Volume 60, Number 4, 2017

Pages 1209-1221

Rudy J. Castellani, George Perry (Handling Editor: Massimo Tabaton)
Dementia Pugilistica Revisited
Abstract: Extensive exposure of boxers to neurotrauma in the early 20th century led to the so-called punch drunk syndrome, which was formally recognized in the medical literature in 1928. “Punch drunk” terminology was replaced by the less derisive ‘dementia pugilistica’ in 1937. In the early case material, the diagnosis of dementia pugilistica required neurological deficits, including slurring dysarthria, ataxia, pyramidal signs, extrapyramidal signs, memory impairment, and personality changes, although the specific clinical substrate has assumed lesser importance in recent years with a shift in focus on molecular pathogenesis. The postmortem neuropathology of dementia pugilistica has also evolved substantially over the past 90 years, from suspected concussion-related hemorrhages to diverse structural and neurofibrillary changes to geographic tauopathy. Progressive neurodegenerative tauopathy is among the prevailing theories for disease pathogenesis, although this may be overly simplistic. Careful examination of historical cases reveals both misdiagnoses and a likelihood that dementia pugilistica at that time was caused by cumulative structural brain injury. More recent neuropathological studies indicate subclinical and possibly static tauopathy in some athletes and non-athletes. It is unclear from the literature whether retired boxers reach the inflection point that tends toward progressive neurodegeneration in the manner of Alzheimer’s disease. Even among historical cases with extreme levels of exposure, progressive disease was exceptional.

Pages 1223-1229

Edward R. Blonz
Alzheimer’s Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis
Abstract: The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer’s disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer’s disease and illuminates new approaches for diagnosis, monitoring, and treatment.

Pages 1231-1235
Short Communication

Nobuo Sakata, Yasuyuki Okumura
Job Loss After Diagnosis of Early-Onset Dementia: A Matched Cohort Study
Abstract: Early-onset dementia (EOD) affects the employment of patients and family members. To demonstrate how likely employees are to leave their jobs after an EOD diagnosis for themselves or a family member, we conducted a matched cohort study of 143 employees and 77 family members diagnosed with EOD using a claims database. We matched these participants to 5 controls each, and followed them for approximately 600 days. In the employee cohort, patients with EOD were more likely to leave their jobs than were controls (hazard ratio: 2.26). This suggests that healthcare providers should offer employment support to patients just after diagnosis.

Pages 1237-1239

Evy Woumans, Jan Versijpt, Anne Sieben, Patrick Santens, Wouter Duyck
Bilingualism and Cognitive Decline: A Story of Pride and Prejudice
Abstract: In a recent review, Mukadam, Sommerlad, and Livingston (2017) argue that bilingualism offers no protection against cognitive decline. The authors examined the results of 13 studies (five prospective, eight retrospective) in which monolinguals and bilinguals were compared for cognitive decline and onset of dementia symptoms. Analysis of four of the five prospective studies resulted in the conclusion that there was no difference between monolinguals and bilinguals, whereas seven of the eight retrospective studies actually showed bilingualism to result in a four-to-five year delay of symptom onset. The authors decided to ignore the results from the retrospective studies in favor of those from the prospective studies, reasoning that the former may be confounded by participants’ cultural background and education levels. In this commentary, we argue that most of these studies actually controlled for these two variables and still found a positive effect of bilingualism. Furthermore, we argue that the meta-analysis of the prospective studies is not complete, lacking the results of two crucial reports. We conclude that the literature offers substantial evidence for a bilingual effect on the development of cognitive decline and dementia.

Pages 1241-1257
Ling Zhang*, Ying Wang*, Xia Xiayu, Changhua Shi, Wei Chen, Nan Song, Xinjing Fu, Rui Zhou, Yan-feng Xu, Lan Huang, Hua Zhu, Yunlin Han, Chuan Qin *These authors contributed equally to this work.
Altered Gut Microbiota in a Mouse Model of Alzheimer’s Disease
Abstract: The topic of gut microbiota is currently attracting considerable interest as a potential factor in Alzheimer’s disease (AD). However, the extent and time course of alterations in the gut microbiota, and their effects on AD pathology remain uncertain. Herein, we compared the fecal microbiomes and fecal short chain fatty acid composition (SCFAs) between wild-type and AD model mice at different ages under strictly controlled specific pathogen free conditions, and also conducted microscopic investigations of intestinal structures. Our results showed that the microbiota composition and diversity were perturbed and the level of SCFAs was reduced in AD mice, predicting alterations in more than 30 metabolic pathways, which may be associated with amyloid deposition and ultrastructural abnormalities in AD mouse intestine. These findings indicate that AD pathology might not only affect brain function directly, but also exacerbate cognitive deficits through reducing the level of SCFAs via alterations of gut microbiota induced by intestinal amyloid deposition. Our data may support a role of gut microbiota, and suggest a novel route for therapeutic intervention in AD.

