Depressive Symptoms Are Not Associated with Predementia Cerebrospinal Fluid Amyloid Pathology.

Introduction: Depressive symptoms are associated with Alzheimer's disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aß) pathology and cognition in predementia AD. Methods: We included subjective cognitive decline (SCD, n = 160) and mild cognitive impairment (MCI, n = 192) from the dementia disease initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aß pathology was determined using cerebrospinal fluid (CSF) Aß42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression. Results: Only the Aß negative MCI group (MCI-Aß-) was associated with depressive symptoms (odds ratio [OR] = 2.65, p = 0.005). Depressive symptoms were associated with worse memory in MCI-Aß- (OR = 0.94, p = 0.039), but with better performance in MCI-Aß+ (OR = 1.103, p = 0.001). Conclusion: Our results suggest that depressive symptoms in MCI are neither associated with Aß pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

Age-adjusted CSF t-tau and NfL do not improve diagnostic accuracy for prodromal Alzheimer's disease.

Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer's disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41-78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.

Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer's disease.

BACKGROUND: Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. METHODS: We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aß42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. RESULTS: Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). CONCLUSIONS: Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

Regression-based normative data for the D-KEFS Color-Word Interference Test in Norwegian adults ages 20-85.

Objective: The Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (CWIT; AKA Stroop test) is a widely used measure of processing speed and executive function. While test materials and instructions have been translated to Norwegian, only American age-adjusted norms from D-KEFS are available in Norway. We here develop norms in a sample of 1011 Norwegians between 20 and 85 years. We provide indexes for stability over time and assess demographic adjustments applying the D-KEFS norms. Method: Participants were healthy Norwegian adults from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 899), the Dementia Disease Initiation (n = 77), and Oslo MCI (n = 35). Using regression-based norming, we estimated linear and non-linear effects of age, education, and sex on the CWIT 1-4 subtests. Stability over time was assessed with intraclass correlation coefficients (ICC). The normative adjustment of the D-KEFS norms was assessed with linear regression models. Results: Increasing age was associated with slower completion on all CWIT subtests in a non-linear fashion (accelerated lowering of performance with older age). Women performed better on CWIT-1&3. Higher education predicted faster completion time on CWIT-3&4. The original age-adjusted norms from D-KEFS did not adjust for sex or education. Furthermore, we observed significant, albeit small effects of age on all CWIT subtests. ICC analyses indicated moderate to good stability over time. Conclusion: We present demographically adjusted regression-based norms and stability indexes for the D-KEFS CWIT subtests. US D-KEFS norms may be inaccurate for Norwegians with high or low educational attainment, especially women.

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer's disease.

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer's disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer's disease pathology. Linear regression was used to assess the influence of CSF determined Aß-plaque (Aß-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aß-/Aß+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aß+ compared to Aß- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aß- vs. Aß+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

Regression-based norms for the FAS phonemic fluency test for ages 40-84 based on a Norwegian sample.

The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway.However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40-84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation.

Regression-based cognitive change norms applied in biochemically defined predementia Alzheimer's disease.

OBJECTIVE: We aim to develop 2-year cognitive change norms for adults ages 41-84 for six cognitive tests, and to evaluate these norms in groups with AD biomarkers. BACKGROUND: Practice effects are common in repeated neuropsychological testing. Not accounting for practice effects may obscure cognitive decline in early Alzheimer's disease (AD). METHOD: We developed standardized regression-based change norms from normative samples consisting of healthy controls from the Dementia Disease Initiation study (n = 125), the Trønderbrain study (n = 57), and the Gothenburg mild cognitive impairment (MCI) study (n = 65). Norms were applied in a sample with cognitive symptoms (subjective cognitive decline or MCI) and AD cerebrospinal fluid (CSF) biomarkers (n = 246), classified according to the A/T/N system. RESULTS: The change norms adjusted for pertinent demographics and practice effects. The group with cognitive complaints displayed a trend toward cognitive decline compared to the normative group, with the A +T/N + subgroup showing the most marked decline. This was observed in tests of episodic memory and cognitive flexibility/divided attention. CONCLUSIONS: We present 2-year cognitive change norms for adults between 41 and 84 years, adjusted for practice and demographics. A web-based change norm calculator is provided. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Regression-based normative data for the Rey Auditory Verbal Learning Test in Norwegian and Swedish adults aged 49-79 and comparison with published norms.

