Volume 55, Number 4, 2017

Pages 1295-1306

Fiammetta Monacelli, Michele Cea, Roberta Borghi, Patrizio Odetti, Alessio Nencioni
Do Cancer Drugs Counteract Neurodegeneration? Repurposing for Alzheimer’s Disease
Abstract: In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer’s disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD.

Pages 1307-1320

Leszek Szablewski
Glucose Transporters in Brain: In Health and in Alzheimer’s Disease
Abstract: Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer’s (AD) and Huntington’s diseases, abnormalities in neuronal glucose metabolism have been showed. The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O-GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD.

Pages 1321-1325
Short Communication

Mariecia D. Fraser, John R.T. Davies, Xianmin Chang (Handling Associate Editor: Anne Fink)
New Gold in Them Thar Hills: Testing a Novel Supply Route for Plant-Derived Galanthamine
Abstract: Many secondary plant compounds are synthesized in response to stressed growing conditions. We tested the feasibility of exploiting this feature in a novel strategy for the commercial production of the plant alkaloid galanthamine. Experimental lines of Narcissus pseudonarcissus were established under marginal upland permanent pasture at four different sites. Over 80% of bulbs successfully established at each site. There was no effect of altitude or planting density on galanthamine concentrations within vegetative tissues, which were higher than anticipated. The results confirm that planting N. pseudonarcissus under grass competition in upland areas could offer a novel and sustainable source of plant-derived galanthamine.

Pages 1327-1333
Short Communication

Andrea Gamir-Morralla, Olivia Belbin, Juan Fortea, Daniel Alcolea, Isidro Ferrer, Alberto Lleó, Teresa Iglesias
Kidins220 Correlates with Tau in Alzheimer’s Disease Brain and Cerebrospinal Fluid
Abstract: Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer’s disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.

Pages 1335-1337
Short Communication

David Bergeron, Antoine Vermette, Justine De La Sablonnière, Anne-Marie Cayer, Robert Jr. Laforce, Rémi W. Bouchard
Finger-to-Nose Test Findings in Alzheimer’s Disease
Abstract: The finger-to-nose test is routinely performed during the clinical assessment of patients with cognitive impairments. Although widely known to screen for cerebellar dysfunction by unmasking appendicular ataxia, we have found that this test could also be interpreted from a cognitive perspective. We describe two typical signs observed at the finger-to-nose test in Alzheimer’s disease (AD) patients: the “second finger syndrome” and the “distal pressure sign”. By retrospectively reviewing the medical records 461 patients followed at our academic memory clinic, we found that these signs are commonplace in AD, but not in vascular dementia or subjective cognitive impairment.

Pages 1339-1349
Sarah A. Chau, Nathan Herrmann, Chelsea Sherman, Jonathan Chung Moshe Eizenman, Alex Kiss, Krista L. Lanctôt
Visual Selective Attention Toward Novel Stimuli Predicts Cognitive Decline in Alzheimer’s Disease Patients
Abstract: Background: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression. Objective: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients. Methods: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners’ Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years. Results: Multivariate linear regressions of 32 AD patients (14 females, age=77.9±7.8, baseline sMMSE=22.2±4.4) indicated that reduced time spent on novel images (t=2.78, p=0.010) was also associated with greater decline in sMMSE scores (R2=0.41, Adjusted R2=0.35, F3,28=6.51, p=0.002), adjusting for attention and baseline sMMSE. Conclusion: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired.

Pages 1351-1362
Esha Gauba, Lan Guo, Heng Du
Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice
Abstract: Brain aging is the known strongest risk factor for Alzheimer’s disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defected F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.

