Volume 73, Number 4, 2020

Pages 1265-1278

Keith A. Shaughnessy, Kyle J. Hackney, Brian C. Clark, William J. Kraemer, Donna J. Terbizan, Ryan R. Bailey, Ryan McGrath
A Narrative Review of Handgrip Strength and Cognitive Functioning: Bringing a New Characteristic to Muscle Memory
Abstract: Background: Measures of handgrip strength have not only emerged as a clinically viable screening tool for determining risk for morbidity, functional disability, and early mortality, but also for helping to identify cognitive deficits. However, the phenomena that links low handgrip strength with cognitive decline remains unclear. The role of the muscular and neural systems, and their adaptations to muscle strengthening activities over the life course, may provide important information for how age-related changes to muscle mass, strength, and neural capacity influence cognition. Moreover, disentangling how handgrip strength and cognitive function are associated may help to inform healthcare providers working with aging adults and guide targeted interventions aiming to preserve muscle and cognitive functioning. Objective: To 1) highlight and summarize evidence examining the associations of handgrip strength and cognitive functioning, and 2) provide directions for future research in this area. Methods: Articles from the PubMed database were searched from November 2018-May 2019. The search term algorithm, inclusion and exclusion criteria were pre-specified by investigators. Results: Several cross-sectional and longitudinal studies have revealed that measures of handgrip strength were associated with cognitive declines regardless of age demographics and the presence of comorbidities. Conclusion: Handgrip strength can be used in clinical and epidemiological settings for helping to determine the onset and progression of cognitive impairment. Future research should continue to examine how handgrip strength and cognitive function are linked.

Pages 1279-1294
Viviana Frantellizzi, Arianna Pani, Maria Ricci, Nicoletta Locuratolo, Francesco Fattapposta, Giuseppe De Vincentis (Handling Associate Editor: Daniele Pastori)
Neuroimaging in Vascular Cognitive Impairment and Dementia: A Systematic Review
Abstract: Cerebrovascular diseases are well established causes of cognitive impairment. Different etiologic entities, such as vascular dementia (VaD), vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorder, are included in the umbrella definition of vascular cognitive impairment and dementia (VCID). Because of the variability of VCID clinical presentation, there is no agreement on criteria defining the neuropathological threshold of this disorder. In fact, VCID is characterized by cerebral hemodynamic alteration which ranges from decreased cerebral blood flow to small vessels disease and involves a multifactorial process that leads to demyelination and gliosis, including blood-brain barrier disruption, hypoxia, and hypoperfusion, oxidative stress, neuroinflammation and alteration on neurovascular unit coupling, cerebral microbleeds, or superficial siderosis. Numerous criteria for the definition of VaD have been described: the National Institute of Neurological Disorders and Stroke Association Internationale pour Recherche´-et-l'Enseignement en Neurosciences criteria, the State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria, DSM-V criteria, the Diagnostic Criteria for Vascular Cognitive Disorders (a VASCOG Statement), and Vascular Impairment of Cognition Classification Consensus Study. Neuroimaging is fundamental for definition and diagnosis of VCID and should be used to assess the extent, location, and type of vascular lesions. MRI is the most sensible technique, especially if used according to standardized protocols, even if CT plays an important role in several conditions. Functional neuroimaging, in particular functional MRI and PET, may facilitate differential diagnosis among different forms of dementia. This systematic review aims to explore the state of the art and future perspective of non-invasive diagnostics of VCID.

Pages 1295-1304
Chiara Stella Turchetta, Maria Stefania De Simone, Roberta Perri, Lucia Fadda, Giulia Caruso, Massimo De Tollis, Carlo Caltagirone, Giovanni Augusto Carlesimo
Forgetting Rates on the Recency Portion of a Word List Predict Conversion from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer’s disease (AD). Consistent with AD patients’ distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients’ conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD.

Pages 1305-1311
Chenjia Xu, Liana G. Apostolova, Adrian L. Oblak, Sujuan Gao
Association of Hypercholesterolemia with Alzheimer’s Disease Pathology and Cerebral Amyloid Angiopathy
Abstract: Background: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer’s disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. Objective: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. Methods: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer's Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. Results: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. Conclusion: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions.

