Volume 60, Number 4, IN PROGRESS

Review
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.

Hypothesis
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.

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.

Commentary
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.

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 be smoother. Moreover, our results suggest that prognosis of institutionalized patients is not unfavorable when compared with patients staying at home.

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.

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.

Patricia R. Manzine, Silvia Pelucchi, Maria A. Horst, Francisco A.C. Vale, Sofia C.I. Pavarini, Matteo Audano, Nico Mitro, Monica Di Luca, Elena Marcello, Marcia R. Cominetti
microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease
Abstract: ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer’s disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.

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.

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.

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.

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 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.

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.

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.

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.

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.

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 preclinical 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.

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.

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.

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.