36 results
93 Impact of Cardiovascular Risk on Cognitive and Brain Aging in Autosomal Dominant Frontotemporal Dementia
- Anna M VandeBunte, Emily W Paolillo, Hyunwoo Lee, Ging-Yuek Robin Hsiung, Adam Staffaroni, Shannon Y Lee, Carmela Tartaglia, Hilary Heur, Joel H Kramer, Brad Boeve, Adam Boxer, Howie Rosen, Kaitlin B Casaletto
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 193-194
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Poor cardiovascular health occurs with age and is associated with increased dementia risk, yet its impact on frontotemporal lobar degeneration (FTLD) and autosomal dominant neurodegenerative disease has not been well established. Examining cardiovascular risk in a population with high genetic vulnerability provides an opportunity to assess the impact of lifestyle factors on brain health outcomes. In the current study, we examined whether systemic vascular burden associates with accelerated cognitive and brain aging outcomes in genetic FTLD.
Participants and Methods:166 adults with autosomal dominant FTLD (C9orf72 n= 97; GRN n= 34; MAPT n= 35; 54% female; Mage = 47.9; Meducation = 15.6 years) enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Longitudinal FTD study (ALLFTD) were included. Participants completed neuroimaging and were screened for cardiovascular risk and functional impairment during a comprehensive neurobehavioral and medical interview. A vascular burden score (VBS) was created by summing vascular risk factors (VRS) [diabetes, hypertension, hyperlipidemia, and sleep apnea] and vascular diseases (VDS) [cerebrovascular disease (e.g., TIA, CVA), cardiac arrhythmia (e.g., atrial fibrillation, pacemaker, defibrillator), coronary artery disease (e.g., myocardial infarction, cardiac bypass, stent), and congestive heart failure] following a previously developed composite (range 0 to 8). We examined the interaction between each vascular health metric (VBS, VDS, VRS) and age (vascular health*age) on clinical severity (CDR plus NACC FTLD-SB), and white matter hyperintensity (WMH) volume outcomes, adjusting for age and sex. Vascular risk, disease, and overall burden scores were examined in separate models.
Results:There was a statistically significant interaction between total VBS and age on both clinical severity (ß=0.20, p=0.044) and WMH burden (ß=0.20, p=0.032). Mutation carriers with higher vascular burden evidenced worse clinical and WMH outcomes for their age. When breaking down the vascular burden score into (separate) vascular risk (VRS) and vascular disease (VDS) scores, the interaction between age and VRS remained significant only for WMH (ß=0.26, p=0.009), but not clinical severity (ß=0.04, p=0.685). On the other hand, the interaction between VDS and age remained significant only for clinical severity (ß=0.20, p=0.041) but not WMH (ß=0.17, p=0.066).
Conclusions:Our results demonstrate that systemic vascular burden is associated with an “accelerated aging” pattern on clinical and white matter outcomes in autosomal dominant FTLD. Specifically, mutation carriers with greater vascular burden show poorer neurobehavioral outcomes for their chronological age. When separating vascular risk from disease, risk was associated with higher age-related WMH burden, whereas disease was associated with poorer age-related clinical severity of mutation carriers. This pattern suggests preferential brain-related effects of vascular risk factors, while the functional impact of such factors may be more closely aligned with fulminant vascular disease. Our results suggest cardiovascular health may be an important, potentially modifiable risk factor to help mitigate the cognitive and behavioral disturbances associated with having a pathogenic variant of autosomal dominant FTLD. Future studies should continue to examine the neuropathological processes underlying the impact of cardiovascular risk in FTLD to inform more precise recommendations, particularly as it relates to lifestyle interventions.
6 Remote Smartphone Cognitive and Motor Testing in Frontotemporal Dementia Research: Feasibility, Reliability, and Validity
- Adam M Staffaroni, Jack Carson Taylor, Annie L Clark, Hilary W Heuer, Amy B Wise, Masood Manoochehri, Leah Forsberg, Carly T Mester, Meghana Roa, Danielle Brushaber, Julio C Rojas, Joel H Kramer, Bradley F Boeve, Howard J Rosen, Adam L Boxer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 604-605
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Therapeutics targeting frontotemporal dementia (FTD) are entering clinical trials. There are challenges to conducting these studies, including the relative rarity of the disease. Remote assessment tools could increase access to clinical research and pave the way for decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning. The objectives were to determine the feasibility and acceptability of collecting remote smartphone data in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive and motor measures.
Participants and Methods:A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD>1 [n=39]; unknown [n=38]) were asked to remotely complete a battery of tests on their smartphones three times over two weeks. Measures included five executive functioning (EF) tests, an adaptive memory test, and participant experience surveys. A subset completed smartphone tests of balance at home (n=31) and a finger tapping test (FTT) in the clinic (n=11). We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated Spearman-Brown split-half reliability (100 iterations) using the first available assessment for each participant. We assessed test-retest reliability across all available assessments by estimating intraclass correlation coefficients (ICC). To investigate construct validity, we fit regression models testing the association of the smartphone measures with gold-standard neuropsychological outcomes (UDS3-EF composite [Staffaroni et al., 2021], CVLT3-Brief Form [CVLT3-BF] Immediate Recall, mechanical FTT), measures of disease severity (CDR®+NACC-FTLD Box Score & Progressive Supranuclear Palsy Rating Scale [PSPRS]), and regional gray matter volumes (cognitive tests only).