Pages 1313-1320
Ji Hyun Han*, Hyo-Jung Lee*, Ji Won Han, Seung Wan Suh, Ju Ri Lee, Seonjeong Byun, Keun Suh Kim, Sung Yeol Kim, Jung-tae Lee, Eunha Yoo, Na-Hee Chang, Tae Hui Kim, Ki Woong Kim (Handling Associate Editor: Maria Vassilaki) *These authors contributed equally to this work.
Loss of Functional Dentition Is Associated with Cognitive Impairment
Abstract: Background: Although tooth loss is known to increase the risk of cognitive impairment and dementia, few studies have investigated the association between functional teeth including rehabilitated lost teeth and cognitive function Objective: We investigated the associations of the numbers of functional teeth and functional occlusal units with cognitive impairment and cognitive function in late life. Methods: The current study was conducted as a part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a community-based elderly cohort study. We analyzed 411 participants who have agreed with the additional dental exam. Geriatric psychiatrists and neuropsychologists administered the Consortium to Establish a Registry for Alzheimer’s disease Assessment Packet Clinical and Neuropsychological Assessment Battery to all participants, and dentists examined their dental status. Results: Higher number of functional teeth (OR = 0.955, 95% CI = 0.914 - 0.997, p = 0.037) and higher number of functional occlusal units (OR = 0.900, 95% CI = 0.813 - 0.996, p = 0.042) were associated with lower odds of cognitive impairment. When we analyzed these relationships separated by the location of teeth, only the numbers of functional teeth (OR = 0.566, 95% C I= 0.373 - 0.857, p = 0.007) and functional occlusal units (OR = 0.399, 95% CI = 0.213 - 0.748, p = 0.004) in the premolar area were associated with lower odds of cognitive impairment. Conclusion: Loss of functional teeth and functional occlusal units (especially in the premolar region) were associated with increased cognitive impairment.

Pages 1321-1330
Lasse Melvaer Giil, Dag Aarsland
Greater Variability in Cognitive Decline in Lewy Body Dementia Compared to Alzheimer’s Disease
Abstract: Studies indicate more rapid cognitive decline in patients with Lewy body dementia (LBD) compared to Alzheimer’s disease (AD). However, there has been less focus on any difference in the variability of cognitive decline. We assessed Mini-Mental State Examination (MMSE) test performance at baseline and annually for 5 years in 222 patients with mild dementia in the DemVest study who had either AD (137) or LBD (85). We used linear mixed models (LMMs) with random intercepts (variability in MMSE at baseline) and slopes (variability in MMSE decline), with years in study, age, gender, and diagnosis as independent variables. A non-linear (quadratic) trajectory was selected, interacting with age and diagnosis. To study differences in variance, we compared a regular LMM (i.e., a homoscedastic model), which assumes equal variance across groups, to a heteroscedastic model, assuming unequal intercept and slope variance based on diagnosis. The heteroscedastic model gave a better fit (Likelihood ratio test: χ2 = 30.3, p < 0.001), showing overall more variability in LBD. Further, the differences in intercept and slope variances were tested using a modified Wald test. The MMSE intercept variance (AD: 2.78, LBD: 7.75, difference: 4.97, p = 0.021) and slope variance (AD: 2.62, LBD 7.81, difference: 5.19, p = 0.004) were both higher in LBD. In conclusion, patients with LBD in the DemVest study have a higher variability in MMSE scores at study inclusion, and in MMSE decline compared to AD. Accordingly, clinical trials on LBD may need a larger sample size compared to AD.

Pages 1331-1342
Yasuhisa Ano, Rena Ohya, Yuta Takaichi, Terukatsu Washinuma, Kazuyuki Uchida, Akihiko Takashima, Hiroyuki Nakayama
β-Lactolin, a Whey-Derived Lacto-Tetrapeptide, Prevents Alzheimer’s Disease Pathologies and Cognitive Decline
Abstract: The prevention of age-related memory decline and dementia has been becoming a high priority because of the rapid growth in aging populations. Accumulating epidemiological and clinical studies indicate that intake of fermented dairy products rich in β-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of β-lactolin on Alzheimer’s disease (AD) pathologies have not been investigated. In the present study, we examined the effects of β-lactolin and whey digestion rich in β-lactolin on AD pathology in 5×FAD transgenic mice and PS19 tauopathy mice. Intake of β-lactolin and whey digestion rich in β-lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-β, ameliorated impaired long-term object memory, and attenuated decreased synaptophysin, dopamine, brain-derived neurotrophic factor, and insulin-like growth factor 1 levels in the cortex in 5×FAD transgenic mice. In addition, intake of β-lactolin and whey digestion rich in β-lactolin improved behavioral abnormality and reduced the ratio of phosphorylated tau to total tau in the cortex in PS19 tauopathy mice. These findings indicate that consumption with β-lactolin and whey digestion rich in β-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment.

Pages 1343-1353
Nawele Boublay, Romain Bouet, Jean-Michel Dorey, Catherine Padovan, Zaza Makaroff, Denis Fédérico, Isabelle Gallice, Marie-Odile Barrellon, Philippe Robert, Olivier Moreaud, Isabelle Rouch, Pierre Krolak-Salmon, Alzheimer’s Disease Neuroimaging Initiative
Brain Volume Predicts Behavioral and Psychological Symptoms in Alzheimer’s Disease
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial. Objective: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD. Methods: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI). Results: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved. Conclusion: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition.