Pages 1259-1266
Elodie Pongan, Jean-Michel Dorey, Pierre Krolak-Salmon, Denis Federico, Claire Sellier, Nicolas Auguste, Florence Fabre, Bernard Laurent, Béatrice Trombert-Paviot, Isabelle Rouch (Handling Associate Editor: Alba Malara)
Predictors of Discharge Destinations and Three-Month Evolution of Patients Initially Hospitalized in a Cognitive Behavioral Unit
Abstract: Background: Previous studies showed that a third of patients living at home entered an institution after hospitalization in Cognitive and Behavioral Units (CBUs). Objective: The main objective of this study was to identify predictors of discharge destination for these patients. The secondary objective was to estimate whether institutionalization can have an impact on a patient’s long-term prognosis. Methods: The study population was selected from the EVITAL study and included 140 participants living at home before hospitalization in CBUs. Factors favoring nursing-home admission were investigated and the impact of discharge destinations (i.e., home or nursing home) on patients’ prognosis was examined. Results: Institutionalized patients were more likely to be women (F=4.7; p=0.03), with a higher dementia severity (F=9.82; p=0.007), often living alone (F=19.69; p=0.001), with a caregiver other than spouse (F=8.93; p= 0.003), and with a higher patient quality of life (QoL) according to the caregiver (F=11.73; p=0.001). When using multivariate logistic linear regressions, we showed a relationship between marital status (OR=0.19, 95% CI: 0.08-0.43, p<0.001), dementia severity (OR=0.15, 95%CI: 0.03-0.79, p=0.03), QoL (OR=0.88, 95%CI: 0.79–0.98, p=0.017), and institutionalization. At three months, a higher overall rate of rehospitalization (F=12.21; p<0.001) and rehospitalization for behavioral and psychological symptoms of dementia (F=6.76; p=0.006) were observed for patients staying at home after CBU discharge. Conclusion: Our study allows for a better understanding of the institutionalization risk factors of the patients hospitalized in CBUs. Identification of these factors could help clinicians to better support patients and to help the transition to be smoother. Moreover, our results suggest that prognosis of institutionalized patients is not unfavorable when compared with patients staying at home.

Pages 1267-1274
Jacopo C. DiFrancesco, Lucio Tremolizzo, Valeria Polonia, Giorgia Giussani, Elisa Bianchi, Carlotta Franchi, Alessandro Nobili, Ildebrando Appollonio, Ettore Beghi, Carlo Ferrarese
Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study
Abstract: Background: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer’s disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Objective: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. Methods: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). Results: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3–28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. Conclusions: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

Pages 1275-1283
Virginia Boccardi, Manuela Conestabile della Staffa, Marta Baroni, Sara Ercolani, Michele Francesco Croce, Carmelinda Ruggiero, Patrizia Mecocci, for the ReGAL study group (Handling Associate Editor: Domenico Pratico)
Prevalence and Correlates of Behavioral Disorders in Old Age Subjects with Cognitive Impairment: Results from the ReGAl Project
Abstract: Background: Presence of behavioral and psychological symptoms of dementia (BPSD) is very common in subjects with cognitive impairment, representing an important determinant of disease progression, institutionalization, and worse prognosis. Knowledge of the prevalence and correlates of BPSD in community-living old subjects with cognitive impairment is limited so far, but it is essential for establishing specifically tailored care and cure in such a vulnerable population. Objective: With this study, we aimed at investigating, in a large sample of old age subjects with cognitive impairment, BPSD prevalence and correlates including the main demographic, clinical, and socio-environmental characteristics. Methods: Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer; Geriatric Network on Alzheimer’s disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). Results: We evaluated data from 4,157 old-age subjects affected by mild cognitive impairment (MCI) (541; 13%) or dementia (3616; 87%). 85.2% of all the population presented with at least one BPSD. Using a factor analysis, we identified four factors of BPSD: psychotic, affective, maniac, and impulse control behaviors. Logistic regression analyses revealed that among the main demographic, clinical, and socio-environmental aspects considered, only comorbidity was associated with all factors, independently of multiple covariates. Conclusion: Identification of BPSD is crucial in everyday clinical practice and necessary to develop specific interventions and to define appropriate outcomes in their management. BPSD occur in a complex psychopathological context, influenced by several demographic and environmental factors that must be taken into account for a correct diagnosis and treatment.