Results:Participants completed 70% of tasks. Most reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning (r’s=0.93-0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent for cognitive tasks (ICC: 0.70-0.96) and were excellent for the balance (ICC=0.97) and good for FTT (ICC=0.89). Smartphone EF measures were strongly associated with the UDS3-EF composite (ß's=0.6-0.8, all p<.001), and the memory test was strongly correlated with total immediate recall on the CVLT3-BF (ß=0.7, p<.001). Smartphone FTT was associated with mechanical FTT (ß=0.9, p=.02), and greater acceleration on the balance test was associated with more motor features (ß=0.6, p=0.02). Worse performance on all cognitive tests was associated with greater disease severity (ß's=0.5-0.7, all p<.001). Poorer performance on the smartphone EF tasks was associated with smaller frontoparietal/subcortical volume (ß's=0.4-0.6, all p<.015) and worse memory scores with smaller hippocampal volume (ß=0.5, p<.001).
Conclusions:These results suggest remote digital data collection of cognitive and motor functioning in FTD research is feasible and acceptable. These findings also support the reliability and validity of unsupervised ALLFTD Mobile App cognitive tests and provide preliminary support for the motor measures, although further study in larger samples is required.
50 Effects of Cerebrovascular Risk Factors and Alzheimer’s Disease Pathology on Executive Function and Memory Changes: Analysis of the National Alzheimer’s Coordinating Center Cohort
- Ankita Chatterjee, Shannon Lee, Valentina Diaz, Kaitlin B Casaletto, Adam M Staffaroni, Joel H Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 562-563
-
- Article
-
- You have access Access
- Export citation
-
Objective:
A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.
Participants and Methods:19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR> 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.
Results:Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p < -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p < -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.
Conclusions:Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.
5 Rejuvenating Blood Factor TIMP2 Relates to Physical Activity and Cognitive Functioning in Older Adults on The Alzheimer’s Disease Continuum
- Emily W Paolillo, Shannon Y Lee, Anna M Vandebunte, Rowan Saloner, Leslie S Gaynor, Joel H Kramer, Kaitlin B Casaletto
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 106-107
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Tissue inhibitor of metalloproteinases 2 (TIMP2) is produced peripherally, crosses the blood-brain barrier, and improves synaptic plasticity and hippocampal-dependent cognition in aged mice; however, the role of TIMP2 in human cognitive aging is unclear. We examined associations of circulating TIMP2 levels in blood with a known plasticity-inducing behavior, physical activity, and cognitive functioning among older adults along the Alzheimer’s disease continuum.
Participants and Methods:Participants included 84 community-dwelling older adults (meanage = 78.8; 57% female; 82% cognitively normal; 14% MCI; 4% mild dementia; 35% PET Aß+) enrolled in the UC San Francisco Memory and Aging Center. All participants completed 30 days of observational FitbitTM monitoring to quantify physical activity (average daily steps), as well as a comprehensive in-person visit including blood draw (proteins assayed on SOMAscan platform), [18F]AV-45 positron emission tomography (PET) to quantify brain beta-amyloid (centiloids), and neuropsychological assessment. Composite cognitive z-scores were calculated for memory (California Verbal Learning Test-II [CVLT-II] and Benson Figure Recall), semantic processing (animal fluency and Boston Naming Test), and executive functioning (digits backwards span, Stroop inhibition, modified trail making test, lexical fluency, and design fluency). Multiple linear regression examined TIMP2 as a function of physical activity, covarying for age and PET centiloids. Additional regression models separately examined cognitive z-scores as a function of TIMP2, covarying for age, sex, education, PET centiloids, and body mass index (BMI).
Results:TIMP2 was not significantly correlated with age, sex, education, or PET centiloids (ps > 0.05); however, TIMP2 was negatively correlated with BMI (r = -0.23, p = 0.036). Greater average daily steps related to higher levels of TIMP2 (b = 0.30, 95%CI = 0.04-0.55, p = 0.022). TIMP2 also related to better semantic processing (b = 0.28, 95%CI = 0.04-0.51, p = 0.021) and executive functioning (b = 0.26, 95%CI = 0.03-0.49, p = 0.028). TIMP2 did not significantly relate to memory (p > 0.05).
Conclusions:Greater physical activity was associated with higher concentrations of blood factor TIMP2, which in turn related to better cognitive functioning independent of Alzheimer’s disease pathology burden. These results support previous mouse models by broadly replicating relationships between TIMP2 and cognition in humans, while also uniquely demonstrating an association between TIMP2 and physical activity, a modifiable protective factor in both typical and diseased cognitive aging. Our domain-specific results, however, suggest that benefits of TIMP2 in humans may involve a broader neuroanatomical network than the hippocampal-specific effects previously shown in mice. Although exact mechanisms of TIMP2 need further examination, TIMP2 is known to be enriched in human umbilical cord plasma, has been shown to be involved in cell-growth promoting activities, and may relate to increased neural plasticity in older age. Further examination of TIMP2 and other novel blood-based proteins as potential therapeutic targets for improved cognitive aging, including in the presence of Alzheimer’s disease, is warranted.