Pages 1355-1361
Karin Gmitterova, Daniela Varges, Matthias Schmitz, Saima Zafar, Fabian Maass, Paul Lingor, Inga Zerr
Chromogranin A Analysis in the Differential Diagnosis Across Lewy Body Disorders
Abstract: Background: Chromogranin A (CgA) is a general marker of gut endocrine cells, which are part of the “gut-brain axis” in Parkinson’s disease (PD). Objective: We analyzed CgA as a marker of synaptic dysfunction to assess its role in the differential diagnosis across different Lewy body disorders. Methods: We analyzed the CgA levels in the cerebrospinal fluid (CSF) and serum from 54 patients covering the spectrum of Lewy body disorders [13 Parkinson’s disease (PD), 17 Parkinson’s disease dementia (PDD), 24 dementia with Lewy bodies (DLB)] and 14 controls using an ELISA. Results: A positive correlation was noted between CSF and serum CgA levels (ρ=0.47, 95% CI: 0.24 to 0.65, p<0.0001). The highest values of CgA in CSF and in serum were measured in DLB and there was a significant difference between DLB and PDD (p=0.03 and p=0.004). The serum levels of CgA in controls achieved lower values compared to DLB (p=0.006). There was a gradual increase in serum levels from PD to PDD and DLB. An inverse correlation was seen between the CSF level of CgA and Aβ42 (ρ= -0.296, 95% CI: -0.51 to – 0.04, p=0.02). Conclusion: The incorporation of CgA analysis as an additional biomarker may be useful in the diagnostic work-up of Lewy body dementia. CgA analysis may be relevant in distinguishing DLB from PDD patients and presumably early stages of PD. Our data on altered serum levels in DLB pave the way to the development of blood-based parameters for the differential diagnosis, which however needs to be confirmed in a prospective study.

Pages 1363-1372
Muhammad Umar Sajjad, Kaj Blennow, Anne Brita Knapskog, Ane-Victoria Idland, Farrukh Abbas Chaudhry, Torgeir Bruun Wyller, Henrik Zetterberg, Leiv Otto Watne (Handling Associate Editor: Eloi Magnin)
Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients
Abstract: Background: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. Objective: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. Methods: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer’s disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. Results: Hip fracture patients had significantly higher IL-8 levels (p < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p = 0.002) in delirium patients with depression. Both TNF-α and IL-1β were undetected in most patients. Conclusions: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.

Pages 1373-1383
Elin Axelsson, Anders Wallin, Johan Svensson (Handling Associate Editor: M. Kamran Ikram)
Patients with the Subcortical Small Vessel Type of Dementia Have Disturbed Cardiometabolic Risk Profile
Abstract: Background: Population-based studies have shown that cardiometabolic status is associated with the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). However, little is known of cardiometabolic risk factors in the subcortical small vessel type of dementia (SSVD), in which WMHs are one of the most prominent manifestations. Objective: To determine whether the profile of cardiometabolic risk factors differed between SSVD, Alzheimer’s disease (AD), mixed dementia (combined AD and SSVD), and healthy controls. Methods: This was a mono-center, cross-sectional study of SSVD (n=40), AD (n=113), mixed dementia (n=62), and healthy controls (n=94). In the statistical analyses, we adjusted for covariates using ANCOVA and binary logistic regression. Results: The prevalence of hypertension was increased in SSVD and mixed dementia (p < 0.001 and p < 0.05 versus controls, respectively). Diabetes was more prevalent in SSVD patients, and body mass index was lower in AD and mixed dementia, compared to the controls (all p < 0.05). Serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) were reduced in the SSVD group (both p < 0.05 versus control). These differences remained after adjustment for covariates. In the SSVD group, Trail Making Test A score correlated positively with systolic blood pressure, mean arterial pressure, and pulse pressure. Conclusion: All dementia groups had an altered cardiometabolic risk profile compared to the controls. The SSVD patients showed increased prevalence of hypertension and diabetes, and in line with previous population-based data, TC and LDL-C in serum were reduced.

Pages 1385-1405
Dickson Wong, Samir Atiya, Jennifer Fogarty, Manuel Montero-Odasso, Stephen H. Pasternak, Chris Brymer, Michael J. Borrie, Robert Bartha (Handling Associate Editor: Michael Hornberger)
Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer’s Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study
ABSTRACT: Identification of biological changes underlying the early symptoms of Alzheimer’s disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.