Pages 1285-1294
Florian U. Fischer, Dominik Wolf, Andreas Fellgiebel for the Alzheimer’s Disease Neuroimaging Initiative
Diaschisis-Like Association of Hippocampal Atrophy and Posterior Cingulate Cortex Hypometabolism in Cognitively Normal Elderly Depends on Impaired Integrity of Parahippocampal Cingulum Fibers
Abstract: Hippocampal atrophy and hypometabolism of the posterior cingulate cortex (PCC), early markers of Alzheimer’s disease (AD), have been shown to be associated in late mild cognitive impairment and early AD via atrophy of connecting cingulum fibers. Recently, a direct association of hippocampal atrophy and PCC hypometabolism has been shown in cognitively normal elderly. We aimed to investigate if this association might be modulated by partly non-hippocampogenic alterations of parahippocampal cingulum (PHC) integrity. 45 cognitively healthy elderly aged 59 to 89 years were included from the Alzheimer’s Disease Neuroimaging Initiative. Hippocampal volumes and PCC glucose metabolism were measured using MRI and FDG-PET. PHC fibers connecting the hippocampus and the PCC were reconstructed using diffusion weighted MRI and measures of diffusivity were calculated. Using robust linear regression, interaction effects of PHC diffusivity and hippocampal volume on PCC metabolism were calculated. For both hemispheres, significant interaction effects were found for PHC mean diffusivity. Interaction effects were such that the association of hippocampal volume and PCC metabolism was higher in subjects with increased mean diffusivity in PHC fibers. In cognitively normal elderly, compromised integrity of the PHC may increase the risk of PCC hypometabolism due to hippocampal atrophy. Spared PHC fiber integrity may protect against PCC hypometabolism due to hippocampal atrophy.

Pages 1295-1312
Ríona Mc Ardle, Rosie Morris, Joanna Wilson, Brook Galna, Alan J. Thomas, Lynn Rochester
What Can Quantitative Gait Analysis Tell Us about Dementia and Its Subtypes? A Structured Review
Abstract: Distinguishing dementia subtypes can be difficult due to similarities in clinical presentation. There is increasing interest in discrete gait characteristics as markers to aid diagnostic algorithms in dementia. This structured review explores the differences in quantitative gait characteristics between dementia and healthy controls, and between four dementia subtypes under single-task conditions: Alzheimer’s disease (AD), dementia with Lewy bodies and Parkinson’s disease dementia, and vascular dementia. Twenty-six papers out of an initial 5,211 were reviewed and interpreted using a validated model of gait. Dementia was associated with gait characteristics grouped by slower pace, impaired rhythm, and increased variability compared to normal aging. Only four studies compared two or more dementia subtypes. People with AD are less impaired in pace, rhythm, and variability domains of gait compared to non-AD dementias. Results demonstrate the potential of gait as a clinical marker to discriminate between dementia subtypes. Larger studies using a more comprehensive battery of gait characteristics and better characterized dementia sub-types are required.

Pages 1313-1324
Kelsey E. McLimans*, Joseph L. Webb*, Vellareddy Anantharam, Anumantha Kanthasamy, Auriel A. Willette, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease
Abstract: Background/Objective: Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer’s disease (AD) diagnosis. Methods: IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations. Results: Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. Conclusions: IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.

Pages 1325-1332
Aditi Joshi, Elvira Jimenez, Mario F. Mendez
Initial Heart Rate Reactivity to Socioemotional Pictures in Early-Onset Alzheimer’s Disease
Abstract: Patients with Alzheimer’s disease (AD) often have generalized anxiety, particularly in early-onset AD (EOAD) or the first stages of their disease. This increased anxiety could be associated with decreased sensorimotor gating with increased attention to significant stimuli from AD pathology in the entorhinal cortex. We investigated whether widening initial attention to socioemotional stimuli was association with anxiety among 16 patients with first stage EOAD compared to 19 normal controls (NCs). The participants underwent assessment of their initial heart rate deceleration (“orienting response”; OR), a measure of attentional refocusing, to pictures (International Affective Picture Stimuli) varying in pleasant-unpleasant valence and social-nonsocial content. The results showed group differences; the EOAD patients had significantly larger ORs than the NCs across conditions, with larger ORs in each valence and social condition. In addition, the EOAD patients, but not the NCs, showed ORs to normally less threatening stimuli, particularly pleasant, but also less significantly, social stimuli. On the Neuropsychiatric Inventory, the ORs among the EOAD patients significantly correlated with anxiety scores. Together, these findings suggest that anxiety in mild EOAD may be associated with widening attentional refocusing to socioemotional stimuli, possibly reflecting decreased sensorimotor gating in the entorhinal cortex. This finding could be a potential biomarker for the first stages of AD.