57 Validation of a List Learning Task for Monolingual Spanish Speaking Older Adults
- Valentina E Diaz, Lucia Lopez, Gloria Aguirre, Karen A Dorsman, Anne-Marie Rodriguez, Jorge Archila Puac, Shannon Lee, Stefanie D Pina-Escudero, Serggio Lanata, Kaitlin Casaletto, Joel H Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 734-735
-
- Article
-
- You have access Access
- Export citation
-
Objective:
The prevalence of dementia is higher among minoritized Hispanic/Latino populations in the U.S. Development of linguistically relevant and validated cognitive assessments are urgently needed to adequately address the care needs of this at-risk group. List learning tasks are widely used to evaluate verbal episodic memory and are consistently shown to be sensitive to memory deficits across various
neurologic etiologies. The aim of this study was to validate a Spanish list learning task developed as a linguistically appropriate measure of memory in a diverse sample of Spanish speaking Bay Area older adults who identify as Hispanic/Latino.
Participants and Methods:Cognitive scores were assessed in 72 Spanish-speaking older adults living in the Bay Area, California, originally from different countries across South and Central America [(n=29 with CDR scores of 0; n=31 with CDRs of 0.5; and n=12 with CDR of 1), aged 54-96, 30% male)], who completed the Spanish list learning task and a brief neuropsychological battery. The list learning task contains 9 words, 3 words from 3 different semantic categories. Category exemplars were excluded. Administration includes three immediate recall trials, a 30-second delay free recall, 10-minute delay free and cued recall, and yes/no recognition. In this initial validation study, we selected the 10-minute delay recall trial as our primary variable and looked at several indices of construct validity. We hypothesized delayed free recall would: 1) correlate highly with other episodic memory tasks, and minimally with non-memory tests (controlling for CDR sum of boxes), and 2) show step-wise declines as total CDR increased from 0 to 1 (controlling for age, sex, and education).
Results:Delayed recall scores of 30-seconds and 10-minutes showed step-wise declines as CDR scores increased (CDR 0 vs. 1, p<0.001 and CDR 0.5 vs. 1, p=0.001). There were no differences in delayed recall between CDR 0 vs. CDR 0.5 (p>0.05). 10-minute delay showed medium-to-large correlations with UDS Craft Story Delayed Recall (partial r =0.45, p<0.001) and Benson Complex Figure Recall (partial r=0.63, p<0.001). Nonsignificant, weaker associations were observed with measures of executive (F Word Verbal Fluency partial r=0.10, Digit Span Forward partial r=0.12), and language (Animal Fluency partial r=0.18) function.
Conclusions:Although there is heterogeneity within Hispanic/Latino populations in the U.S., findings begin to support ecological and construct validity of the Spanish list learning task as a measure of verbal memory in older Spanish-speaking adults in the Bay Area. Supporting ecological validity, delayed recall scores significantly differentiated functionally impaired (CDR=1) from functionally mild or unimpaired older adults (CDR=0 or 0.5), though evidenced less sensitivity differentiating unimpaired from mild stages of illness. The Spanish list learning task evidenced strong construct validity as a measure of episodic memory, including strong correlations with other validated memory tasks, and non-significant correlations with non-memory tasks. Larger studies should account for diversity of Spanish speakers in the U.S to see how region of origin, education, and differences between first- and second-generation Spanish speakers influences performance on the task. Future work incorporating imaging markers of brain structure may help further validate the Spanish list learning task as an appropriate measure of memory.
57 Traumatic Brain Injury and Concussion in Patients with Frontotemporal Dementia Spectrum Diagnoses
- Jessica Bove, Marguerite Knudtson, Michelle You, Michael L Alosco, Jesse Mez, Bruce L Miller, Howie J Rosen, Maria Luisa Gorno-Tempini, William W Seeley, Joel H Kramer, Russell M Bauer, Breton M Asken
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 568-569
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Traumatic brain injury (TBI) and concussion are associated with increased dementia risk. Accurate TBI/concussion exposure estimates are relatively unknown for less common neurodegenerative conditions like frontotemporal dementia (FTD). We evaluated lifetime TBI and concussion frequency in patients diagnosed with a range of FTD spectrum conditions and related prior head trauma to cavum septum pellucidum (CSP) characteristics observable on MRI.