Pages 1407-1419
Jan A.F. Coebergh, Steven McDowell, Theodorus C.A.M. van Woerkom, Jan P. Koopman, Jacqueline Mulder, Sebastiaan F.T.M Bruijn
Auditory Agnosia for Environmental Sounds in Alzheimer’s Disease: Not Hearing and Not Listening?
Abstract: Auditory agnosia for environmental sounds (AES) is an example of central auditory dysfunction. It is presumed to be independent of language deficits and in presence of normal hearing. We undertook a detailed neuropsychological assessment including environmental sound naming and recognition in 34 clinically mild Alzheimer's disease (AD) patients and 29 age-matched healthy control subjects. In patients with AD, audiometry was performed to assess the impact on test performance, and in normal controls the Hearing Handicap Inventory for the Elderly – Screening Version to exclude more than mild hearing loss. We adapted a validated environmental sound battery and found near perfect scores in controls. We found that environmental sound agnosia is common in mild AD. We found a statistically significant difference in mean pure tone audiometry in the best ear between patients with and those patients without naming deficits of 11.3 dB (p=0.010) and of 14.7 dB (p=0.000) between those with and without recognition deficits. Statistical significance remained after correcting for age, aphasia, Mini-Mental State Examination score, and working memory. Slight and moderate peripheral hearing loss increases the odds ratio of recognition deficits by 13.75 (confidence interval 2.3-81.5) compared to normal hearing patients. We did not find evidence for different forms of AES. This work suggests that an interaction between peripheral hearing loss and AD pathology produces problems with environmental sound recognition. It confirms that the relationship between hearing and dementia is complex but also suggests that interventions to prevent and treat hearing loss could have an effect on AD in its clinical expression.

Pages 1421-1434
Sumana R. Chintapaludi*, Asli Uyar*, Harriet M. Jackson, Casey J. Acklin, Xulong Wang, Michael Sasner, Gregory W. Carter, Gareth R. Howell *These authors contributed equally to this work.
Staging Alzheimer’s Disease in the Brain and Retina of B6.APP/PS1 Mice by Transcriptional Profiling
Abstract: Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, tau pathology, neuroinflammation, and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and neuroinflammation involving both astrocytes and microglia beginning around 4-6 months of age. However, significant tau pathology and neurodegeneration are not apparent in this model even when assessed at old age. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD.

Pages 1435-1444
Tan Zhao*, Meina Quan*, Jianping Jia
Functional Connectivity of Default Mode Network Subsystems in the Presymptomatic Stage of Autosomal Dominant Alzheimer’s Disease
*These authors contributed equally to this work.
Background: The default mode network (DMN) could be divided into subsystems, the functional connectivity of which are different across the Alzheimer’s disease (AD) spectrum. However, the functional connectivity patterns within the subsystems are unknown in presymptomatic autosomal dominant AD (ADAD). Objective: To investigate functional connectivity patterns within the subsystems of the DMN in presymptomatic subjects carrying PSEN1, PSEN2, or APP gene mutations. Methods: Twenty-six presymptomatic mutation carriers (PMC) and twenty-nine cognitively normal non-carriers as normal controls (NC) from the same families underwent resting state functional MRI and structural MRI. Seed-based analyses were done to obtain functional connectivity of posterior and anterior DMN. For the regions that showed significant connectivity difference between PMC and NC, volumes were extracted and compared between the two groups. Connectivity measures were then correlated with cognitive tests scores. Results: The posterior DMN showed connectivity decrease in the PMC group as compared with the NC group, which was primarily the connectivity of left precuneus with right precuneus and superior frontal gyrus; the anterior DMN showed significant connectivity decrease in the PMC group, which was the connectivity of medial frontal gyrus with middle frontal gyrus. In the brain regions showing connectivity changes in the PMC group, there was no group difference in volume. A positive correlation was observed between the precuneus connectivity value and Mini-Mental State Examination total score. Conclusion: Functional connectivity within both posterior and anterior DMN were disrupted in the presymptomatic stage of ADAD. Connectivity disruption within the posterior DMN may be useful for early identification of general cognitive decline and a potential imaging biomarker for early diagnosis.

Pages 1445-1453
Juan C. Meléndez, Encarnación Satorres, Itxasne Oliva (Handling Associate Editor: Marcia Dourado)
Comparing the Effect of Interference on an Emotional Stroop Task in Older Adults with and without Alzheimer’s Disease
Abstract: Background: Impairments in the ability to recognize facial affective expressions may lead to social dysfunction and difficulties with interpersonal communication. Objective: The objective was to compare the attentional responses on a Stroop emotional task using words and faces by testing whether the two stimuli differ in the degree of interference they produce in patients with Alzheimer’s disease (AD). Methods: There were 75 participants: 25 healthy older adults, 25 with mild AD, and 25 with moderate AD. A variation of the classic emotional Stroop test was administered. This task combined emotional words (happy or sad) superimposed on facial expressions (happy or sad), where the words were either incongruent or congruent with the emotion expressed by the face stimuli. Results: Facilitation was shown on negative words in healthy older adults, and significant effects were obtained for condition, valence, group, and the condition x group interaction. Although less interference was observed on negative stimuli, the fastest reaction times were found for congruent positive stimuli. The effect of interference in healthy older adults is similar in both conditions. However, in the AD groups, there is less interference on the words task than on the faces task. Conclusion: The more complex nature of faces, as opposed to the over-learning and automaticity of words, may explain the higher interference in AD patients in the faces condition. In patients with AD, words can be a better method for recognizing emotions than affective facial expressions.