Pages 1333-1349
Lucas S. Broster, Shonna L. Jenkins, Sarah D. Holmes, Gregory A. Jicha, Yang Jiang
Low Arousal Positive Emotional Stimuli Attenuate Aberrant Working Memory Processing in Persons with Mild Cognitive Impairment
Abstract: Emotional enhancement effects on memory have been reported to mitigate the pathophysiology of Alzheimer’s disease (AD). However, relative to their manifestation in persons without pathologic aging, these effects may be reduced in magnitude or even deleterious, especially in tasks that more closely model ecologic memory performance. Based upon a synthesis of such reports, we hypothesized that in persons with AD low arousal positive stimuli would evoke relatively intact emotional enhancement effects, but that high arousal negative stimuli would evoke disordered emotional enhancement effects. To assess this, participants with and without mild cognitive impairment (MCI) presumed to be due to AD performed an emotionally-valenced short-term memory task while encephalography was recorded. Results indicated that for persons with MCI, high arousal negative stimuli led to working memory processing patterns previously associated with MCI presumed due to AD and dementia of the Alzheimer-type. In contrast, low arousal positive stimuli evoked a processing pattern similar to MCI participants’ unaffected spouses. Our current findings suggest that low arousal positive stimuli attenuate working memory deficits of MCI due to AD.

Pages 1351-1364
Min Sheng*, Hanzhang Lu*, Peiying Liu, Yang Li, Harshan Ravi, Shin-Lei Peng, Ramon Diaz-Arrastia, Michael D. Devous, Kyle B. Womack (Handling Associate Editor: Jurgen Claassen) *These authors contributed equally to this work.
Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. Objective: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. Methods: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. Results: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p=0.03, p=0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. Conclusion: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Pages 1365-1377
Rui Guo, Gang Fan, Jian Zhang, Chunxiao Wu, Yifeng Du, Hui Ye, Zhang Li, Lili Wang, Zhihui Zhang, Lu Zhang, Yueran Zhao, Zhiming Lu
A 9-microRNA Signature in Serum Serves as a Noninvasive Biomarker in Early Diagnosis of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common type of age-related neurodegenerative disorder; nevertheless, nowadays there are no reliable biomarkers or non-invasive techniques available for its early detection. Recent studies have indicated that the circulating level profiles of microRNAs (miRNAs) have the potential to be used as valuable biomarkers for diagnosis, staging, and progress monitoring of various diseases. Here we report a novel 9-miRNA signature (hsa-miR-26a-5p, hsa-miR-181c-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-148b-5p, hsa-miR-106b-3p, hsa-miR-6119-5p, hsa-miR-1246, and hsa-miR-660-5p) that can be utilized as biomarker for detecting AD. We respectively profiled the serum miRNAs from 19 AD patients and 9 healthy control (HC) participants using the Next-Generation Sequencing (NGS). The NGS results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) on a larger cohort of 121 AD and 86 HC cases. All the patients were divided into three groups (mild, moderate, and severe AD) based on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our research indicates that abnormal expression of distinct serum miRNAs occurs at different stages of AD. The difference of the area under the receiver operator characteristics curve (AUC) between the AD and the HC is between 70% and 85%. Among the 9 miRNAs, hsa-miR-22-3p has the best sensitivity (81.8%) and specificity (70.9%). The miRNA-panel is more valuable for AD diagnosis. The data suggest that the differentially expressed serum miRNAs could be used as biomarkers to improve the diagnosis of AD, particularly at the early stage, and to classify its clinical stages.

Pages 1379-1385
Euan N. Paterson, Michael A. Williams, Peter Passmore, Giuliana Silvestri, Tom J. MacGillivray, Alexander P. Maxwell, Gareth J. McKay (Handling Associate Editor: Patrick Kehoe)
Estimated Glomerular Filtration Rate is not Associated with Alzheimer’s Disease in a Northern Ireland Cohort
Abstract: Background: Alzheimer’s disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk. Objective: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors. Methods: A cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOE ε4 genotype, systolic blood pressure, education (left school at 14), and smoking status). Results: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOE ε4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders. Conclusion: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals.