Participants and Methods:We administered the Ohio State University TBI Identification and Boston University Head Impact Exposure Assessment to 108 patients (age 69.5 ± 8.0, 35% female, 93% white or unknown race) diagnosed at the UCSF Memory and Aging Center with one of the following FTD or related conditions: behavioral variant frontotemporal dementia (N=39), semantic variant primary progressive aphasia (N=16), nonfluent variant PPA (N=23), corticobasal syndrome (N=14), or progressive supranuclear palsy (N=16). Data were also obtained from 217 controls (“HC”; age 76.8 ± 8.0, 53% female, 91% white or unknown race). CSP characteristics were defined based on width or “grade” (0-1 vs. 2+) and length of anterior-posterior separation (millimeters). We first describe frequency of any and multiple (2+) prior TBI based on different but commonly used definitions: TBI with loss of consciousness (LOC), TBI with LOC or posttraumatic amnesia (LOC/PTA), TBI with LOC/PTA or other symptoms like dizziness, nausea, “seeing stars,” etc. (“concussion”). TBI/concussion frequency was then compared between FTD and HC using chi-square. Associations between TBI/concussion and CSP characteristics were analyzed with chi-square (CSP grade) and Mann-Whitney U tests (CSP length). We explored sex differences due to typically higher rates of TBI among males.
Results:History of any TBI with LOC (FTD=20.0%, HC=19.2%), TBI with LOC/PTA (FTD:32.2%, HC=31.5%), and concussion (FTD: 50.0%, HC=44.3%) was common but not different between study groups (p’s>.4). In both FTD and HC, prior TBI/concussion was nominally more frequent in males but not significantly greater than females. Frequency of repeat TBI/concussion (2+) also did not differ significantly between FTD and HC (repeat TBI with LOC: 6.7% vs. 3.3%, TBI with LOC/PTA: 12.2% vs. 10.3%, concussion: 30.2% vs. 28.7%; p’s>.2). Prior TBI/concussion was not significantly related to CSP grade or length in the total sample or within the FTD or HC groups.
Conclusions:TBI/concussion rates depend heavily on the symptom definition used for classifying prior injury. Lifetime symptomatic TBI/concussion is common but has an unclear impact on risk for FTD-related diagnoses. Larger samples are needed to appropriately evaluate sex differences, to evaluate whether TBI/concussion rates differ between specific FTD phenotypes, and to understand the rates and effects of more extensive repetitive head trauma (symptomatic and asymptomatic) in patients with FTD.
6 The Moderating Role of Physical Activity on Hippocampal Iron Deposition and Memory Outcomes in Typically Aging Older Adults
- Shannon Y Lee, Emily W Paolillo, Rowan Saloner, Torie Tsuei, Anna VandeBunte, Joel H Kramer, Kaitlin B Casaletto
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 794-795
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Quantitative Susceptibility Mapping (QSM) is an MRI-based technique that sensitively measures in-vivo iron deposition via relaxation and magnetic susceptibility of brain tissue. Iron is essential for brain homeostasis, including oxidative metabolism, formation and maintenance of neural networks, and myelin synthesis. While increased levels of iron deposition occur during normal aging, high levels may have detrimental effects. Previous work has linked excessive brain iron accumulation to oxidative stress, beta-amyloid and tau toxicity, neurodegeneration, and cognitive dysfunction, particularly memory loss. Physical activity, on the other hand, correlates with higher synaptic integrity and memory performance, even in the presence of neuropathology. To date, it is unknown how physical activity may affect iron deposition-related cognition changes. We examined the moderating role of physical activity on the relationship between QSM hippocampal iron deposition and verbal memory in typically aging adults.
Participants and Methods:62 cognitively unimpaired older adults from the UCSF Memory and Aging Center (age mean(SD) = 78.34(7.28) years; 56% women; education mean(SD) = 17.94(1.72) years; 85% non-Hispanic White) completed neuropsychological testing and brain MRI during annual research visits, followed by Fitbit™ physical activity monitoring for 30 days. Average total daily steps were aggregated. Participants completed 3T Prisma neuroimaging with QSM, and regional iron deposition levels were quantified. All subjects also underwent diffusion tensor imaging (fractional anisotropy). Verbal memory was assessed via long delay free recall scores from the California Verbal Learning Test II (CVLT-II). Linear regression examined verbal memory as a function of hippocampal QSM (bilateral), physical activity, and their interaction. Models covaried for age, sex, and education. Additional models separately examined left and right hippocampal QSM, as well as subcortical QSM to determine lateralization and specificity of verbal memory effects to hippocampal iron deposition, respectively.
Results:Univariably, higher bilateral hippocampal QSM correlated with worse verbal memory (r= 0.35; p= 0.015). Adjusting for demographics, physical activity moderated the relationship between bilateral hippocampal QSM and verbal memory (ß= 0.41, p= 0.011), such that at higher levels of physical activity, the negative relationship between hippocampal QSM and verbal memory was significantly attenuated. Results persisted when adjusting for DTI integrity of the uncinate fasciculus and fornix white matter tracts. Lateralization models were both significant, suggesting that results were not dominantly driven by either left (ß= 0.34, p= 0.048), or right (ß=0.31, p= 0.035) hippocampal QSM. In contrast, subcortical QSM did not correlate with memory performance (r= 0.13, p > 0.05) or interact with physical activity on verbal memory outcomes (p > 0.05).