Pages 1363-1377
Katherine Reiter, Kristy A. Nielson, Sally Durgerian, John L. Woodard, J. Carson Smith, Michael Seidenberg, Dana A. Kelly, Stephen M. Rao (Handling Associate Editor: Mark Bondi)
Five-Year Longitudinal Brain Volume Change in Healthy Elders at Genetic Risk for Alzheimer’s Disease
Abstract: Neuropathological changes associated with Alzheimer’s disease (AD) precede symptom onset by more than a decade. Possession of an apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset AD. Cross-sectional studies of cognitively intact elders have noted smaller hippocampal/medial temporal volumes in ε4 carriers (ε4+) compared to ε4 non-carriers (ε4-). Few studies, however, have examined long-term, longitudinal, anatomical brain changes comparing healthy ε4+ and ε4- individuals. The current five-year study examined global and regional volumes of cortical and subcortical grey and white matter and ventricular size in 42 ε4+ and 30 ε4- individuals. Cognitively intact participants, ages 65-85 at study entry, underwent repeat anatomical MRI scans on three occasions: baseline, 1.5, and 4.75 years. Results indicated no between group volumetric differences at baseline. Over the follow-up interval, the ε4+ group experienced a greater rate of volume loss in total grey matter, bilateral hippocampi, right hippocampal subfields, bilateral lingual gyri, parahippocampal gyrus, and right lateral orbitofrontal cortex compared to the ε4- group. Greater loss in grey matter volumes in ε4+ participants were accompanied by greater increases in lateral, third, and fourth ventricular volumes. Rate of change in white matter volumes did not differentiate the groups. The current results indicate that longitudinal measurements of brain atrophy can serve as a sensitive biomarker for identifying neuropathological changes in persons at genetic risk for AD and potentially, for assessing the efficacy of treatments designed to slow or prevent disease progression during the preclinical stage of AD.

Pages 1379-1394
Stefan J. Teipel, Felix Keller, Jochen R. Thyrian, Urs Strohmaier, Attila Altiner, Wolfgang Hoffmann, Ingo Kilimann
Hippocampus and Basal Forebrain Volumetry for Dementia and Mild Cognitive Impairment Diagnosis: Could It Be Useful in Primary Care?
Abstract: Background: Once a patient or a knowledgeable informant has noticed decline in memory or other cognitive functions, initiation of early dementia assessment is recommended. Hippocampus and cholinergic basal forebrain (BF) volumetry supports the detection of prodromal and early stages of Alzheimer’s disease (AD) dementia in highly selected patient populations. Objective: To compare effect size and diagnostic accuracy of hippocampus and BF volumetry between patients recruited in highly specialized versus primary care and to assess the effect of white matter lesions as a proxy for cerebrovascular comorbidity on diagnostic accuracy. Methods: We determined hippocampus and BF volumes and white matter lesion load from MRI scans of 71 participants included in primary care intervention trial (clinicaltrials.gov identifier: NCT01401582) and a matched 71 participants stemming from a memory clinic. Samples included healthy controls and people with mild cognitive impairment (MCI), AD dementia, mixed dementia, and non-AD related dementias. Results: Volumetric measures reached similar effect sizes and cross-validated levels of accuracy in the primary care and the memory clinic samples for the discrimination of AD and mixed dementia cases from healthy controls. In the primary care MCI cases, volumetric measures reached only random guessing levels of accuracy. White matter lesions had only a modest effect on effect size and diagnostic accuracy. Conclusions: Hippocampus and BF volumetry may usefully be employed for the identification of AD and mixed dementia, but the detection of MCI does not benefit from the use of these volumetric markers in a primary care setting.

Pages 1395-1401
Hui Jin Ryu, Minyoung Kim, Yeonsil Moon, Yeji Choi, Jiyoung Han, James E. Galvin, Seol-Heui Han (Handling Associate Editor: Sang Won Seo)
Validation of the Korean Version of the Lewy Body Composite Risk Score (K-LBCRS)
Abstract: The Lewy body composite risk score (LBCRS) is a useful clinical screening tool to help determine whether the dementia is related to Lewy body pathology. The purpose of this study is to verify reliability, validity, and diagnostic usefulness of Korean version of LBCRS (K-LBCRS). CDR-sum of boxes, Mini-Mental State Examination, and standardized scales related to cognition, mood, behavior, and motor function were administered to a total of 107 subjects, including 30 dementia with Lewy bodies (DLB), 54 Alzheimer's disease (AD), and 23 cognitively normal elderly people and their collateral informants. Internal consistency of the K-LBCRS was good with Cronbach’s alpha of 0.85, and concurrent validity was also satisfactory, with K-LBCRS correlating highly with CDR-SB and other scales. The test-retest reliability was very high with a Pearson correlation coefficient of 0.97. The mean scores of K-LBCRS were significantly different among three groups, with DLB (6.2±2.4), AD (1.4±1.3), and controls (0.3±0.6). We identified a cut-off score of 3 as best to differentiate between DLB and AD, having AUC of 0.97 (95% CI 0.94-1.00), sensitivity 97%, specificity 83%, positive predictive value 76%, negative predictive value 98%, which is the same score suggested in the original study. This study shows K-LBCRS as a new useful screening tool for Korean DLB patients in clinical settings.