Objective: The Rey Auditory Verbal Learning Test (RAVLT) is a widely used measure of episodic verbal memory. To our knowledge, culturally adapted and demographically adjusted norms for the RAVLT are currently not available for Norwegian and Swedish adults, and imported North American norms are often used. We here develop regression-based norms for Norwegian and Swedish adults and compare our norms to North American norms in an independent sample of cognitively healthy adults. Method: Participants were 244 healthy adults from Norway and Sweden between the aged 49 and 79 years, with between 6 and 24 years of education. Using a multiple multivariate regression-based norming procedure, we estimated effects of age, sex, and years of education on basic and derived RAVLT test scores. The newly developed norms were assessed in an independent comparison group of cognitively healthy adults (n = 145) and compared to recently published North American regression-based norms. Results: Lower age, female sex and more years of education predicted higher performance on the RAVLT. The new norms adequately adjusted for age, education, and sex in the independent comparison group. The American norms corrected for demographics on all RAVLT trials except trials 4, 7, list B, and trials 1-5 total. Test-retest (M = 2.55 years) reliability varied from poor to good. Conclusion: We propose regression-based norms for the RAVLT adjusting for pertinent demographics. The norms may be used for assessment of Norwegian and Swedish adults between the aged of 49 and 79 years, with between 6 and 24 years of education.

Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden.

Importance: Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives: To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants: This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-ß 42 (Aß42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures: Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results: A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; ß = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; ß = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aß42 burden (ß = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: ß = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: ß = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance: The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

Stable cerebrospinal fluid neurogranin and ß-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients.

Cerebrospinal fluid (CSF) ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.

Reduction in manual asymmetry and decline in fine manual dexterity in right-handed older adults with mild cognitive impairment.

Research in Parkinson's or Alzheimer's disease suggests that hand function is affected by neurodegenerative diseases. However, little is known about the relationship between hand function and mild cognitive impairment (MCI). Therefore, we conducted a kinematic analysis of unimanual hand movements in MCI patients to answer whether manual asymmetries and manual dexterity are affected or preserved in this condition. Forty-one MCI patients and fifty healthy controls were tested with the Purdue Pegboard test. All participants were right-handed. Kinematic analyses (by hand) were calculated for path length, angle, and linear and angular velocities during reaching, grasping, transport and inserting. Group differences were tested by with factorial MANOVAs and laterality indexes (LI) were assessed. Groups were compared on "Right-Left" hand correlations to identify kinematics that best single-out patients. Kinematics from grasping and inserting were significantly more deteriorated in the MCI group, while outcomes for reaching and transport denoted superior performance. LIs data showed symmetry of movements in the MCI group, during reaching and transport. Comparisons of "Right-Left" hand correlations revealed that kinematics in reaching and transport were more symmetrical in patients. This study showed a deterioration of fine manual dexterity, an enhancement in gross dexterity of upper-limbs, and symmetrical movements in MCI patients.

Assessing a Sensory-Motor-Cognition Triad in Amnestic Mild Cognitive Impairment With Dichotic Listening While Walking: A Dual-Task Paradigm.

