943; p=0.031), score of CDR-SB (HR, 1.845; p<0.001) and ADAS 11 (HR, 1.144; p<0.001), and hippocampal volume (HR, 0.002; p=0.005) were also identified as predictors of dementia progression in aMCI subjects. Conclusions: Large amyloid burden measured from amyloid PET scan could be a predictor of faster cognitive decline in aMCI patients.

Pages 485-501
Takeshi Kawarabayashi, Teruhiko Terakawa, Atsushi Takahashi, Hisakazu Hasegawa, Sakiko Narita, Kaoru Sato, Takumi Nakamura, Yusuke Seino, Mie Hirohata, Nobue Baba, Tetsuya Ueda, Yasuo Harigaya, Fuyuki Kametani, Nobuyuki Maruyama, Masao Ishimoto, Peter St. George-Hyslop, Mikio Shoji
Oral Immunization with Soybean Storage Protein Containing Amyloid-β 4-10 Prevents Spatial Learning Decline
Abstract: Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aβ4-10, named Aβ+, for oral Aβ immunization. One mg of Aβ+ or control protein (Aβ-) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aβ+ immunization raised both anti-Aβ antibodies and cellular immune responses. Spatial learning decline was prevented in the Aβ+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-β protein precursor was not different between Aβ+ and Aβ- groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aβ+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

Pages 503-511
Teruyuki Matsuoka, Zahinoor Ismail, Jin Narumoto (Handling Associate Editor: Carlo Abbate)
Prevalence of Mild Behavioral Impairment and Risk of Dementia in a Psychiatric Outpatient Clinic
Abstract: Background: Mild behavioral impairment (MBI) has been proposed as risk factor for dementia, and for some, an early manifestation of dementia. Objective: We examined the prevalence of MBI in the psychiatric outpatient clinic, and compared the incidence of dementia in MBI with that in other psychiatric diseases. Methods: Retrospective chart review was conducted in 2,853 consecutive outpatients over the age of 50. MBI was diagnosed according to the International Society to Advance Alzheimer’s Research and Treatment research diagnostic criteria. The incidence rate of dementia was examined in the patients who were followed up for at least 1 month. Kaplan-Meier survival analyses and Cox proportional hazards regression models were performed to compare the time to onset of dementia between MBI and other psychiatric diseases. Results: The prevalence of MBI was 3.5% and the incidence of dementia was 30.7 cases per 1000 person-years. The hazard ratio (HR) for dementia was higher for MBI than other psychiatric diseases (HR: 8.07, 95% confidence interval: 4.34-15.03, p < 0.001). In MCI patients, the cumulative survival in MCI with affective dysregulation tended to be lower than that in MCI without (p = 0.090). Conclusions: Psychiatric outpatients often meet MBI criteria. MBI, especially the affective dysregulation domain, increases the risk of dementia in this psychiatric outpatient population. Since late-onset psychiatric and behavioral symptoms may be prodromal symptoms of dementia in some, careful observation is needed, and psychiatric clinicians should keep prodromal dementia on their differential diagnosis when assessing those with new onset psychiatric symptomatology in older adults.

Pages 513-522
Yoshitaka Nakagawa, Michitaka Funayama, Masahiro Kato
Logoclonia Might Be a Characteristic of Logopenic Variant Primary Progressive Aphasia at an Advanced Stage: Potential Mechanisms Underlying Logoclonia
Abstract: Logoclonia, which is the meaningless repetition of a syllable, particularly an end syllable of a word, has been described in patients with dementia for a century. The mechanisms behind logoclonia, however, have yet to be clarified. Among 914 patients with aphasia, five patients presented with logoclonia, all of whom were categorized as having logopenic variant PPA (lvPPA) during the initial stage of their illness and met the clinical criteria for diagnosis of probable Alzheimer’s disease. Cognitively, they were all severely impaired when they presented with logoclonia. During the progression from lvPPA to logoclonia in these patients, their naming abilities and phonological output function deteriorated despite their retained speech fluency. Logoclonia might be a characteristic sign of advanced-stage lvPPA. Although logoclonia might be associated with perseveration, deterioration in naming abilities and phonological output function along with retained speech fluency might form the basis for the development of logoclonia.

Pages 532-538
Patricia Martín-Maestro, Ricardo Gargini, Esther García, Diana Simón, Jesús Avila, Vega García-Escudero
Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer’s Disease
Abstract: Mitochondrial alterations and oxidative stress are common features of Alzheimer’s disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer’s disease.