Pages 1387-1395
Babette L.R. Reijs, Stephanie J.B. Vos, Hilkka Soininen, Jyrki Lötjonen, Juha Koikkalainen, Maria Pikkarainen, Anette Hall, Ritva Vanninen, Yawu Liu, Sanna-Kaisa Herukka, Yvonne Freund-Levi, Giovanni B. Frisoni, Lutz Frölich, Flavio Nobili, Marcel Olde Rikkert, Luiza Spiru, Magda Tsolaki, Åsa K. Wallin, Philip Scheltens, Frans Verhey, Pieter Jelle Visser
Association Between Later Life Lifestyle Factors and Alzheimer’s Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study
Abstract: Background: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer’s disease (AD) remains unclear. Objective: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. Methods: We selected individuals with SCD (n=111) and MCI (n=353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. Results: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. Conclusions: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

Pages 1397-1410
Cindy K. Barha, Ging-Yuek R. Hsiung, John R. Best, Jennifer C. Davis, Janice J. Eng, Claudia Jacova, Philip E. Lee, Michelle Munkacsy, Winnie Cheung, Teresa Liu-Ambrose (Handling Associate Editor: Jeff Burns)
Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial
Abstract: Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Fifty-eight older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

Pages 1411-1427
Masaaki Waragai, Masaru Moriya, Takeshi Nojo
Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer’s Disease: A 7-Year Follow-Up Study
Abstract: Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional ¹H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice.

Pages 1429-1442
Jeyapriya Raja Sundaram, Charlene Priscilla Poore, Noor Hazim Bin Sulaimee, Tej Pareek, Wei Fun Cheong, Markus R. Wenk, Harish C. Pant, Sally A. Frautschy, Chian-Ming Low, Sashi Kesavapany
Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer’s Disease
Abstract: Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

Pages 1443-1450
Doeschka A. Ferro, Susanne J. van Veluw, Huiberdina L. Koek, Lieza G. Exalto, Geert Jan Biessels on behalf of the Utrecht Vascular Cognitive Impairment (VCI) study group
Cortical Cerebral Microinfarcts on 3 Tesla MRI in Patients with Vascular Cognitive Impairment
Abstract: Background: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI. Objective: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI). Method: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria. Result: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains. Conclusion: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.

Pages 1451-1459
Julien Dumurgier, Bernard J. Hanseeuw, Frances B. Hatling, Kelly A. Judge, Aaron P. Schultz, Jasmeer P. Chhatwal, Deborah Blacker, Reisa A. Sperling, Keith A. Johnson, Bradley T. Hyman, Teresa Gómez-Isla
Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults
Abstract: Background: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move toward preclinical stages. Objective: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1-42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

Pages 1461-1476
Kristina Yordanova, Philipp Koldrack, Christina Heine, Ron Henkel, Mike Martin, Stefan Teipel, Thomas Kirste
Situation Model for Situation-Aware Assistance of Dementia Patients in Outdoor Mobility
Abstract: Background: Dementia impairs spatial orientation and route planning, thus often affecting the patient’s ability to move outdoors and maintain social activities. Situation-aware deliberative assistive technology devices (ATD) can substitute impaired cognitive function in order to maintain one’s level of social activity. To build such a system, one needs domain knowledge about the patient’s situation and needs. We call this collection of knowledge situation model. Objective: To construct a situation model for the outdoor mobility of people with dementia (PwD). The model serves two purposes: 1) as a knowledge base from which to build an ATD describing the mobility of PwD; and 2) as a codebook for the annotation of the recorded behavior. Methods: We perform systematic knowledge elicitation to obtain the relevant knowledge. The OBO Edit tool is used for implementing and validating the situation model. The model is evaluated by using it as a codebook for annotating the behavior of PwD during a mobility study and interrater agreement is computed. In addition, clinical experts perform manual evaluation and curation of the model. Results: The situation model consists of 115 concepts with 11 relation types between them. The results from the annotation showed substantial overlapping between two annotators (Cohen’s kappa of 0.61). Conclusion: The situation model is a first attempt to systematically collect and organize information related to the outdoor mobility of PwD for the purposes of situation-aware assistance. The model is the base for building an ATD able to provide situation-aware assistance and to potentially improve the quality of life of PwD.

Pages 1477-1487
Ron L.H. Handels, Anders Wimo, Richard Dodel, Milica G. Kramberger, Pieter Jelle Visser, José Luis Molinuevo, Frans R. J. Verhey, Bengt Winblad (Handling Associate Editor: Sophie Vandepitte)
Cost-Utility of Using Alzheimer’s Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia
Abstract: Background: Diagnostic research criteria for Alzheimer’s disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI. Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon. Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416. Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization.