Pages 1403-1416
Hiroaki Kazui, Ryuichi Takahashi, Yuki Yamamoto, Kenji Yoshiyama, Hideki Kanemoto, Yukiko Suzuki, Shunsuke Sato, Shingo Azuma, Takashi Suehiro, Eku Shimosegawa, Kazunari Ishii, Toshihisa Tanaka (Handling Associate Editor: Akihiko Nunomura)
Neural Basis of Apathy in Patients with Amnestic Mild Cognitive Impairment

Abstract: Background: Although apathy is associated with damage to the frontal and temporal lobes in Alzheimer’s disease (AD), the crucial regions for apathy in patients with amnestic mild cognitive impairment (aMCI) are unknown. Objective: To identify brain regions associated with apathy in aMCI patients. Methods: The subjects of this study were 98 aMCI patients who were entered in our dementia registry between March 1, 2009 and April 30, 2015 and who satisfied our criteria for aMCI. The associations between the apathy score of the Neuropsychiatric Inventory and the gray matter volumes of different regions were analyzed using voxel-based morphometry. The association between apathy score and regional cerebral blood flow (rCBF) measured with single photon emission computed tomography (SPECT) was analyzed using Statistical Parametric Mapping. Results: The aMCI patients were classified into aMCI with and without “SPECT images suggestive of AD” (aMCI-AD+ and aMCI-AD-, respectively) based on the Z-score summation analysis method. In aMCI-AD+ (n=31), apathy was significantly and negatively correlated with gray matter volume in the right caudate nucleus and with rCBF in five regions (left posterior-medial frontal lobe, right superior frontal lobe, bilateral culmen-fusiform gyri, and left occipital lobe). In aMCI-AD- (n=67), apathy was significantly and negatively correlated with gray matter volumes in five regions but it was not correlated with rCBF in any regions. Conclusion: In patients with a high probability of being in the aMCI stage of AD, apathy was associated with atrophy of the right caudate nucleus and hypoperfusion in the frontal, temporal and occipital lobes.

Pages 1417-1427
Nicola Voyle, Hamel Patel, Amos Folarin, Stephen Newhouse, Caroline Johnston, Pieter Jelle Visser, Richard J.B. Dobson*, Steven J. Kiddle*, the EDAR and DESCRIPA study groups and the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Gary Arendash) *These authors are joint senior authors.
Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid
Abstract: Background: The search for a biomarker of Alzheimer’s disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau. Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF. Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype (‘basic model’). Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of tau, Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 58.4%, 66.0%, and 73.3% respectively). Similar results were seen in ADNI 2 test data. Conclusion: We see that a case/control PGRS is no more predictive of Aβ or tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated. *‘Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response’. **‘Development of screening guidelines and criteria for pre-dementia Alzheimer’s disease’.

Pages 1429-1435
Sofía Abrevaya, Lucas Sedeño, Sol Fitipaldi, David Pineda, Francisco Lopera, Omar Buritica, Andrés Villegas, Catalina Bustamante, Diana Gomez, Natalia Trujillo, Ricardo Pautassi, Agustín Ibáñez, Adolfo M. García (Handling Associate Editor: Fiona Kumfor)
The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson’s Disease
Abstract: Action verbs are critically embodied in motor brain networks. In Parkinson’s disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients’ level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients’ reliance on this alternative route. These results offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD.