Pages 539-550
David H. Gustafson Jr., David H. Gustafson Sr., Olivia J. Cody, Ming Yuan-Chih, Darcie C. Johnston, Sanjay Asthana
Pilot Test of a Computer-Based System to Help Family Caregivers of Dementia Patients
Abstract: Background: Family members absorb much of the care of dementia patients. The burden of care substantially impacts caregivers' health, further straining our healthcare system. By 2050, the incidence of Alzheimer's disease will more than double, increasing the numbers of family caregivers proportionally. Interventions that reduce their burden are needed to preserve their health as well as the viability of the healthcare system. Objective: This paper reports on the development and feasibility testing of a computer-based system intended to improve the lives of caregivers. D-CHESS (Dementia–Comprehensive Health Enhancement Support System) allows users to obtain information, communicate with other caregivers, get help with care decisions, and share information with experts. Method: Thirty-one caregivers were randomly assigned to an intervention group receiving D-CHESS for 6 months or to a control group receiving a caregiving book. Surveys at 0, 2, 4, and 6 months evaluated caregiver burden, family conflict, satisfaction with decisions, social support, loneliness, anxiety, depression, and coping competence. Results: Survey findings suggest D-CHESS participants may perform better on measures of social support, anxiety, loneliness, and coping competence; the groups were equivalent on caregiver burden, decision satisfaction, and depression, and the control group reported less family conflict than the intervention. D-CHESS use data suggested enhancements to system design and content to increase awareness and use of various features. Conclusion: This study suggests that D-CHESS has potential to positively impact family caregivers and that the system merits further development and investigation with a full-scale clinical trial.

Pages 551-560
Chinedu T Udeh-Momoh, Bowen Su, Stephanie Evans, Bang Zheng, Shireen Sindi, Ioanna Tzoulaki, Robert Perneczky, Lefkos T Middleton; for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Julius Popp)
Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults
Abstract: Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer’s disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42/reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol+abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ × reserve interaction for clinical progression was noted (adjusted HR=0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aβ+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aβ42. High reserve reduces the associated AD progression risk in these high-risk individuals.

Pages 561-570
Fulin Gao, Yuhong Jing, Peixi Zang, Xiaojuan Hu, Cheng Gu, Ruipeng Wu, Bingyan Chai, Yi Zhang
Vascular Cognitive Impairment Caused by Cerebral Small Vessel Disease Is Associated with the TLR4 in the Hippocampus
Abstract:Background: Cerebral small vessel disease (CSVD) can lead to leukodystrophy and cognitive impairment. The inflammatory response mediated by Toll-like receptor 4 (TLR4) is involved in the pathological process of CSVD, but the roles of TLR4 in vascular cognitive impairment (VCI) following CSVD are not clear. Objective: To explore the roles and mechanisms of TLR4 in the development of VCI. Methods: Male spontaneous hypertension rats (SHR) and Wistar Kyoto rats (WKY) were monitored for blood pressure (BP). The spatial learning and memory were assessed every 6 weeks using Morris water maze (MWM). Blood samples from femoral artery were collected and serum was isolated. Cerebral white matter damage was evaluated using a 3.0T magnetic resonance imaging (MRI) every 12 weeks. After 35 weeks, all rats were decapitated, and the expression of TLR4 in the hippocampus was determined using western blot. The number of positive cells of TLR4, active astrocyte and microglia in hippocampus were measured using immunohistochemistry and immunofluorescence. Results: Compared with WKY, the BP of SHR was maintained at a high level. Spatial learning and memory declined. IL-1β and TNF-α levels were elevated. Cranial coronal scanning with T2-weighted MRI showed high signal intensity in corpus callosum and external capsule of SHR. Furthermore, in SHR, the expression of TLR4, GFAP, and Iba1 in the hippocampus were increased. Conclusion: Hypertension can cause small vascular damage and partial white matter degeneration in the brain. SHR showed cognitive impairment with increasing age. High expression of TLR4 and glial cell response in hippocampus is one of the key mechanisms of this disease.

Pages 571-583
Miaojing Xu*, Yingwei Huang*, Pingping Song, Yaowei Huang, Wei Huang Han-Ting Zhang, Yafang Hu *These authors contributed equally to this work.
AAV9-Mediated Cdk5 Inhibitory Peptide Reduces Hyperphosphorylated Tau and Inflammation and Ameliorates Behavioral Changes Caused by Overexpression of p25 in the Brain
Abstract: Background: Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer’s disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice. Objective: First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether CIP delivered by adeno-associated virus serotype 9 (AAV9) virus can ameliorate neuronal toxicity induced by p25. Methods: The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice. Results: The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α, which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice. Conclusion: AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities.

Pages 585-593
Kota Tsutsumimoto, Takehiko Doi, Sho Nakakubo, Minji Kim, Satoshi Kurita, Hideaki Ishii, Hiroyuki Shimada, Ichiro Kawachi
Impact of Social Frailty on Alzheimer’s Disease Onset: A 53-Month Longitudinal Cohort Study
Abstract: We investigated the association between social frailty and Alzheimer’s disease (AD) incidence among community-dwelling older adults in Japan. A 53-month follow-up cohort study was conducted in Obu City, Japan. Participants comprised 3,720 community-dwelling older adults (mean age, 71.7 years; 48.4% men). The operational definition of social frailty comprised five items: going out infrequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not always talking with someone each day. During follow-up, the cumulative AD incidence risk between socially robust, pre-frail, and frail groups was 4.1%, 5.5%, and 10.7%, respectively. In both crude (HR 2.72, 95% CI 1.90–3.89, p < 0.001) and adjusted Cox proportional hazards models (HR 1.53, 95% CI 1.03–2.28, p = 0.035), social frailty was associated with a significantly higher AD incidence risk. The present study revealed that social frailty is strongly associated with AD incidence among Japanese older adults. Further research should elucidate whether social frailty prevention is effective for decreasing AD risk.