Conclusions:Physical activity significantly moderated the negative relationship between hippocampal QSM and verbal memory performance. Higher exercise engagement may buffer the adverse effect of hippocampal iron deposition on memory, potentially through its role in maintenance of myelin and synaptic integrity and/or protecting against other neurotoxic events (e.g., oxidative stress, neuronal cell death). Our results support that physical activity continues to be a modifiable risk factor that may offer a protective role in neurobiological pathways of memory and cognitive decline.
73 Sex Differences in Verbal Memory and Alzheimer’s Disease Biomarkers in Clinically Normal Older Adults: Role of SNAP-25 Genetics
- Rowan Saloner, Emily W Paolillo, Kevin J Wojta, Corrina Fonseca, Eva Q Gontrum, Argentina Lario-Lago, Gil D Rabinovici, Jennifer S Yokoyama, Jessica E Rexach, Joel H Kramer, Kaitlin B Casaletto
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 377-378
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Females outperform males on verbal memory tests across the lifespan. Females also exhibit greater Alzheimer’s disease (AD) pathology at preclinical stages and faster atrophy and memory decline during disease progression. Synaptic factors influence the accumulation of AD proteins and may underpin cognitive resilience against AD, though their role in sex-related cognitive and brain aging is unknown. We tested interactive effects of sex and genetic variation in SNAP-25, which encodes a presynaptic protein that is dysregulated in AD, on cognition and AD-related biomarkers in cognitively unimpaired older adults.
Participants and Methods:Participants included a discovery cohort of 311 cognitively unimpaired older adults (age mean [range]=70 [44-100]; 56% female; education mean=17.3 years; 24% APOE-e4+), and an independent, demographically-comparable replication cohort of 82 cognitively unimpaired older adults. All participants completed neurological examination, informant interview (CDR=0), neuropsychological testing, and blood draw. Participants were genotyped for the SNAP-25 rs105132 (T→C) single-nucleotide polymorphism via Sequenom (discovery cohort) or Omni 2.5M (replication cohort). In vitro models show the C-allele is associated with increased SNAP-25 expression compared to T/T genotype. A subset of the discovery cohort completed structural MRI (n=237) and florbetapir Aβ-PET (n=97). Regression analyses across cohorts examined the interaction of sex and SNAP-25 genotype (T/T homozygotes [53% prevalence] vs. C-carriers [47% prevalence]) on cognitive z-scores (verbal memory, visual memory, executive function, language), adjusting for age, education, APOE-e4, and APOE-e4 x sex. Discovery cohort models also examined sex-dependent effects of SNAP-25 on temporal lobe volumes and Aβ-PET positivity.
Results:SNAP-25 T/T vs. C-carriers did not differ on demographics or APOE-e4 status across cohorts or within sexes. Sex interacted with SNAP-25 to predict verbal memory (p=.024) and language (p=.008) in the discovery cohort, with similar verbal memory differences observed in the replication cohort. In sex-stratified analyses, C-carriers exhibited better verbal memory than T/T carriers among females (d range: 0.41 to 0.64, p range: .008 to .046), but not males (d range: 0.03 to 0.12, p range: .499 to .924). In SNAP-25-stratified analyses, female verbal memory advantages were larger among C-carriers (d range: 0.74 to 0.89, p range: <.001 to .034) than T/T (d range: 0.13 to 0.36, p range: .022 to .682). Sex also interacted with SNAP-25 to predict Aβ-PET positivity (p=.046) such that female C-carriers exhibited the lowest prevalence of Aβ-PET positivity (13%) compared to other groups (23% to 35%). C-carriers exhibited larger temporal lobe volumes across sex, yet this effect only reached statistical significance among females (females: d=0.41, p=.018; males: d=0.26, p=.179). In post-hoc analyses, larger temporal lobe volumes were selectively associated with better verbal memory in female C-carriers (β=0.36, p=.026; other groups: |βs|<0.10, ps>.538).
Conclusions:Among clinically normal older adults, we demonstrate female-specific advantages of carrying the SNAP-25 rs105132 C-allele across cognitive, neural, and molecular markers of AD. The rs105132 C-allele putatively reflects higher endogenous levels of SNAP-25. Our findings suggest a female-specific pathway of cognitive and neural resistance, whereby higher genetically-driven expression of SNAP-25 may reduce likelihood of amyloid plaque formation and support verbal memory, possibly through fortification of temporal lobe structure.
Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment
- Breton M. Asken, Lawren VandeVrede, Julio C. Rojas, Corrina Fonseca, Adam M. Staffaroni, Fanny M. Elahi, Cutter A. Lindbergh, Alexandra C. Apple, Michelle You, Sophia Weiner-Light, Nivetha Brathaban, Nicole Fernandes, Adam L. Boxer, Bruce L. Miller, Howie J. Rosen, Joel H. Kramer, Kaitlin B. Casaletto
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 28 / Issue 6 / July 2022
- Published online by Cambridge University Press:
- 22 June 2021, pp. 588-599
-
- Article
- Export citation
-
Objective:
There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer’s dementia.