Pages 1437-1443
Eva Mª Arroyo-Anlló, Adèle Turpin Bouston, Marie-Noëlle Fargeau, Begoña Orgaz Baz, Roger Gil
Self-Consciousness Deficits in Alzheimer’s Disease and Frontotemporal Dementia
Abstract: Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The main aim of this paper is to compare SC in patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Three groups (control and patient groups) of 23 subjects each were assessed using an SC questionnaire. Both types of dementia clearly induce an alteration of SC. The bvFTD group showed a greater impairment in SC than the AD and control groups. The SC score was strongly associated with frontal functions. The most significantly impaired SC aspects in the bvFTD group were Anosognosia, Introspection, and Moral Judgments. For the AD group, the significantly impaired aspects of SC were Anosognosia and Prospective Memory. The differences in SC between the AD and bvFTD groups were essentially centered on the Anosognosia, Moral Judgments, and Introspection aspects, which were highly impaired in the bvFTD patients. This suggests that SC is related to orbito-frontal functioning and thus, to the default mode network.

Pages 1445-1451
Tamires Alves Sarno, Leda Leme Talib, Helena Passarelli Giroud Joaquim, Jessyka Maria de França Bram, Wagner Farid Gattaz, Orestes Vicente Forlenza
Protein Expression of BACE1 is Downregulated by Donepezil in Alzheimer’s Disease Platelets
Abstract: Background: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer’s disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD. Objective: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil. Methods: Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting. Results: AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months. Conclusion: Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

Pages 1453-1461
George P. Paraskevas, Dimitriοs Kaselimis, Evie Kourtidou, Vasilios Constantinides, Anastasia Bougea, Costas Potagas, Ioannis Evdokimidis, Elisabeth Kapaki
Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia
Abstract: Background: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer’s disease (AD) are the most common etiologies. Objective: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA. Methods: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP-181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls. Results: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τP-181/Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τP-181/τΤ ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43). Conclusion: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology.

Pages 1463-1469
Stephan Müller, Oliver Preische, Petra Heymann, Ulrich Elbing, Christoph Laske
Diagnostic Value of a Tablet-Based Drawing Task for Discrimination of Patients in the Early Course of Alzheimer’s Disease from Healthy Individuals
Abstract: There is a considerable delay in the diagnosis of dementia, which may reduce the effectiveness of available treatments. Thus, it is of great interest to develop fast and easy to perform, non-invasive and non-expensive diagnostic measures for the early detection of cognitive impairment and dementia. Here we investigate movement kinematics between 20 patients with early dementia due to Alzheimer’s disease (eDAT), 30 patients with amnestic MCI (aMCI), and 20 cognitively healthy control (HC) individuals while copying a three-dimensional house using a digitizing tablet. Receiver-operating characteristic (ROC) curves and logistic regression analyzes have been conducted to explore whether alterations in movement kinematics could be used to discriminate patients with aMCI and eDAT from healthy individuals. Time-in-air (i.e., transitioning from one stroke to the next without touching the surface) differed significantly between patients with aMCI, eDAT, and HCs demonstrating an excellent sensitivity and a moderate specificity to discriminate aMCI subjects from normal elderly and an excellent sensitivity and specificity to discriminate patients affected by mild Alzheimer’s disease from healthy individuals. Time-on-surface (i.e., time while stylus is touching the surface) differed only between HCs and patients with eDAT but not between HCs and patients with aMCI. Furthermore, total-time (i.e., time-in-air plus time-on-surface) did not differ between patients with aMCI and early dementia due to AD. Modern digitizing devices offer the opportunity to measure a broad range of visuoconstructive abilities that may be used as a fast and easy to perform screening instrument for the early detection of cognitive impairment and dementia in primary care.

Pages 1471-1480
Samir Abu Rumeileh, Francesca Lattanzio, Michelangelo Stanzani Maserati, Romana Rizzi, Sabina Capellari, Piero Parchi (Handling Associate Editor: Katharina Stoeck)
Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer’s Disease with Emphasis on Atypical Disease Variants
Abstract: According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer’s disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau × Aβ42)/(p-tau × t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the “atypical” disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