A contemporary topic in aging research relates to the significance of cognitive changes proper to mild cognitive impairment (MCI) to higher risk of falls and gait deteriorations. The present study addresses this question in the amnestic type of MCI (aMCI) by examining a triad of interrelated comorbidities occurring in the MCI condition: attentional impairments, hearing loss and gait disturbances. To this end, we applied a dichotic listening (DL) test during over-ground walking. DL assesses spontaneous and lateralized auditory attention in three conditions (i.e., free report or Non-forced (NF), Forced-Right (FR) ear and Forced-Left (FL) ear). Earlier reports suggest that this dual-task paradigm evoke asymmetric gait effects on healthy controls, which are moderated by degree of hearing loss. Therefore, the aim of the present study was to evaluate the effects of DL on bilateral (data from both limbs) and lateralized (each limb separately) gait outcomes in a group of forty-three aMCI participants (mean = 71.19) and fifty-two healthy older controls (mean = 70.90) by using hearing loss as a covariate in all analyses. Results showed the aMCI group presented overall compromised gait parameters, especially higher gait variability in all DL conditions during lateralized attentional control. These findings were observed bilaterally, and no lateralized effects on gait were observed. Only after controlling for hearing acuity, gait asymmetries on step length variability emerged almost exclusively in healthy controls. It was concluded that hearing loss in the aMCI group together with higher attentional impairments preclude aMCI individuals to properly execute DL and therefore, they do not display gait asymmetries. The present data demonstrate that varied demands on attentional control dependent on hearing acuity affects gait negatively in healthy older adults and aMCI individuals in very different ways. The appearance of asymmetric effects seems to be a perturbation related to normal aging, while the lack of asymmetries but exaggerated gait variability characterizes aMCI. The present findings show the intricate interplay of sensory, cognitive, and motor deteriorations in different group of older adults, which stresses the need of addressing co-occurring comorbidities behind gait perturbations in individuals prone to develop a dementia state.

What does hand motor function tell us about our aging brain in association with WMH?

BACKGROUND: White matter hyperintensities (WMH) are a common cerebral finding in older people. WMH are usually asymptomatic, but excessive WMH are associated with cognitive decline and dementia. WMH are also among the neurological findings most consistently associated with declining motor performance in healthy ageing. AIMS: To determine if WMH load is associated with simple and complex motor movements in dominant and non-dominant hands in cognitively intact older subjects. METHODS: Hand motor performance was assessed with the Purdue Pegboard and Finger-tapping tests on 44 healthy right-handed participants, mean age 70.9 years (range 59-84 years). Participants also underwent magnetic resonance (MR) imaging, which were used to quantify WMH volume. The effect of WMH on the motor parameters was assessed via mediation analyses. RESULTS: WMH load increased significantly with age, while the motor scores decreased significantly with age. WMH load mediated only the relationship between age and left-hand pegboard scores. DISCUSSION: WMH mediated only the more complex Purdue Pegboard task for the non-dominant hand. This is likely because complex movements in the non-dominant hand recruit a larger cerebral network, which is more vulnerable to WMH. CONCLUSIONS: Complex hand movements in the non-dominant hand are mediated by WMH. Subtle loss of motor movements of non-dominant hand might predict future excessive white matter atrophy.

Evaluation of Error Production in Animal Fluency and Its Relationship to Frontal Tracts in Normal Aging and Mild Alzheimer's Disease: A Combined LDA and Time-Course Analysis Investigation.

Semantic verbal fluency (VF), assessed by animal category, is a task widely used for early detection of dementia. A feature not regularly assessed is the occurrence of errors such as perseverations and intrusions. So far, no investigation has analyzed the how and when of error occurrence during semantic VF in aging populations, together with their possible neural correlates. The present study aims to address the issue using a combined methodology based on latent Dirichlet allocation (LDA) analysis for word classification together with a time-course analysis identifying exact time of errors' occurrence. LDA is a modeling technique that discloses hidden semantic structures based on a given corpus of documents. We evaluated a sample of 66 participants divided into a healthy young group (n = 24), healthy older adult group (n = 23), and group of patients with mild Alzheimer's disease (AD) (n = 19). We performed DTI analyses to evaluate the white matter integrity of three frontal tracts purportedly underlying error commission: anterior thalamic radiation, frontal aslant tract, and uncinate fasciculus. Contrasts of DTI metrics were performed on the older groups who were further classified into high-error rate and low-error rate subgroups. Results demonstrated a unique deployment of error commission in the patient group characterized by high incidence of intrusions in the first 15 s and higher rate of perseverations toward the end of the trial. Healthy groups predominantly showed very low incidence of perseverations. The DTI analyses revealed that the patients with AD committing high-error rate presented significantly more degenerated frontal tracts in the left hemisphere. Thus, our findings demonstrated that the appearance of intrusions, together with left hemisphere degeneration of frontal tracts, is a pathognomic trait of mild AD. Furthermore, our data suggest that the error commission of patients with AD arises from executive and working memory impairments related partly to deteriorated left frontal tracts.