Methods:We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.
Results:Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = −0.33, p = .002; Cohort 2: β = −0.36, p = .03) and parietal ROIs (Cohort 1: β = −0.31, p = .01; Cohort 2: β = −0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = −0.38, p = .01; Cohort 2: β = −0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.
Conclusions:Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.
Wisdom and fluid intelligence are dissociable in healthy older adults
- Cutter A. Lindbergh, Heather Romero-Kornblum, Sophia Weiner-Light, J. Clayton Young, Corrina Fonseca, Michelle You, Amy Wolf, Adam M. Staffaroni, Rebecca Daly, Dilip V. Jeste, Joel H. Kramer, Winston Chiong, the Hillblom Aging Network
-
- Journal:
- International Psychogeriatrics / Volume 34 / Issue 3 / March 2022
- Published online by Cambridge University Press:
- 10 May 2021, pp. 229-239
-
- Article
-
- You have access Access
- Open access
- HTML
- Export citation
-
Objectives:
The relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs.
Design:Cross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).
Setting:Memory and Aging Center at the University of California San Francisco, located in the USA.
Participants:141 healthy older adults (mean age = 76 years; 56% female).
Measurements:Wisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging.
Results:Wisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI −0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = −0.197 [95% CI −0.351, −0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes.
Conclusions:Our findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.
Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults
- Cutter A. Lindbergh, Nicole Walker, Renaud La Joie, Sophia Weiner-Light, Adam M. Staffaroni, Kaitlin B. Casaletto, Fanny Elahi, Samantha M. Walters, Michelle You, Devyn Cotter, Breton Asken, Alexandra C. Apple, Elena Tsoy, John Neuhaus, Corrina Fonseca, Amy Wolf, Yann Cobigo, Howie Rosen, Joel H. Kramer, the Hillblom Aging Network
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 27 / Issue 4 / April 2021
- Published online by Cambridge University Press:
- 14 October 2020, pp. 382-388
-
- Article
- Export citation
-
Objective: We evaluated whether memory recall following an extended (1 week) delay predicts cognitive and brain structural trajectories in older adultsMethod:
Clinically normal older adults (52–92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178–207, mean ages = 74–76) at annual study visits occurring approximately 15–18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics.
Results:Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044).
Conclusions:Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx)
White Matter Correlates of Cognitive Performance on the UCSF Brain Health Assessment
- Andrea G. Alioto, Paige Mumford, Amy Wolf, Kaitlin B. Casaletto, Sabrina Erlhoff, Tacie Moskowitz, Joel H. Kramer, Katherine P. Rankin, Katherine L. Possin
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 25 / Issue 6 / July 2019
- Published online by Cambridge University Press:
- 26 April 2019, pp. 654-658
-
- Article
- Export citation
-
Objective: White matter (WM) microstructural changes are increasingly recognized as a mechanism of age-related cognitive differences. This study examined the associations between patterns of WM microstructure and cognitive performance on the University of California, San Francisco (UCSF) Brain Health Assessment (BHA) subtests of memory (Favorites), executive functions and speed (Match), and visuospatial skills (Line Orientation) within a sample of older adults. Method: Fractional anisotropy (FA) in WM tracts and BHA performance were examined in 84 older adults diagnosed as neurologically healthy (47), with mild cognitive impairment (19), or with dementia (18). The relationships between FA and subtest performances were evaluated using regression analyses. We then explored whether regional WM predicted performance after accounting for variance explained by global FA. Results: Memory performance was associated with FA of the fornix and the superior cerebellar peduncle; and executive functions and speed, with the body of the corpus callosum. The fornix–memory association and the corpus callosum–executive association remained significant after accounting for global FA. Neither tract-based nor global FA was associated with visuospatial performance. Conclusions: Memory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age- and disease-related cognitive decline.