Pages 1455-1466
Yongqiang Liu*, Cheng Kong*, Li Gong, Xiaohui Zhang, Yuefei Zhu, Haichao Wang, Xiao Qu, Renyuan Gao, Fang Yin, Xueyuan Liu, Huanlong Qin *These authors contributed equally to this work.
The Association of Post-Stroke Cognitive Impairment and Gut Microbiota and its Corresponding Metabolites
Abstract: Background: Post-stroke cognitive impairment (PSCI) is an important factor causing disabilities after acute ischemic stroke (AIS). Emerging evidence suggested that gut microbiota play an important role in cognitive impairment. Objective: This study aimed to explore the association between PSCI and gut microbiota. Method: 65 patients with newly diagnostic AIS finished the fecal collection on admission and cognitive assessment 3 months later in the clinic. Fecal samples were subjected to 16SrRNA gene sequencing and gas chromatography-mass spectrometry analysis. Additionally, we enrolled new 18 AIS patients, whose treatment was supplemented by probiotics, to assess the potential of microbial treatment in PSCI. Results: PSCI patients were characterized by the significantly decreased alpha-diversity, disturbed microbial composition, and corresponding metabolites compared with non-PSCI patients. Increased Fusobacterium and deficiency of microbial metabolized short-chain fatty acids (SCFAs) were significantly associated with PSCI. A model based on gut microbiota and SCFAs could predict 3 months or longer PSCI early and accurately after stroke onset. While traditional probiotic administration had little effect on PSCI, it could ameliorate patients’ mood, including depression and anxiety in the 3 months after stroke. Conclusion: Our study revealed the association between PSCI and gut microbiota and its corresponding metabolites for the first time, suggesting the potential for applying microbiota and its corresponding metabolites to early clinical diagnosis and treatment of PSCI.

Pages 1467-1479
Aline Mendes, François R. Herrmann, Max Scheffler, Gemma Gabriel, Lukas Sveikata, Barinjaka Rakotomiaramanana, Giovanni B. Frisoni, Dina Zekry, Gabriel Gold
Cortical Superficial Siderosis: A Descriptive Analysis in a Memory Clinic Population
Abstract: Background: Cortical superficial siderosis (cSS) is a hemorrhagic marker of blood-brain barrier disruption detected in brain MRI. Together with cerebral microbleeds (CMB), they are recognized as a small vessel disease marker associated with cerebral amyloid angiopathy. Objective: This study aims to determine the prevalence and the characteristics of cSS in a memory clinic population. Methods: Cross-sectional retrospective analysis of 613 patients from Geneva University Hospitals memory clinic. All patients underwent standardized brain MRI and neuropsychological assessment with diagnosis confirmed by an expert. The presence of cSS was visually assessed and classified as focal (restricted to 3 sulci) or disseminated within the correspondent topography. CMB were classified according to the Microbleed Anatomical Rating Scale. Results: cSS was detected in 26/613 patients (4.2%), classified as disseminated in 5/26 cases (19%). Alzheimer’s disease (AD) and AD associated with a significant vascular component were the diagnoses more frequently related to cSS (18/26; 69%). Patients with cSS had an increased prevalence of both hypertension (81% versus 57%; p=0.015) and WMH burden (p=0.012). The overall prevalence of cerebral microbleeds (69% versus 32%; p<0.01), as well as their mean number (0.69 ± 0.47 versus 0.32 ± 0.46; p<0.01) were both increased in patients with cSS. In the logistic regression model, the presence of 5 or more CMB (OR 11.35; 95% CI 4.68-27.55; p<0.01) and hypertension (OR 3.31; 95% CI 1.19-9.15; p=0.021) were significantly associated with cSS. Conclusions: cSS is observed in patients diagnosed with AD and AD with a vascular component, being independently associated with multiple CMB and hypertension.

Pages 1481-1499
Elisa Tuzzi, David Z. Balla, Joana R.A. Loureiro, Manuela Neumann, Christoph Laske, Rolf Pohmann, Oliver Preische, Klaus Scheffler, Gisela E. Hagberg
Ultra-High Field MRI in Alzheimer’s Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo compared to Histology
Abstract: Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

Pages 1501-1509
Chin Hong Tan, Saima Hilal, Xin Xu, Henri Vrooman, Ching-Yu Cheng, Tien Yin Wong, Narayanaswamy Venketasubramanian, Christopher Chen
MRI Markers of Mixed Pathology and Cognitive Impairment in Multiethnic Asians
Abstract: There is a need to elucidate the combined influence of neurodegeneration and cerebrovascular disease (CeVD) on cognitive impairment, especially in diverse populations. Here, we evaluated 840 multiethnic individuals (mean age = 70.18) across the disease spectrum from the Epidemiology of Dementia in Singapore study. First, we determined whether a validated quantitative MRI score of mixed pathology is associated with clinical diagnosis and whether the score differed between ethnicities (Chinese, Malays, and Indians). We then evaluated whether the score was associated with multidomain cognitive impairment and if additional measures of CeVD were further associated with cognitive impairment. We found that lower quantitative MRI scores were associated with severity of clinical diagnosis and Chinese individuals had the highest quantitative MRI scores, followed by Indians and Malays. Lower quantitative MRI scores were also associated with lower performance in attention, language, visuoconstruction, visuomotor, visual, and verbal memory domains. Lastly, the presence of intracranial stenosis and cortical cerebral microinfarcts, but not cerebral microbleeds, were associated with memory performance beyond quantitative MRI scores. Taken together, our results demonstrate the utility of using multiple MRI markers of neurodegeneration and CeVD for identifying multiethnic Asians with the greatest cognitive impairment due to mixed pathology.