Pages 1481-1487
Michiya Igase, Maya Ohara, Keiji Igase, Takeaki Kato, Yoko Okada, Masayuki Ochi, Yasuharu Tabara, Katsuhiko Kohara, Yasumasa Oyagi
Skin Autofluorescence Examination as a Diagnostic Tool for Mild Cognitive Impairment in Healthy People
Abstract: Background: Accumulation of advanced glycation endproducts (AGEs) is thought to be involved in the pathogenesis of dementia, especially Alzheimer’s disease. Tissue AGE accumulation can be estimated using the relative simple noninvasive measurement of skin autofluorescence (SAF), a method based on the fluorescent properties of some AGEs. However, possible involvement of tissue AGE accumulation in mild cognitive impairment (MCI) has not been fully investigated. Objective: We investigated whether tissue AGE accumulation estimated by SAF is associated with mild cognitive impairment. Methods: We analyzed 226 community-dwelling subjects. In addition to several atherosclerosis-related clinical parameters, MCI screening test, assessment of brain atrophy, and SAF were performed on people aged >40 years. MCI was assessed using the Japanese version of the MCI screening method. Atrophy of the brain was assessed by examining the temporal horn area (THA) by brain MRI. Results: SAF was significantly higher in participants with MCI than in those with normal cognitive function (2.56±0.55 versus 2.10±0.41; p<0.001). Logistic regression analyses with adjustment for confounding factors including age and THA showed that high SAF > 2.27 was significantly related to the presence of MCI (odds, 6.402; 95% CI, 1.590–25.773, p=0.009). Conclusion: We found an association between SAF and MCI, which was independent of brain atrophy, in healthy subjects.

Pages 1489-1496
María Carmona-Iragui, Telma Santos, Sebastián Videla, Susana Fernández, Bessy Benejam, Laura Videla, Daniel Alcolea, Kaj Blennow, Rafael Blesa, Alberto Lleó, Juan Fortea (Handling Associate Editor: Philip Scheltens)
Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in Subjects with Down Syndrome
Abstract: Background: Alzheimer’s disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. Objective: To analyze the frequency of complications after a LP in DS. Methods: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. Results: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. Conclusion: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

Pages 1497-1507
Megan Quarmley, Paul J. Moberg, Dawn Mechanic-Hamilton, Sushila Kabadi, Steven E. Arnold, David A. Wolk, David R. Roalf (Handling Associate Editor: Latha Velayudhan)
Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease
Abstract: Background: Measurements of olfaction may serve as useful biomarkers of incipient dementia. Here we examine the improvement in diagnostic accuracy of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) when assessing both cognitive functioning and odor identification. Objective: To determine the utility of odor identification as a supplementary screening test in incipient AD. Methods: Sniffin’ Sticks Odor Identification Test (SS-OIT) and the Montreal Cognitive Assessment (MoCA) were administered in 262 AD, 174 MCI [150 amnestic (aMCI), and 24 non-amnestic (naMCI)], and 292 healthy older adults (HOA). Results: Odor identification scores were higher in HOA relative to MCI or AD groups, and MCI outperformed AD. Odor identification scores were higher in aMCI single domain than aMCI multiple domain. Complementing MoCA scores with the SS-OIT significantly improved diagnostic accuracy of individuals with AD and MCI, including within MCI subgroups. Discussion: Odor identification is a useful supplementary screening tool that provides additional information relevant for clinical categorization of AD and MCI, including those who are at highest risk to convert to AD.

Pages 1509-1517
Vanessa Valdiglesias, Ana Maseda, Laura Lorenzo-López, Eduardo Pásaro, José C. Millán-Calenti, Blanca Laffon
Is Salivary Chromogranin A a Valid Psychological Stress Biomarker During Sensory Stimulation in People with Advanced Dementia?
Abstract: Salivary chromogranin A (sCgA) is gaining attention as a biomarker of psychological stress. The objective of this work was to determine whether individualized music intervention and multisensory stimulation environment (MSSE) in a Snoezelen room produce changes in sCgA in severely demented older patients, and to assess the possible existence of differences in sCgA levels between the two types of interventions. Older adults with severe dementia (n=22) were randomly assigned to two intervention groups. They participated in MSSE or individualized music interventions in 30-min weekly sessions for 16 weeks. Levels of sCgA were evaluated before and after a session, or 30-min interval, at four different time points: before starting the trial, in the middle and end of the intervention period, and two months later. Comparison of sCgA values obtained after each session with those obtained before (or at the same hour in before trial and follow-up samplings) showed no significant differences either in the individualized music or in the MSSE group at any sampling time. Comparison between the two types of interventions, both before and after each session, in the four sampling times, did not produce any significant difference either. Furthermore, no significant correlation was obtained between agitation, anxiety, cognitive function, and dementia severity with sCgA levels. In conclusion, despite beneficial effects of both individualized music and MSSE interventions being previously reported on neuropsychiatric outcomes for older patients with dementia, sCgA seems to not be a good indicator of these benefits.