Visuospatial Functioning in the Primary Progressive Aphasias
- Christa L. Watson, Katherine Possin, I. Elaine Allen, H. Isabel Hubbard, Marita Meyer, Ariane E. Welch, Gil D. Rabinovici, Howard Rosen, Katherine P. Rankin, Zachary Miller, Miguel A. Santos-Santos, Joel H. Kramer, Bruce L. Miller, Maria Luisa Gorno-Tempini
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 24 / Issue 3 / March 2018
- Published online by Cambridge University Press:
- 17 October 2017, pp. 259-268
-
- Article
- Export citation
-
Objectives: The aim of this study was to identify whether the three main primary progressive aphasia (PPA) variants would show differential profiles on measures of visuospatial cognition. We hypothesized that the logopenic variant would have the most difficulty across tasks requiring visuospatial and visual memory abilities. Methods: PPA patients (n=156), diagnosed using current criteria, and controls were tested on a battery of tests tapping different aspects of visuospatial cognition. We compared the groups on an overall visuospatial factor; construction, immediate recall, delayed recall, and executive functioning composites; and on individual tests. Cross-sectional and longitudinal comparisons were made, adjusted for disease severity, age, and education. Results: The logopenic variant had significantly lower scores on the visuospatial factor and the most impaired scores on all composites. The nonfluent variant had significant difficulty on all visuospatial composites except the delayed recall, which differentiated them from the logopenic variant. In contrast, the semantic variants performed poorly only on delayed recall of visual information. The logopenic and nonfluent variants showed decline in figure copying performance over time, whereas in the semantic variant, this skill was remarkably preserved. Conclusions: This extensive examination of performance on visuospatial tasks in the PPA variants solidifies some previous findings, for example, delayed recall of visual stimuli adds value in differential diagnosis between logopenic variant PPA and nonfluent variant PPA variants, and illuminates the possibility of common mechanisms that underlie both linguistic and non-linguistic deficits in the variants. Furthermore, this is the first study that has investigated visuospatial functioning over time in the PPA variants. (JINS, 2018, 24, 259–268)
Neuropsychological Profile of Lifetime Traumatic Brain Injury in Older Veterans
- Allison R. Kaup, Carrie Peltz, Kimbra Kenney, Joel H. Kramer, Ramon Diaz-Arrastia, Kristine Yaffe
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 23 / Issue 1 / January 2017
- Published online by Cambridge University Press:
- 04 October 2016, pp. 56-64
-
- Article
- Export citation
-
Objectives: The aim of this study was to characterize the neuropsychological profile of lifetime traumatic brain injury (TBI) in older Veterans. Methods: Participants were 169 older Veterans [mean age=79.1 years (range, 51–97 years), 89% male, 92% Caucasian], 88 with lifetime TBI and 81 without TBI, living in Veterans’ retirement homes in independent residence. TBI history was ascertained with the Ohio State TBI Identification Method structured interview. Cognition was assessed with neuropsychological tests: Raw scores were converted to Z-scores compared to age-corrected normative data and combined into five domain composite Z-scores (attention/working memory, learning/memory, language, processing speed, executive functioning). We investigated the association between TBI and performance in each cognitive domain in linear mixed effects models, with and without adjustment for demographics, medical comorbidities, and psychiatric variables. Results: Compared to those without TBI, older Veterans with TBI had greater deficits in processing speed (estimate=−.52; p=.01; f2=.08 in fully adjusted model) and executive functioning (estimate=−.41; p=.02; f2=.06 in fully adjusted model) but performed similarly in the attention/working memory, learning/memory, and language domains (all p>.05). TBI-associated deficits were most prominent among individuals with multiple mild TBIs and those with any moderate-to-severe TBI, but were not clearly present among those with single mild TBI. Conclusions: The neuropsychological profile of lifetime TBI in older Veterans is characterized by slowed processing speed and executive dysfunction, especially among those with greater injury burden. This pattern may reflect long-standing deficits or a TBI-associated cognitive decline process distinct from Alzheimer’s disease. (JINS, 2017, 23, 56–64)
Relationship between Insulin-Resistance Processing Speed and Specific Executive Function Profiles in Neurologically Intact Older Adults
- Darvis T. Frazier, Brianne M. Bettcher, Shubir Dutt, Nihar Patel, Dan Mungas, Joshua Miller, Ralph Green, Joel H. Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 21 / Issue 8 / September 2015
- Published online by Cambridge University Press:
- 14 August 2015, pp. 622-628
-
- Article
- Export citation
-
This study investigated the relationship between insulin-resistance and constituent components of executive function in a sample of neurologically intact older adult subjects using the homeostasis model assessment (HOMA-IR) and latent factors of working memory, cognitive control and processing speed derived from confirmatory factor analysis. Low-density lipoprotein (LDL), mean arterial pressure (MAP), along with body mass index (BMI) and white matter hypointensity (WMH) were used to control for vascular risk factors, adiposity and cerebrovascular injury. The study included 119 elderly subjects recruited from the University of California, San Francisco Memory and Aging Center. Subjects underwent neuropsychological assessment, fasting blood draw and brain magnetic resonance imaging (MRI). Partial correlations and linear regression models were used to examine the HOMA-IR-executive function relationship. Pearson correlation adjusting for age showed a significant relationship between HOMA-IR and working memory (rp=−.18; p=.047), a trend with cognitive control (rp=−.17; p=.068), and no relationship with processing speed (rp=.013; p=.892). Linear regression models adjusting for demographic factors (age, education, and gender), LDL, MAP, BMI, and WMH indicated that HOMA-IR was negatively associated with cognitive control (r=−.256; p=.026) and working memory (r=−.234; p=.054). These results suggest a greater level of peripheral insulin-resistance is associated with decreased cognitive control and working memory. After controlling for demographic factors, vascular risk, adiposity and cerebrovascular injury, HOMA-IR remained significantly associated with cognitive control, with working memory showing a trend. These findings substantiate the insulin-resistance-executive function hypothesis and suggest a complex interaction, demonstrated by the differential impact of insulin-resistance on processing speed and specific aspects of executive function. (JINS, 2015, 21, 622–628)