Pages 1489-1498
Karolina Sejunaite, Claudia Lanza, Matthias W. Riepe
Everyday Memory in Patients with Alzheimer’s Disease: Fragmentary and Distorted
Abstract: Background: Errors of omission are an established hallmark of memory impairment in Alzheimer’s disease (AD). Much less is known about other memory errors in AD such as false memories. Objective: We investigated false memories in healthy elderly controls (HC; n = 23) and patients with AD (n = 20) using real-life tasks of watching news and commercials. Methods: Participants received a comprehensive neuropsychological assessment and were shown original news and commercials with a subsequent recognition task to assess veridical and false memories. Results: Subjective estimate of the number of errors were alike in HC and patients with AD. However, memory performance in both the news and the commercials task was significantly worse in patients with AD. Trail-Making Test and Symbol-Span Test were significant predictors of false memories on viewing news and commercials. In patients with AD, levels of Aβ1-42, but not levels of tau-protein were correlated with false memories in both tasks. Conclusions: Everyday life in patients with AD is impeded not due to the incompleteness of memory but also due to its distortions. Furthermore, it is hindered by the lack of awareness towards these deficits. False memory content in patients with AD is associated with Aβ42 levels in the CSF as a surrogate of the overall extent to which the brain has been affected by AD pathology. Future studies will need to address the impact of this duality of memory failure on everyday life of patients with AD and their proxies in greater detail.

Pages 1499-1510
Julija Stelmokas, Lance Yassay, Bruno Giordani, Hiroko H. Dodge, Ivo D. Dinov, Arijit Bhaumik, K. Sathian, Benjamin M. Hampstead (Handling Associate Editor: Duke Han)
Translational MRI Volumetry with NeuroQuant: Effects of Version and Normative Data on Relationships with Memory Performance in Healthy Older Adults and Patients with Mild Cognitive Impairment
Abstract: NeuroQuant (NQ) is a fully-automated program that overcomes several existing limitations in the clinical translation of MRI-derived volumetry. The current study characterized differences between the original (NQ1) and an updated NQ version (NQ2) by 1) replicating previously identified relationships between neuropsychological test performance and medial temporal lobe volumes, 2) evaluating the level of agreement between NQ versions, and 3) determining if the addition of NQ2 age-/sex-based z-scores hold greater clinical utility for prediction of memory impairment than standard percent of intracranial volume (%ICV) values. Sixty-seven healthy older adults and 65 mild cognitive impairment patients underwent structural MRI and completed cognitive testing, including the Immediate and Delayed Memory indices from the Repeatable Battery for the Assessment of Neuropsychological Status. Results generally replicated previous relationships between key medial temporal lobe regions and memory test performance, though comparison of NQ regions revealed statistically different values that were biased toward one version or the other depending on the region. NQ2 hippocampal z-scores explained additional variance in memory performance relative to %ICV values. Findings indicate that NQ1/2 medial temporal lobe volumes, especially age- and sex-based z-scores, hold clinical value, though caution is warranted when directly comparing volumes across NQ versions.

Pages 1511-1524
Kelly Hares, James Scott Miners, Amelia Jane Cook, Claire Rice, Neil Scolding, Seth Love, Alastair Wilkins (Handling Associate Editor: Illana Gozes)
Overexpression of Kinesin Superfamily Motor Proteins in Alzheimer’s Disease
Abstract: Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer’s disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AβPP and soluble Aβ in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.

Pages 1525-1531
D. P. Devanand, Cody Lentz, Richard E. Chunga, Adam Ciarleglio, Jennifer M. Scodes, Howard Andrews, Peter W. Schofield, Yaakov Stern, Edward D. Huey, Karen Bell, Gregory H. Pelton (Handling Associate Editor: Gwenn Smith)
Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment
Abstract: Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease pathology. Objective: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). Methods: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. Results: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE 4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07). Conclusions: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

Pages 1533-1545
Sara van Duijn, Marjolein Bulk, Sjoerd G. van Duinen, Rob J.A. Nabuurs, Mark A. van Buchem, Louise van der Weerd, Remco Natté
Cortical Iron Reflects Severity of Alzheimer’s Disease
Abstract: Abnormal iron distribution in the isocortex is increasingly recognized as an in vivo marker for Alzheimer’s disease (AD). However, the contribution of iron accumulation to the AD pathology is still poorly understood. In this study, we investigated: 1) frontal cortical iron distribution in AD and normal aging and 2) the relation between iron distribution and degree of AD pathology. We used formalin fixed paraffin embedded frontal cortex from 10 AD patients, 10 elder, 10 middle aged, and 10 young controls and visualized iron with a modified Perl’s histochemical procedure. AD and elderly subjects were not different with respect to age and sex distribution. Iron distribution in the frontal cortex was not affected by normal aging but was clearly different between AD and controls. AD showed accumulation of iron in plaques, activated microglia, and, in the most severe cases, in the mid-cortical layers along myelinated fibers. The degree of altered iron accumulations was correlated to the amount of amyloid-β plaques and tau pathology in the same block, as well as to Braak stage (p< 0.001). AD and normal aging show different iron and myelin distribution in frontal cortex. These changes appear to occur after the development of the AD pathological hallmarks. These findings may help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in the frontal cortex.