Pages 1519-1528
Simrin Sennik, Tom A. Schweizer, Corinne E. Fischer, David G. Munoz
Risk Factors and Pathological Substrates associated with Agitation/Aggression in Alzheimer’s Disease: A Preliminary Study using NACC Data
Abstract: Background: Neuropsychiatric symptoms are common manifestations of Alzheimer’s disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. Objective: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. Methods: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. Results: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p=0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. Conclusions: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Pages 1529-1536
Annachiara Cagnin*, Federica Fragiacomo*, Giulia Camporese, Matteo Turco, Cinzia Bussè, Mario Ermani, Sara Montagnese *These authors contributed equally to this work.
Sleep-Wake Profile in Dementia with Lewy Bodies, Alzheimer’s Disease, and Normal Aging
Abstract: Background: Alterations of the sleep-wake cycle are common features of neurodegenerative dementia. Objectives: To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), and healthy controls. Methods: 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries. Results: Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p<0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score= RBD+: 5.2±3.7; RBD-: 2.1±3.2, p=0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls. Discussion: RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

Pages 1537-1548
Ann-Marie Waldron, Leonie wyffels, Jeroen Verhaeghe, Jill C. Richardson, Mark Schmidt, Sigrid Stroobants, Xavier Langlois, Steven Staelens
Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model
Abstract: We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer’s disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

Pages 1549-1570
Dolores Del Prete, Jan M. Suski, Bénédicte Oulès, Delphine Debayle, Anne Sophie Gay, Sandra Lacas-Gervais, Renaud Bussiere, Charlotte Bauer, Paolo Pinton, Patrizia Paterlini-Bréchot, Mariusz R. Wieckowski, Frédéric Checler, Mounia Chami (Handling Associate Editor: Othman Ghribi)
Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes
Abstract: Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer’s disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

Pages 1571-1582
Iman Beheshti, Norihide Maikusa, Hiroshi Matsuda, Hasan Demirel, Gholamreza Anbarjafari, for the Japanese-Alzheimer’s Disease Neuroimaging Initiative
Histogram-Based Feature Extraction from Individual Gray Matter Similarity-Matrix for Alzheimer’s Disease Classification
Abstract: Automatic computer-aided diagnosis (CAD) systems have been widely used in classification of patients who suffer from Alzheimer’s disease (AD). This paper presents an automatic CAD system based on histogram feature extraction from single-subject gray matter similarity-matrix for classifying the AD patients from healthy controls (HC) using structural magnetic resonance imaging (MRI) data. The proposed CAD system is composed of five stages. In the first stage, segmentation is employed to perform pre-processing on the MRI images, and segment into gray matter, white matter, and cerebrospinal fluid using the voxel-based morphometric toolbox procedure. In the second stage, gray matter MRI scans are used to construct similarity-matrices. In the third stage, a novel statistical feature-generation process is proposed, utilizing the histogram of the individual similarity-matrix to represent statistical patterns of the respective similarity-matrices of different size and order into fixed-size feature-vectors. In the fourth stage, we propose to combine MRI measures with a neuropsychological test, the Functional Assessment Questionnaire (FAQ), to improve the classification accuracy. Finally, the classification is performed using a support vector machine and evaluated with the 10-fold cross-validation strategy. We evaluated the proposed method on 99 AD and 102 HC subjects from the J-ADNI. The proposed CAD system yields an 84.07% classification accuracy using MRI measures and 97.01% for combining MRI measures with FAQ scores, respectively. The experimental results indicate that the performance of the proposed system is competitive with respect to state-of-the-art techniques reported in the literature.