Pages 595-607
Giovanni Palermo, Luca Tommasini, Gayanè Aghakhanyan, Daniela Frosini, Martina Giuntini, Gloria Tognoni, Ubaldo Bonuccelli, Duccio Volterrani, Roberto Ceravolo (Handling Associate Editor: Annachiara Cagnin)
Clinical Correlates of Cerebral Amyloid Deposition in Parkinson’s Disease Dementia: Evidence from a PET Study
Abstract: Background: Dementia in Parkinson’s disease (PDD) is common presumably due to combined neuropathological substrates. Amyloid-β (Aβ) plaques are well described in PDD but their contribution in synucleinopathies is still controversial. Objective: To investigate regional [18F]Florbetapir binding and its relative contribution to cognitive dysfunction in a cohort of PDD patients and to test whether PDD patients with comorbid amyloidopathy have different clinical and neuropsychological characteristics. Methods: 21 PDD patients, 20 with Alzheimer’s disease (AD), and 9 control subjects underwent amyloid positron emission tomography (PET) imaging, neurological, and neuropsychological assessment. Radioligand binding was compared across the groups. PDD scans were interpreted qualitatively and semiquantitatively and categorized as positive or negative. Annual longitudinal Mini-Mental State Examination (MMSE) of PDD subjects was retrospectively collected in order to relate Aβ burden to the course of cognitive impairment. Results: [18F]Florbetapir PET imaging was positive in 11 PDD patients (52.38%) using the semi-quantitative method. There were no group differences between PDD subjects with increased cortical [18F]Florbetapir (+) and those without (-), according to demographic and clinical parameters. PDD+ performed worse on Digit Span Forward, Rey Auditory Verbal Learning Test, and delayed recall than the PDD- with a significant negative correlation between global cortical retention and specific memory tests. Aβ load did not correlate with MMSE ratings although PDD+ demonstrated a faster clinical progression of dementia. Conclusions: Significant Aβ deposition is common in PDD patients contributing to memory impairment and driving a faster rate of cognitive decline.

Pages 609-617
Julianna Bauman, Laura E. Gibbons, Mackenzie Moore, Shubhabrata Mukherjee, Susan M. McCurry, Wayne McCormick, James D. Bowen, Emily Trittschuh, Maria Glymour, Jesse Mez, Andrew J. Saykin, Kristen Dams-O’Conner, David A. Bennett, Eric B. Larson, Paul K. Crane for the Executive Prominent AD (EPAD) investigators (Handling Associate Editor: Gabriella Santangelo)
Associations Between Depression, Traumatic Brain Injury, and Cognitively-Defined Late-Onset Alzheimer’s Disease Subgroups
Abstract: Background: There is considerable heterogeneity in clinical presentation among people with late-onset Alzheimer’s disease (LOAD). We have categorized people with LOAD into subgroups based on relative impairments across cognitive domains. These 6 groups are people with no relatively impaired domains (AD-No Domains), 4 groups with one relatively impaired domain (AD-Memory, AD-Executive, AD-Language, and AD-Visuospatial), and a group with multiple relatively impaired domains (AD-Multiple Domains). Our previous analysis demonstrated that genetic factors vary across cognitively-defined LOAD groups. Objective: To determine whether risks associated with depression and traumatic brain injury with loss of consciousness (TBI) for cognitively defined LOAD subgroups are similar. Methods: We used cognitive data at LOAD diagnosis from three prospective cohort studies to determine cognitively-defined subgroups. We compared subgroups in endorsement of items from the Centers for Epidemiological Studies Depression (CES-D) scale and history of TBI. Results: Among 1,505 people with LOAD from the three studies, there were substantial differences across subgroups in total CES-D score, with lower scores (less depression) for people with AD with relative impairments in memory (AD-Memory) compared to those in other groups. Differences were noteworthy for the sleep-related item of the CES-D, as people with AD-Memory were less likely to report restless sleep than people in other groups. There were no differences in TBI history across groups. Conclusions: Differences in risk factor associations across subgroups such as differences in endorsement of depression symptoms and restless sleep provide support for the hypothesis that there are biologically coherent subgroups of AD.

Pages 619-620
Yan-Jiang Wang, M.D., Ph.D and Xian-Le Bu, M.D., Ph.D., recipients of the 2019 Alzheimer Award