Pages 1511-1523
Marina Buciuc, Alexandra M. Wennberg, Stephen D. Weigand, Melissa E. Murray, Matthew L. Senjem, Anthony J. Spychalla, Bradley F. Boeve, David S. Knopman, Clifford R. Jack Jr, Kejal Kantarci, Joseph E. Parisi, Dennis W. Dickson, Ronald C. Petersen, Jennifer L. Whitwell, Keith A. Josephs (Handling Associate Editor: Josephine Barnes)
Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes
Abstract: Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer’s disease (AD), but whether the association is modified by other factors is unknown. Objective: To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE) ɛ4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage. Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE ɛ4, presence of LBs, Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Results: Older age, female gender, APOE ɛ4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOE ɛ4 carriers (p=0.04). Conclusion: Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.

Pages 1525-1539
Debora Hashiguchi, Henrique Correia Campos, Raphael Wuo-Silva, Jean Faber, Sérgio Gomes da Silva, Antonio Augusto Coppi, Ricardo Mario Arida, Beatriz Monteiro Longo
Resistance Exercise Decreases Amyloid Load and Modulates Inflammatory Responses in the APP/PS1 Mouse Model for Alzheimer’s Disease
Abstract: Neuroinflammation has been shown to play a crucial role in the development of Alzheimer's disease (AD) and also has an association with amyloid-β (Aβ) plaques, a hallmark of this disease. Physical exercise has emerged as an alternative treatment for pathological impairment in AD. In light of this evidence, together with the fact that the hippocampus is one of the first structures to be affected in AD, we analyzed hippocampal changes in Aβ load, inflammatory responses, and locomotor activity in transgenic APP/PS1 mouse model for AD submitted to a resistance exercise (RE) program. One month after the start of the RE program, the locomotor hyperactivity related to AD behavior was reduced and microglia recruitment was increased, which in turn may have contributed to the decrease in the volume of Aβ plaques. In addition, the RE program restored the levels of IL-1α, IL-4, and IL-6 cytokines to control levels. Our study indicates that RE has beneficial effects on the locomotor behavior, amyloid burden, and inflammation of AD pathology and can therefore be used as a therapy to improve the clinical symptoms and neurophysiological alterations in AD. To the best of our knowledge, this is the first study to use a resistance exercise program in transgenic AD model.

Pages 1541-1554
Olga Prikhodko, Kevin D. Rynearson, Travis Sekhon, Mike M. Mante, Phuong D. Nguyen, Robert A. Rissman, Rudolph E. Tanzi, Steven L. Wagner
The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer’s Disease
Abstract: Background: In the amyloid hypothesis of Alzheimer’s disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects. Objective: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology.

Pages 1555-1563
Junhong Yu, Qiushi Feng, Jintai Yu, Yi Zeng, Lei Feng (Handling Associate Editor: Guodong Lu)
Late-Life Cognitive Trajectories and their Associated Lifestyle Factors
Abstract: Significant variability exists in the trajectories of late-life cognitive decline; however, their associated lifestyle factors remain less studied. We examined these trajectories among elderly participants from the recent five waves (at three-year intervals) of the Chinese Longitudinal Healthy Longevity Study (CLHLS) from 2002 to 2014. Participants from this cohort were included if they completed at least four waves of measurements. Mini–Mental State Examination (MMSE) scores, demographics, medical diagnoses (e.g., hypertension, diabetes, and heart disease), and lifestyle-related information (e.g., smoking, drinking alcohol, and exercise) were collected from participants (N= 2,584; mean age at baseline=73.3) at least four times across 12 years. MMSE scores were entered into a latent class mixed model analysis. Subsequently, demographic, medical, and lifestyle predictors were entered into multinomial logistic regression models to predict the trajectories. One of the four emerged classes (no decline) was characterized by an absence of cognitive decline; the other three exhibited various degrees of cognitive decline. The inclusion of lifestyle factors significantly improved the prediction of the different trajectories, above and beyond demographics and medical variables; the ‘no decline’ class was significantly more likely to report exercising regularly. Changes in cognitive functioning across the late-life period are characterized by multiple trajectories. Cognitive decline is not inevitable across the late-life period; the absence of such cognitive decline is partly explained by certain lifestyle factors.