Pages 1583-1594
Tim Fleiner, Stefan Leucht, Hans Foerstl, Wiebren Zijlstra, Peter Haussermann
Effects of Short-Term Exercise Interventions on Behavioral and Psychological Symptoms in Patients with Dementia: A Systematic Review
Abstract: Observational and interventional studies indicate a direct link between the patients’ physical activity and the extent of behavioral and psychological symptoms of dementia (BPSD). At present, there are no evidence-based recommendations for physical exercise in the acute dementia care settings. Hence, this systematic review investigates the effects of short-term exercise trials on BPSD. Trials with a length up to three months investigating the effects of structured exercise interventions on BPSD in acute dementia care settings were included. Five trials, referring to a total of N=206 patients, met the inclusion criteria. The trial durations ranged from three up to twelve weeks. All trials conducted three sessions per week of 30 to 45 minutes. Three trials reported significant reductions of BPSD and differences in comparison to the pre-test and control groups. Out of the three trials investigating the effects of exercise interventions on depressive symptoms, one reported significant reduction and two reported no differences in pre-post analysis. Exercise represents a potentially worthwhile approach for the treatment of patients suffering from BPSD. Given the scarcity of available studies, more randomized controlled short-term exercise trials in acute dementia care settings are needed to define appropriate exercise recommendations for clinicians treating these patients.

Pages 1595-1603
Andrea Slachevsky, Leonardo Guzmán-Martínez, Carolina Delgado, Pablo Reyes, Gonzalo A. Farías, Carlos Muñoz, Eduardo Bravo, Mauricio Farías, Patricia Flores, Cristian Garrido, James T. Becker, Oscar L. López, Ricardo B. Maccioni (Handling Associate Editor: Paulo Caramelli)
Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer’s Disease
Abstract: Background: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer’s disease (AD), which are mainly composed of hyperphosphorylated tau protein. Objectives: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects. Methods: We examined 53 AD patients and 37 cognitively normal subjects recruited from a Dementia Unit at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI was analyzed using voxel-based morphology in 41 AD patients. Results: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region. Conclusions: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

Pages 1605-1619
Christine M. Dengler-Crish, Matthew A. Smith, Gina N. Wilson (Handling Associate Editor: Lea Grinberg)
Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease
Abstract: Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate the rate in patients with Alzheimer’s disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome, changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age—time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)—a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in the tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.

Pages 1621-1638
Elena Mariani, Rabih Chattat, Myrra Vernooij-Dassen, Raymond Koopmans, Yvonne Engels (Handling Associate Editor: Patrizia Mecocci)
Care Plan Improvement in Nursing Homes: An Integrative Review
Abstract: Background: Care planning nowadays is a key activity in the provision of services to nursing home residents. A care plan describes the residents’ needs and the actions to address them, providing both individualized and standardized interventions and should be updated as changes in the residents’ conditions occur. Objective: The aim of this review was to identify the core elements of the implementation of changes in nursing homes’ care plans, by providing an overview of the type of stakeholders involved, describing the implementation strategies used, and exploring how care plans changed. Methods: An integrative literature review was used to evaluate intervention studies taking place in nursing homes. Data were collected from PubMed, CINHAL-EBSCO, and PsycINFO. English language articles published between 1995 and April 2015 were included. Data analysis followed the strategy of Knafl and Whittemore. Results: Twenty-six articles were included. The stakeholders involved were professionals, family caregivers, and patients. Only a few studies directly involved residents and family caregivers in the quality improvement process. The implementation strategies used were technology implementation, audit, training, feedback, and supervision. The majority of interventions changed the residents’ care plans in terms of developing a more standardized care documentation that primarily focuses on its quality. Only some interventions developed more tailored care plans that focus on individualized needs. Conclusion: Care plans generally failed in providing both standardized and personalized interventions. Efforts should be made to directly involve residents in care planning and provide professionals with efficient tools to report care goals and actions in care plans.