Predictive and diagnostic utility of brief neuropsychological assessment in detecting Alzheimer's pathology and progression to dementia.

Objective: To assess the role of brief neuropsychological assessments in prediction and identification of Alzheimer's disease (AD) pathology and progression to AD dementia. Method: Adults (N = 255; range = 40-81 years) with self-reported cognitive decline underwent baseline and 2-year follow-up clinical assessment, including a brief neuropsychological screening and lumbar puncture. Five different mild cognitive impairment (MCI) algorithms were applied on baseline cognitive test results: one conventional, three amnestic (lenient, stringent, multidomain), and one comprehensive criterion. We compared predictive and diagnostic accuracy of these MCI criteria by performing logistic regression analyses and calculating diagnostic accuracy measures for 2-year outcomes of (1) clinical diagnosis of AD dementia and (2) cerebrospinal fluid biomarkers in the Alzheimer's continuum. Results: The lenient amnestic MCI criterion showed the largest effect size for predicting progression to AD dementia (OR = 13.762, 99% CI = 1.969-96.194, p = .001) and AD biomarkers (OR = 4.855, 99% CI = 1.974-11.924, p < .001) after 2 years. This criterion was sensitive for progression to dementia (sensitivity = 92.0%, specificity = 54.8%, positive likelihood ratio [LR+] = 2.03, LR- = 0.15) and showed the highest overall diagnostic accuracy for AD biomarkers (sensitivity = 72.7%, specificity = 59.1%, LR+ = 1.78, negative likelihood ratio [LR-] = 0.46). The multidomain amnestic MCI criterion produced the highest specificity for dementia (sensitivity = 76.0%, specificity = 73.0%, LR+ = 2.82, LR- = 0.33) and AD biomarkers (sensitivity = 46.8% specificity = 70.9% LR+ = 1.61, LR- = 0.75). Conclusions: Defining MCI using a brief neuropsychological battery provided limited accuracy for progression to AD dementia and cerebrospinal fluid Aß. The lenient amnestic MCI criterion identified the highest number of individuals who progressed to clinical AD or showed biomarker pathology, but this approach included a substantial number of false positives. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Demographically adjusted trail making test norms in a Scandinavian sample from 41 to 84 years.

OBJECTIVE: The trail making test (TMT) is one of the most widely used neuropsychological tests. TMT-A provides measures of visual scanning/visuomotor speed and TMT-B involves additional demands on executive functions. Derived scores TMT B-A and TMT B/A enhance measures of executive functioning. However, simple B-A subtraction may lead to false estimates of executive dysfunction in clinical samples. Norms for TMT have been published in several countries but are currently lacking for Scandinavia. METHODS: A total of 292 healthy controls between age 41 and 84 years were included from the Norwegian "Dementia Disease Initiation" (DDI) study (n = 170) and the Gothenburg Mild Cognitive Impairment (MCI) study (n = 122). We used a regression-based procedure to develop demographically adjusted norms for basic (TMT-A and TMT-B) and derived measures (TMT B-A and B/A). We also propose a regression-based alternative to the TMT B-A measure named "TMT-ß". The proposed norms were compared to norms from Heaton et al. and Tombaugh. RESULTS: Due to differences in the estimated normative effects of demographics on performance, the proposed norms for TMT were better suited in the Scandinavian sample compared with published non-Scandinavian norms. The proposed TMT-ß measure was highly correlated to TMT B-A (r = 0.969, p < 0.001). CONCLUSION: We here propose demographically adjusted norms for the TMT for ages 41 through 84 years based on a Scandinavian sample. We also present the regression-based derived measure TMT-ß which may resolve issues with the conventional TMT B-A measure.