Pages 1565-1573
Ziyun Xu*, Jianjun Wang*, Hanqing Lyu, Runshi Wang, Yuanming Hu, Zhouke Guo, Jinping Xu, Qingmao Hu *These authors contributed equally in this work.
Alterations of White Matter Microstructure in Subcortical Vascular Mild Cognitive Impairment with and without Depressive Symptoms
Abstract: Background: Depressive symptoms were thought to increase the risk of vascular dementia. Previous studies reported widespread white matter damages in the subcortical vascular mild cognitive impairment (svMCI), but little is known about the mechanism of depressive symptoms in svMCI. Objective: In the current study, we aim to explore the white matter microstructural alterations in svMCI with depressive symptoms, and their associations with clinical measurements. Methods: Fifty-eight subjects including 18 svMCI with depression (svMCI+D), 17 svMCI without depression (svMCI-D), and 23 normal controls (NC) were included in the study. Voxel-based analyses were performed on fractional anisotropy (FA) and mean diffusivity (MD). Results: Compared to NC, both svMCI groups showed decreased FA in the bilateral insula and the left precentral gyrus, and increased MD in the cerebellum. Compared to svMCI-D, svMCI+D showed increased FA in left precentral gyrus. Moreover, svMCI+D showed significant correlation between the increased MD in the cerebellum and the Hamilton Depression Rating Scale (HAMD) scores. Conclusion: Our findings of white matter alterations might be associated with executive function and memory performance in the svMCI patients. Moreover, the structural alterations in the cerebellum might underlie the mechanism of depressive symptoms in svMCI patients.

Pages 1575-1583
Neus Falgàs*, Mircea Balasa*, Núria Bargalló, Sergi Borrego-Écija, Oscar Ramos-Campoy, Guadalupe Fernández-Villullas, Beatriz Bosch, Jaume Olives, Adrià Tort-Merino, Anna Antonell, Magdalena Castellví, Isabel E. Allen, Raquel Sánchez-Valle, Albert Lladó *These authors contributed equally to this work.
Diagnostic Accuracy of MRI Visual Rating Scales in the Diagnosis of Early Onset Cognitive Impairment
Abstract: Background: The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker. Objective: We aim to determine the distribution and diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias. Methods: We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer’s disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients [11 with behavioral variant (bvFTD), nine with semantic variant of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA)], 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed. Results: Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders. Conclusions: The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker.

Pages 1585-1595
Júlia Faura, Alejandro Bustamante, Anna Penalba, Dolors Giralt, Alba Simats, Elena Martínez-Sáez, Daniel Alcolea, Juan Fortea, Alberto Lleó, Charlotte E. Teunissen, Wiesje M. van der Flier, Laura Ibañez, Oscar Harari, Carlos Cruchaga, Mar Hernández-Guillamón, Pilar Delgado, Joan Montaner
CCL23: A Chemokine Associated with Progression from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer’s disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n=53; study 2, n=200) and two longitudinal (study 3, n=74; study 4, n=332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR)=2.5 (confidence interval (CI) 95%: 1.2-5.3), p=0.02) and in the CSF in study 4 (HR=3.05 (CI 95%: 1.02-5), p=0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOE ε4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33-597.76) versus 377.94 pg/mL (IQR: 267.16-529.19), p=0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression.

Pages 1597-1606
Kenjiro Ono, Daisy Zhao, Qingli Wu, James Simon, Jun Wang, Aurelian Radu, Giulio Maria Pasinetti
Pine Bark Polyphenolic Extract Attenuates Amyloid-β and Tau Misfolding in a Model System of Alzheimer’s Disease Neuropathology
Abstract: Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer’s disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-β protein (Aβ). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aβ1-40 and Aβ1-42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-β-Glucuronide, Me-(±)-C-O-β-glucuronide, EC-O-β-glucuronide, and (±)-C-O-β-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.

Pages 1607-1614
Mélanie Planton*, Laure Saint-Aubert*, Nicolas Raposo, Pierre Payoux, Anne-Sophie Salabert, Jean-François Albucher, Jean-Marc Olivot, Patrice Péran, Jérémie Pariente *These authors contributed equally to this work.
Florbetapir Regional Distribution in Cerebral Amyloid Angiopathy and Alzheimer’s Disease: A PET Study
Abstract: Background: Sporadic cerebral amyloid angiopathy shows progressive amyloid-β deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. Objective: To investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer’s disease (MCI-AD). Methods: We assessed [18F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis. Results: Global florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21-1.41] versus 1.44 [1.35-1.66]; p=0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (p=0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients. Conclusions: Patients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid.