Pages 1639-1657
Sneha Pandya, Amy Kuceyeski, Ashish Raj, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Asa Hatami)
The Brain’s Structural Connectome Mediates the Relationship between Regional Neuroimaging Biomarkers in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD), one of the most common causes of dementia in adults, is a progressive neurodegenerative disorder exhibiting well-defined neuropathological hallmarks. It is known that disease pathology involves misfolded amyloid-β (Aβ) and tau proteins, and exhibits a relatively stereotyped progression over decades. The relationship between AD neuropathological hallmarks (Aβ, hypometabolism, and tau proteins) and imaging biomarkers (MRI, AV-45/FDG-PET) is not fully understood. In addition, biomarker pathologies are oftentimes discordant, wherein it may show varying levels of abnormality across brain regions. Evidence based on recent elucidation of trans-neuronal “prion-like” transmission and other available data already suggests that disease spread follows the brain’s fiber connectivity network. Thereby, the brain’s connectome information can be used to predict the process of disease spread in AD. A recently established mathematical model of AD pathology spread using a connectome-based network diffusion model was successful in encapsulating neurodegenerative progression. Motivated by these network-based findings, the current study explores whether and how network connectivity mediates the interactions between various AD biomarkers. We hypothesized that the structural connectivity matrix will mediate the cross-sectional association between regional AD-associated hypometabolism and Aβ deposition. Given recent reports of inherent or lifetime activity of brain regions as strong predictors of Aβ deposition in patients, we also tested whether healthy metabolism exerts a network-mediated effect on Aβ deposition and hypometabolism in AD patients. We found that regional Aβ deposition is best predicted by a linear combination of both regional healthy local metabolism and connectome-mediated regional healthy metabolism.

Pages 1659-1666
Giulia M. Sancesario, Sofia Toniolo, Davide Chiasserini, Simona G. Di Santo, Josh Zeeger, Gaetano Bernardi for SIBioC-Study Group of Clinical Biochemistry of Biological Fluids other than Blood, Massimo Musicco for SINdem-ITALPLANED, Carlo Caltagirone, Lucilla Parnetti, Sergio Bernardini
The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease Diagnosis: The Italian Selfie
Abstract: Although the use of cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42), tau (T-tau), and phosphorylated tau (p-tau181) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a “selfie” of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of CSF biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost–benefit analysis should be promoted by scientific societies and national health services.

Pages 1667-1681
Silvia Hilt*, Tang Tang*, Jeffrey H. Walton, Madhu Budamagunta, Izumi Maezawa, Tamás Kálai, Kálmán Hideg, Vikrant Singh, Heike Wulff, Qizhi Gong, Lee-Way Jin, Angelique Louie, John C. Voss (Handling Associate Editor: Ikuo Tooyama) *These authors contributed equally to this work.
A Metal-Free Method for Producing MRI Contrast at Amyloid-β
Abstract: Alzheimer’s disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.

Pages 1683-1692
Ying Wang, Zhu Zhou, Hua Tan, Shenghua Zhu, Yiran Wang, Yingxia Sun, Xin-Min Li, Jun-Feng Wang (Handling Associate Editor: Wolff Kirsch)
Nitrosylation of Vesicular Transporters in Brain of Amyloid Precursor Protein/Presenilin 1 Double Transgenic Mice
Abstract: Nitric oxide can attack thiol groups of cysteine residues in proteins and induce protein cysteine S-nitrosylation. Cholinergic and glutamatergic systems are dysregulated in Alzheimer’s disease. Vesicular acetylcholine transporter (VAChT) and vesicular glutamate transporter 1 (VGLUT1) are important in packaging acetylcholine and glutamate into vesicles, which is an important step for neurotransmission. Previously we found that VAChT and VGLUT1 can be nitrosylated and that S-nitrosylation of these transporters inhibits vesicular uptake of acetylcholine and glutamate. To understand the role of VAChT and VGLUT1 nitrosylation in the pathophysiological development of Alzheimer’s disease, we analyzed nitrosylation of VAChT and VGLUT1 in brain of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice, an animal model for Alzheimer’s disease. Using a Morris water maze test, we found that 9- and 12-month-old APP/PS1 mice showed memory deficit, compared to wild type mice. We further found that total protein nitrosylation was increased in frontal cortex and hippocampus of 9- and 12-month-old APP/PS1 mice. Although nitrosylation of VAChT and VGLUT1 was not changed in hippocampus of 9- and 12-month-old APP/PS1 mice, nitrosylation of VAChT and VGLUT1 was significantly increased in frontal cortex of APP/PS1 mice at these ages. We also found that nitrosylation of VAChT and VGLUT1 was increased in hippocampus (but not frontal cortex) of 3-month-old APP/PS1 mice. These findings suggest that nitrosylation of VAChT and VGLUT1 may be associated with dysfunctional acetylcholinergic and glutamatergic neurotransmission in Alzheimer’s disease.