The Role of Moderating Variables on BOLD fMRI Response During Semantic Verbal Fluency and Finger Tapping in Active and Educated Healthy Seniors.

Semantic verbal fluency is among the most employed tasks in cognitive aging research and substantial work is devoted to understanding the underlying mechanisms behind age-related differences at the neural and behavioral levels. The present investigation aimed to evaluate the role of moderating variables, such as age, sex, MMSE, and proxies of cognitive reserve (CR) on the hemodynamic response evoked by semantic verbal fluency in healthy young and healthy older adults. So far, no study has been conducted to this end. To elucidate the exclusive effect of the mentioned variables on brain activation during semantic fluency, finger tapping was included as a control task. Results showed that disregarding adjustments for age, older adults displayed important parietal activations during semantic fluency as well as during finger-tapping. Specifically, the anterior intra-parietal sulcus (IPS) and left inferior parietal lobule (IPL) were areas activated in both tasks in the older group. Younger adults, only displayed parietal activations related to age and sex when these demographics were employed as predictors. Concerning proxies of CR in semantic fluency, the only vocabulary was an important moderator in both age groups. Higher vocabulary scores were associated with lesser activation in occipital areas. Education did not show significant correlations with brain activity during semantic fluency in any of the groups. However, both CR proxies were significantly correlated to brain activations of older adults during finger tapping. Specifically, vocabulary was associated with frontal regions, while education correlated with parietal lobe and cingulate gyrus. Finally, the effects of MMSE were mostly observed on brain activation of older adults in both tasks. These findings demonstrate that the effects of moderating variables on shaping brain activation are intricate and not exclusive of complex verbal tasks. Thus, before adjusting for "nuisance variables," their importance needs to be established. This is especially true for samples including older adults for whom a motor task may be a demanding operation due to normal age-related processes of dedifferentiation.

Amyloid Plaques and Symptoms of Depression Links to Medical Help-Seeking due to Subjective Cognitive Decline.

BACKGROUND: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. OBJECTIVE: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. METHODS: We compared levels of cerebrospinal fluid (CSF) Aß1 - 42, cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n = 88), SCD with a history of medical help seeking (SCD-HS, n = 67), and SCD non help-seekers (SCD-NHS, n = 44). Cases with evidence of amyloid plaques (CSF Aß1 - 42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. RESULTS: The SCD-HS group had lower CSF Aß1 - 42 (p < 0.01), lower word list learning and memory recall (p < 0.0001), and an increased level of depressive symptoms (p < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n = 12, 18%) and amyloid plaques (n = 18, 27%) compared to SCD-NHS (n = 1, 2% and n = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. CONCLUSION: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.

White matter correlates of gait perturbations resulting from spontaneous and lateralized attention in healthy older adults: A dual-task study.

To date the neural mechanisms behind gait perturbations caused by dual-task paradigms are still unknown. Therefore, the present study examined white matter correlates of gait perturbations caused by a dichotic listening task where spontaneous (free focus of attention) and lateralized attentional control (voluntary attention directed to right or left-ear) were tested. Fifty-nine right-handed, healthy older adults (59-88 years) were evaluated during single-task walking and three dual-task conditions. Dual-task costs were calculated for mean (DTCM) and coefficients of variation (DTCCoV) in gait speed, step length, stride length and step width. Volume, fractional anisotropy and mean diffusivity were estimated using global probabilistic tractography for the 18 major brain tracts and correlated with the DTCs. Data demonstrated that DTCs on gait speed and step length significantly correlated with white matter integrity and volume in various tracts. Perturbations on gait speed caused by spontaneous attention were related to frontal circuitry integrity including corpus callosum, while perturbations on gait speed and step length produced by voluntary lateralized attention were associated to tracts subserving visuomotor integration and frontal function.