Pages 1547-1565
Séverine André, Emilie Ansciaux, Elamine Saidi, Lionel Larbanoix, Dimitri Stanicki, Denis Nonclercq, Luce Vander Elst, Sophie Laurent, Robert N. Muller, Carmen Burtea
Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier
Abstract: The diagnosis of Alzheimer’s disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls’-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

Pages 1567-1578
Sophie Dardenne, Julien Delrieu, Sandrine Sourdet, Christelle Cantet, Sandrine Andrieu, Hélène Mathiex-Fortunet, Bertrand Fougère, Bruno Vellas
Memory Complaints and Cognitive Decline: Data from the GUIDAGE Study
Abstract: Background: Subjective cognitive decline (SCD) may be a very early symptom of Alzheimer’s disease (AD) and may be associated with a cognitive decline in a cognitively normal population. The McNair and Kahn Scale was used to assess memory complaints in the GuidAge study. Objective: Our objectives were to examine if the McNair and Kahn Scale can predict cognitive decline and to screen which (if any) of the question(s) of this scale would better predict this cognitive decline. Methods: The GuidAge study was a phase III, multicenter, randomized, double blind, placebo-controlled study. Individuals aged 70 years and older, without cognitive impairment (Clinical Dementia Rate (CDR = 0)) at baseline who had spontaneously reported SCD were included in this study. The 20-item version of the McNair and Kahn Scale was used to assess SCD and a standardized neuropsychological assessment was used to assess the cognitive status. Results: 1,307 patients with SCD and with CDR = 0 at baseline were included. During the 5 years of follow-up, 519 patients showed cognitive decline. Incidence of aggravation score of CDR was 13.40% person years (95% CI [12.24-14.56]). Results showed a significant relationship between the McNair and Kahn Scale score and decline in cognitive performance (HR 1.012; 95% CI [1.002-1.021]; p = 0.0156). Among the 20 items, 5 were statistically significant to predict cognitive decline after adjustment. Conclusion: SCD is a promising indicator of memory impairment. Our study found that using the McNair and Kahn scale can predict cognitive decline. A 5-item version of this scale could be used to screen patients in clinical practice and in clinical research.

Pages 1579-1587
Hyemin Jang, Byoung Seok Ye, Sookyoung Woo, Sun Woo Kim, Juhee Chin, Seong Hye Choi, Jee Hyang Jeong, Soo Jin Yoon, Bora Yoon, Kyung Won Park, Yun Jeong Hong, Hee Jin Kim, Samuel N. Lockhart, Duk L. Na, Sang Won Seo (Handling Associate Editor: YongSoo Shim)
Prediction Model of Conversion to Dementia Risk in Subjects with Amnestic Mild Cognitive Impairment: A Longitudinal, Multi-Center Clinic-Based Study
Abstract: Background: Patients with amnestic mild cognitive impairment (aMCI) have an increased risk of dementia. However, conversion rate varies. Therefore, predicting the dementia conversion in these patients is important. Objective: We aimed to develop a nomogram to predict dementia conversion in aMCI subjects using neuropsychological profiles. Methods: A total of 338 aMCI patients from two hospital-based cohorts were used in analysis. All patients were classified into 1) verbal, visual, or both, 2) early or late, and 3) single or multiple-domain aMCI according to the modality, severity of memory dysfunction, and multiplicity of involved cognitive domains, respectively. Patients were followed up, and conversion to dementia within 3 years was defined as the primary outcome. Our patients were divided into a training data set and a validation data set. The associations of potential covariates with outcome were tested, and nomogram was constructed by logistic regression model. We also developed another model with APOE data, which included 242 patients. Results: In logistic regression models, both modalities compared with visual only (OR 4.44, 95% CI 1.83–10.75, p=0.001), late compared to early (OR 2.59, 95% CI 1.17–5.72, p=0.019), and multiple compared to single domain (OR 3.51, 95% CI 1.62–7.60, p=0.002) aMCI were significantly associated with dementia conversion within 3 years. A nomogram incorporating these clinical variables was constructed on the training data set and validated on the validation data set. Both nomograms with and without APOE data showed good prediction performance (c-statistics ≥ 0.75). Conclusions: This study showed that several neuropsychological profiles of aMCI are significantly associated with imminent dementia conversion, and a nomogram incorporating these clinical subtypes is simple and useful to help to predict disease progression.