Special Series Introduction: NIH EXAMINER and the Assessment of Executive Functioning
- Joel H. Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 20 / Issue 1 / January 2014
- Published online by Cambridge University Press:
- 28 October 2013, pp. 8-10
-
- Article
- Export citation
NIH EXAMINER: Conceptualization and Development of an Executive Function Battery
- Joel H. Kramer, Dan Mungas, Katherine L. Possin, Katherine P. Rankin, Adam L. Boxer, Howard J. Rosen, Alan Bostrom, Lena Sinha, Ashley Berhel, Mary Widmeyer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 20 / Issue 1 / January 2014
- Published online by Cambridge University Press:
- 08 October 2013, pp. 11-19
-
- Article
- Export citation
-
Executive functioning is widely targeted when human cognition is assessed, but there is little consensus on how it should be operationalized and measured. Recognizing the difficulties associated with establishing standard operational definitions of executive functioning, the National Institute of Neurological Disorders and Stroke entered into a contract with the University of California-San Francisco to develop psychometrically robust executive measurement tools that would be accepted by the neurology clinical trials and clinical research communities. This effort, entitled Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER), resulted in a series of tasks targeting working memory, inhibition, set shifting, fluency, insight, planning, social cognition and behavior. We describe battery conceptualization and development, data collection, scale construction based on item response theory, and lay the foundation for studying the battery's utility and validity for specific assessment and research goals. (JINS, 2013, 19, 1–9)
Ecological Validity and Neuroanatomical Correlates of the NIH EXAMINER Executive Composite Score
- Katherine L. Possin, Amanda K. LaMarre, Kristie A. Wood, Dan M. Mungas, Joel H. Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 20 / Issue 1 / January 2014
- Published online by Cambridge University Press:
- 14 June 2013, pp. 20-28
-
- Article
- Export citation
-
Executive functions refer to a constellation of higher-level cognitive abilities that enable goal-oriented behavior. The NIH EXAMINER battery was designed to assess executive functions comprehensively and efficiently. Performance can be summarized by a single score, the “Executive Composite,” which combines measures of inhibition, set-shifting, fluency, and working memory. We evaluated the ecological validity of the Executive Composite in a sample of 225 mixed neurological patients and controls using the Frontal Systems Behavior Scale (FrSBe), an informant-based measure of real-world executive behavior. In addition, we investigated the neuroanatomical correlates of the Executive Composite using voxel-based morphometry in a sample of 37 participants diagnosed with dementia, mild cognitive impairment, or as neurologically healthy. The Executive Composite accounted for 28% of the variance in Frontal Systems Behavior Scale scores beyond age. Even after including two widely used executive function tests (Trails B and Stroop) as covariates, the Executive Composite remained a significant predictor of real-world behavior. Anatomically, poorer scores on the Executive Composite were associated with smaller right and left dorsolateral prefrontal volumes, brain regions critical for good executive control. Taken together, these results suggest that the Executive Composite measures important aspects of executive function not captured by standard measures and reflects the integrity of frontal systems. (JINS, 2013, 19, 1–9)
The Frontal-Anatomic Specificity of Design Fluency Repetitions and Their Diagnostic Relevance for Behavioral Variant Frontotemporal Dementia
- Katherine L. Possin, Serana K. Chester, Victor Laluz, Alan Bostrom, Howard J. Rosen, Bruce L. Miller, Joel H. Kramer
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 18 / Issue 5 / September 2012
- Published online by Cambridge University Press:
- 27 July 2012, pp. 834-844
-
- Article
- Export citation
-
On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer's disease, semantic dementia, progressive supranuclear palsy, or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD. (JINS, 2012, 18, 1–11)
Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum
- Elysa J. Marco, Kathryn M. Harrell, Warren S. Brown, Susanna S. Hill, Rita J. Jeremy, Joel H. Kramer, Elliott H. Sherr, Lynn K. Paul
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 18 / Issue 3 / May 2012
- Published online by Cambridge University Press:
- 06 March 2012, pp. 521-529
-
- Article
- Export citation
-
Corpus callosum malformation and dysfunction are increasingly recognized causes of cognitive and behavioral disability. Individuals with agenesis of the corpus callosum (AgCC) offer unique insights regarding the cognitive skills that depend specifically upon callosal connectivity. We examined the impact of AgCC on cognitive inhibition, flexibility, and processing speed using the Color-Word Interference Test (CWIT) and Trail Making Test (TMT) from the Delis-Kaplan Executive Function System. We compared 36 individuals with AgCC and IQs within the normal range to 56 matched controls. The AgCC cohort was impaired on timed measures of inhibition and flexibility; however, group differences on CWIT Inhibition, CWIT Inhibition/Switching and TMT Number-Letter Switching appear to be largely explained by slow performance in basic operations such as color naming and letter sequencing. On CWIT Inhibition/Switching, the AgCC group was found to commit significantly more errors which suggests that slow performance is not secondary to a cautious strategy. Therefore, while individuals with agenesis of the corpus callosum show real deficits on tasks of executive function, this impairment appears to be primarily a consequence of slow cognitive processing. Additional studies are needed to investigate the impact of AgCC on other aspects of higher order cortical function. (JINS, 2012, 18, 521–529)