Pages 1615-1626
Boris-Stephan Rauchmann, Angélique Sadlon, Robert Perneczky for the Alzheimer's Disease Neuroimaging Initiative
Soluble TREM2 and Inflammatory Proteins in Alzheimer’s Disease Cerebrospinal Fluid
Abstract: The present study explores the associations of soluble TREM2, an important regulator of microglial activity linked to Alzheimer’s disease (AD), with other known inflammatory proteins in cerebrospinal fluid (CSF). We studied 303 participants, including 89 controls, 135 mild cognitive impairment, and 79 AD dementia patients. Using established CSF biomarkers, subjects were classified according to the National Institute on Aging-Alzheimer’s Association research framework, which groups markers into those of amyloid-β deposition (A), tau pathology (T), and neurodegeneration (N). TNFR1, TNFR2, TGF-β1, TGFβ2, IL-9, TNF-α, ICAM1, and VCAM1 showed significant concentration differences between the ATN groups, with higher concentrations in more advanced disease categories. sTREM2 was positively associated with the pro-inflammatory proteins TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, and IP-10 and negatively with IL-21; also, positive associations with the anti-inflammatory proteins TGFβ1, IL-10, and IL-9 were found. Pathway enrichment analysis highlighted the involvement of sTREM2 in key functional clusters including immunoglobulin and cytokine production and cellular response to lipopolysaccharides, cytokines, and steroid hormones. Our work provides further evidence in support of TREM2 as a marker of neuroinflammatory response in AD.

Pages 1627-1635
Matthew Mold, Caroline Linhart, Johana Gómez-Ramírez, Andrés Villegas-Lanau, Christopher Exley
Aluminum and Amyloid-β in Familial Alzheimer’s Disease
Abstract: Genetic predispositions associated with metabolism of the amyloid-β protein precursor underlie familial Alzheimer’s disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-β. Human exposure to aluminum is linked to the etiology of Alzheimer’s disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer’s disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer’s disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer’s disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-β to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer’s disease. Aluminum and amyloid-β were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-β in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-β and allows postulation that genetic predispositions defining familial Alzheimer’s disease underlie this relationship.

Pages 1637-1645
Ran Furman, Sharon C.W. Ng, Hiroaki Komatsu, Paul H. Axelsen
Quantitative Mass Spectrometric Assay of Whole and CNBr-Cleaved Amyloid-β Peptides in Human Brain
Abstract: Various amyloid-β (Aβ) peptides accumulate in brain in Alzheimer’s disease, and the amounts of specific peptide variants may have pathological significance. The quantitative determination of these variants is challenging because losses inevitably occur during tissue processing and analysis. This report describes the use of stable-isotope-labeled Aβ peptides as internal standards for quantitative mass spectrometric assays, and the use of cyanogen bromide (CNBr) to remove C-terminal residues beyond Met35. The removal of residues beyond Met35 reduces losses due to aggregation, and facilitates the detection of post-translationally modified Aβ peptides. Results from 8 human brain samples suggest that the tissue concentrations of the 42-residue Aβ peptide tend to be similar in different patients. Concentrations of the 40-residue Aβ peptide are more variable, and may be greater or lesser than the 42-residue peptide. The concentration of the CNBr cleavage product closely matches the sum of the 40-residue and 42-residue peptide concentrations, indicating that these two Aβ peptides account for most of the C-terminal variants in these patients. CNBr treatment facilitated the detection of post-translational modifications such as pyroglutamyl and hexose-modified Aβ peptides.

Pages 1647-1659
Marco Spallazzi, Giovanni Michelini, Federica Barocco, Francesca Dieci, Sandra Copelli, Giovanni Messa, Maura Scarlattei, Giovanni Pavesi, Livia Ruffini, Paolo Caffarra
The Role of Free and Cued Selective Reminding Test in Predicting [18F]Florbetaben PET Results in Mild Cognitive Impairment and Mild Dementia
Abstract: Background: Free and Cued Selective Reminding Test (FCSRT) is a reliable cognitive marker for Alzheimer’s disease (AD), and the identification of neuropsychological tests sensitive to the early signs of AD pathology is crucial both in research and clinical practice. Objective: The study aimed to ascertain the ability of FCSRT in predicting the amyloid load as determined from amyloid PET imaging (Amy-PET) in patients with cognitive disorders. Methods: For our purpose, 79 patients (71 MCI, 8 mild dementia) underwent a complete workup for dementia, including the FCSRT assessment and a [18F]florbetaben PET scan. FCSRT subitem scores were used as predictors in different binomial regression models. Results: Immediate free recall and delayed free recall were the best predictors overall in the whole sample; whereas in patients < 76 years, all models further improved with immediate total recall (ITR) and Index of Sensitivity of Cueing (ISC) resulting the most accurate in anticipating Amy-PET results, with a likelihood of being Amy-PET positive greater than 85% for ITR and ISC scores of less than 25 and 0.5, respectively. Conclusion: FCSRT proved itself to be a valid tool in dementia diagnosis, also being able to correlate with amyloid pathology. The possibility to predict Amy-PET results through a simple and reliable neuropsychological test might be helpful for clinicians in the dementia field, adding value to a paper and pencil tool compared to most costly biomarkers.