Pages 1589-1600
Miranda Tuwaig, Mélissa Savard, Benoît Jutras, Judes Poirier, D. Louis Collins, Pedro Rosa-Neto, David Fontaine, John C.S. Breitner, for the PREVENT-AD Research Group
Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer’s Disease
Abstract: Prevention of dementia due to Alzheimer’s disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of “normal” aging. A different approach involves testing of “central auditory processing” (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOE 4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

Pages 1601-1609
Anna Torrens-Burton, Nasreen Basoudan, Antony J. Bayer, Andrea Tales
Perception and Reality of Cognitive Function: Information Processing Speed, Perceived Memory Function, and Perceived Task Difficulty in Older Adults
Abstract: This study examines the relationships between two measures of information processing speed associated with executive function (Trail Making Test and a computer-based visual search test), the perceived difficulty of the tasks, and perceived memory function (measured by the Memory Functioning Questionnaire) in older adults (aged 50+ y) with normal general health, cognition (Montreal Cognitive Assessment score of 26+), and mood. The participants were recruited from the community rather than through clinical services, and none had ever sought or received help from a health professional for a memory complaint or mental health problem. For both the trail making and the visual search tests, mean information processing speed was not correlated significantly with perceived memory function. Some individuals did, however, reveal substantially slower information processing speeds (outliers) that may have clinical significance and indicate those who may benefit most from further assessment and follow up. For the trail making, but not the visual search task, higher levels of subjective memory dysfunction were associated with a greater perception of task difficulty. The relationship between actual information processing speed and perceived task difficulty also varied with respect to the task used. These findings highlight the importance of taking into account the type of task and metacognition factors when examining the integrity of information processing speed in older adults, particularly as this measure is now specifically cited as a key cognitive subdomain within the diagnostic framework for neurocognitive disorders.

Pages 1611-1620
Ryan J. Piers, Kathryn N. Devlin, Boting Ning, Yulin Liu, Ben Wasserman, Joseph M. Massaro, Melissa Lamar, Catherine C. Price, Rod Swenson, Randall Davis, Dana L. Penney, Rhoda Au*, David J. Libon* *These authors contributed equally as senior authors.
Age and Graphomotor Decision Making Assessed with the Digital Clock Drawing Test: The Framingham Heart Study
Abstract: Background: Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format. Objective: Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision-making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order, decision-making latencies. Methods: A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for “10 after 11”. Six age groups (age range 28-98) were constructed. Results: Differences between age groups were found for total time to completion, total pen stroke count and higher-order, decision-making latencies in both command and copy test conditions. Conclusion: Longer age-related decision-making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer’s disease and other insidious neurodegenerative disorders.

Pages 1621-1631
Bjørn-Eivind Kirsebom, Ragna Espenes, Knut Waterloo, Erik Hessen, Stein Harald Johnsen, Geir Bråthen, Dag Aarsland, Tormod Fladby (Handling Associate Editor: Frank Jessen)
Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients
Abstract: Background: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning. Objective: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants. Methods: We included 431 participants 40-80 years old. Participants were classified as controls (n=132) or symptom group (n=299). The symptom group comprised of subjective cognitive decline (SCD, n=163) and mild cognitive impairment (MCI, n=136). We compared cognitive performance and demographics in memory clinic-referrals (n=86) to self-referred participants responding to advertisements and news bulletins (n=179). Participants recruited by other means were excluded from analysis (n=34). Results: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group. Conclusion: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

Pages 1633-1640
Ronald L. Cowan, Paul A. Beach, Sebastian W. Atalla, Mary S. Dietrich, Stephen P. Bruehl, Jie Deng, Jinjiao Wang, Paul A. Newhouse, John C. Gore, Todd B. Monroe
Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer’s Disease: A Cross-Sectional Brief Report
Abstract: Background: People with Alzheimer’s disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD. Objective: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD. Methods: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median=74) and AD severity-matched (Mini-Mental State Exam score <24, median=16) communicative people who completed thermal psychophysics. Results: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p=0.004, unpleasantness: p<0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen’s d=0.72, p=0.051, moderate: Cohen’s d=0.80, p =0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen’s d=0.80, p=0.072, moderate: Cohen’s d=1.32, p=0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs=0.29 and rs=0.20 respectively, p>0.05). Conclusions: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

Pages 1641-1652
Loïc Dayon, Jérôme Wojcik, Antonio Núñez Galindo, John Corthésy, Ornella Cominetti, Aikaterini Oikonomidi, Hugues Henry, Eugenia Migliavacca, Gene L. Bowman, Julius Popp (Handling Associate Editor: D. Allan Butterfield)
Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer’s Disease Pathology in Older Adults
Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer’s disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia. Objective: Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis. Methods: We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Aβ1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42 > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42 < 724 pg/mL. Results: Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%. Conclusion: Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD.