Electrophysiological alterations during action semantic processing in Parkinson's disease.

Assessments of action semantics consistently reveal markers of Parkinson's disease (PD). However, neurophysiological signatures of the domain remain under-examined in this population, especially under conditions that allow patients to process stimuli without stringent time constraints. Here we assessed event-related potentials and time-frequency modulations in healthy individuals (HPs) and PD patients during a delayed-response semantic judgment task involving related and unrelated action-picture pairs. Both groups had shorter response times for related than for unrelated trials, but they exhibited discrepant electrophysiological patterns. HPs presented significantly greater N400 amplitudes as well as theta enhancement and mu desynchronization for unrelated relative to related trials. Conversely, N400 and theta modulations were abolished in the patients, who further exhibited a contralateralized cluster in the mu range. None of these patterns were associated with the participants' cognitive status. Our results suggest that PD involves multidimensional neurophysiological disruptions during action-concept processing, even under task conditions that elicit canonical behavioral effects. New constraints thus emerge for translational neurocognitive models of the disease.

Associations of category fluency clustering performance with in vivo brain pathology in autosomal dominant Alzheimer's disease.

OBJECTIVES: Alzheimer's disease (AD) is known to impact semantic access, which is frequently evaluated using the Category Fluency (Animals) test. Recent studies have suggested that in addition to overall category fluency scores (total number of words produced over time), poor clustering could signal AD-related cognitive difficulties. In this study, we examined the association between category fluency clustering performance (i.e., stating words sequentially that are all contained within a subcategory, such as domestic animals) and brain pathology in individuals with autosomal dominant Alzheimer's disease (ADAD). METHODS: A total of 29 non-demented carriers of the Presenilin1 E280A ADAD mutation and 32 noncarrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate in vivo amyloid-beta in the neocortex and tau in medial temporal lobe regions. Differences between carriers and noncarriers on cognitive tests were assessed with Mann-Whitney tests; associations between cognitive test performance and brain pathology were assessed with Spearman correlations. RESULTS: Animal fluency scores did not differ between carriers and noncarriers. Carriers, however, showed a stronger association between animal fluency clustering and in vivo AD brain pathology (neocortical amyloid and entorhinal tau) relative to noncarriers. CONCLUSION: This study indicates that using category fluency clustering, but not total score, is related to AD pathophysiology in the preclinical and early stages of the disease.

Subjective Cognitive and Communicative Complaints and Health-Related Quality of Life in Parkinson's Disease with and without Mild Cognitive Impairment.

INTRODUCTION: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored. OBJECTIVE: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints. METHODS: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted. RESULTS: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores. CONCLUSIONS: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Spectral features of resting-state EEG in Parkinson's Disease: A multicenter study using functional data analysis.

OBJECTIVE: This study aims 1) To analyse differences in resting-state electroencephalogram (rs-EEG) spectral features of Parkinson's Disease (PD) and healthy subjects (non-PD) using Functional Data Analysis (FDA) and 2) To explore, in four independent cohorts, the external validity and reproducibility of the findings using both epoch-to-epoch FDA and averaged-epochs approach. METHODS: We included 169 subjects (85 non-PD; 84 PD) from four centres. Rs-EEG signals were preprocessed with a combination of automated pipelines. Sensor-level relative power spectral density (PSD), dominant frequency (DF), and DF variability (DFV) features were extracted. Differences in each feature were compared between PD and non-PD on averaged epochs and using FDA to model the epoch-to-epoch change of each feature. RESULTS: For averaged epochs, significantly higher theta relative PSD in PD was found across all datasets. Also, higher pre-alpha relative PSD was observed in three of four datasets in PD patients. For FDA, similar findings were achieved in theta, but all datasets showed consistently significant posterior pre-alpha differences across multiple epochs. CONCLUSIONS: Increased generalised theta, with posterior pre-alpha relative PSD, was the most reproducible finding in PD. SIGNIFICANCE: Rs-EEG theta and pre-alpha findings are generalisable in PD. FDA constitutes a reliable and powerful tool to analyse epoch-to-epoch the rs-EEG.

Detecting Parkinson's disease and its cognitive phenotypes via automated semantic analyses of action stories.

Action-concept outcomes are useful targets to identify Parkinson's disease (PD) patients and differentiate between those with and without mild cognitive impairment (PD-MCI, PD-nMCI). Yet, most approaches employ burdensome examiner-dependent tasks, limiting their utility. We introduce a framework capturing action-concept markers automatically in natural speech. Patients from both subgroups and controls retold an action-laden and a non-action-laden text (AT, nAT). In each retelling, we weighed action and non-action concepts through our automated Proximity-to-Reference-Semantic-Field (P-RSF) metric, for analysis via ANCOVAs (controlling for cognitive dysfunction) and support vector machines. Patients were differentiated from controls based on AT (but not nAT) P-RSF scores. The same occurred in PD-nMCI patients. Conversely, PD-MCI patients exhibited reduced P-RSF scores for both texts. Direct discrimination between patient subgroups was not systematic, but it yielded best outcomes via AT scores. Our approach outperformed classifiers based on corpus-derived embeddings. This framework opens scalable avenues to support PD diagnosis and phenotyping.

Sex differences in cognitive resilience in preclinical autosomal-dominant Alzheimer's disease carriers and non-carriers: Baseline findings from the API ADAD Colombia Trial.

INTRODUCTION: Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers. METHODS: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing. RESULTS: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. DISCUSSION: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.

Subjective Cognitive Decline and its Relation to Verbal Memory and Sex in Cognitively Unimpaired Individuals from a Colombian Cohort with Autosomal-Dominant Alzheimer's Disease.

OBJECTIVE: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. METHODS: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. RESULTS: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory. CONCLUSIONS: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Subjective Cognitive and Communicative Complaints and Health-Related Quality of Life in Parkinson's Disease with and without Mild Cognitive Impairment.

INTRODUCTION: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored. OBJECTIVE: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints. METHODS: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted. RESULTS: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores. CONCLUSIONS: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.

Cognitive Determinants of Dysarthria in Parkinson's Disease: An Automated Machine Learning Approach.

BACKGROUND: Dysarthric symptoms in Parkinson's disease (PD) vary greatly across cohorts. Abundant research suggests that such heterogeneity could reflect subject-level and task-related cognitive factors. However, the interplay of these variables during motor speech remains underexplored, let alone by administering validated materials to carefully matched samples with varying cognitive profiles and combining automated tools with machine learning methods. OBJECTIVE: We aimed to identify which speech dimensions best identify patients with PD in cognitively heterogeneous, cognitively preserved, and cognitively impaired groups through tasks with low (reading) and high (retelling) processing demands. METHODS: We used support vector machines to analyze prosodic, articulatory, and phonemic identifiability features. Patient groups were compared with healthy control subjects and against each other in both tasks, using each measure separately and in combination. RESULTS: Relative to control subjects, patients in cognitively heterogeneous and cognitively preserved groups were best discriminated by combined dysarthric signs during reading (accuracy = 84% and 80.2%). Conversely, patients with cognitive impairment were maximally discriminated from control subjects when considering phonemic identifiability during retelling (accuracy = 86.9%). This same pattern maximally distinguished between cognitively spared and impaired patients (accuracy = 72.1%). Also, cognitive (executive) symptom severity was predicted by prosody in cognitively preserved patients and by phonemic identifiability in cognitively heterogeneous and impaired groups. No measure predicted overall motor dysfunction in any group. CONCLUSIONS: Predominant dysarthric symptoms appear to be best captured through undemanding tasks in cognitively heterogeneous and preserved cohorts and through cognitively loaded tasks in patients with cognitive impairment. Further applications of this framework could enhance dysarthria assessments in PD. © 2021 International Parkinson and Movement Disorder Society.

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. OBJECTIVE: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. METHODS: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. RESULTS: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. CONCLUSION: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers.

BACKGROUND: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aß) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aß burden to characterize the presence and age at onset of cerebellar Aß deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. METHODS: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aß-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. RESULTS: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). CONCLUSION: This PET study provides evidence of cerebellar Aß plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia. OBJECTIVE: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. METHODS: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. RESULTS: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p < 0.001), lacunes (B = 0.30, p < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. CONCLUSION: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Associations between subregional thalamic volume and brain pathology in autosomal dominant Alzheimer's disease.

Histopathological reports suggest that subregions of the thalamus, which regulates multiple physiological and cognitive processes, are not uniformly affected by Alzheimer's disease. Despite this, structural neuroimaging studies often consider the thalamus as a single region. Identification of in vivo Alzheimer's-dependent volumetric changes in thalamic subregions may aid the characterization of early nuclei-specific neurodegeneration in Alzheimer's disease. Here, we leveraged access to the largest single-mutation cohort of autosomal-dominant Alzheimer's disease to test whether cross-sectional abnormalities in subregional thalamic volumes are evident in non-demented mutation carriers (n = 31), compared to non-carriers (n = 36), and whether subregional thalamic volume is associated with age, markers of brain pathology and cognitive performance. Using automatic parcellation we examined the thalamus in six subregions (anterior, lateral, ventral, intralaminar, medial, and posterior) and their relation to age and brain pathology (amyloid and tau), as measured by PET imaging. No between-group differences were observed in the volume of the thalamic subregions. In carriers, lower volume in the medial subregion was related to increased cortical amyloid and entorhinal tau burden. These findings suggest that thalamic Alzheimer's-related volumetric reductions are not uniform even in preclinical and prodromal stages of autosomal-dominant Alzheimer's disease and therefore, this structure should not be considered as a single, unitary structure in Alzheimer's disease research.

The impact of COVID-19 on the well-being and cognition of older adults living in the United States and Latin America.

BACKGROUND: In the COVID-19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic's impact on the well-being and cognition of older adults living in the United States (US), Argentina, Chile, Mexico, and Peru. METHODS: 1,608 (646 White, 852 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and four Latin American countries aged ≥ 55 years completed an online survey regarding well-being and cognition during the pandemic between May and September 2020. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups and older adults living in Argentina, Chile, Mexico, and Peru. FINDINGS: Mean age for all participants was 66.7 (SD = 7.7) years and mean education was 15.4 (SD = 2.7) years. Compared to Whites, Latinos living in the US reported greater economic impact (p < .001, ηp 2  = 0.031); while Blacks reported experiencing discrimination more often (p < .001, ηp 2  = 0.050). Blacks and Latinos reported more positive coping (p < .001, ηp 2  = 0.040). Compared to Latinos living in the US, Latinos in Chile, Mexico, and Peru reported greater pandemic impact, Latinos in Mexico and Peru reported more positive coping, Latinos in Argentina, Mexico, and Peru had greater economic impact, and Latinos in Argentina, Chile, and Peru reported less discrimination. INTERPRETATION: The COVID-19 pandemic has differentially impacted the well-being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic's impact. FUNDING: Massachusetts General Hospital Department of Psychiatry.

Resting-state EEG alpha/theta ratio related to neuropsychological test performance in Parkinson's Disease.

OBJECTIVE: To determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson's Disease (PD) non-demented patients. METHODS: 36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis. RESULTS: The α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD. CONCLUSIONS: Reduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD. SIGNIFICANCE: Visuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia.

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

BACKGROUND: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-ß (Aß) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. METHODS: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aß (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. RESULTS: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aß accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. CONCLUSIONS: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aß burden and neocortical tau accumulation in ADAD.

Normative data stratified by age and education for a Spanish neuropsychological test battery: Results from the Colombian Alzheimer's prevention initiative registry.

Neuropsychologists continue to face challenges when assessing Spanish-speaking individuals due to limited availability of normative data. We developed comprehensive normative data stratified by age and education for a Spanish neuropsychological test battery used by the Grupo de Neurociencias de Antioquia (Colombia) and the Colombian Alzheimer's Prevention Initiative Registry, which have followed large families at risk for autosomal-dominant Alzheimer's disease (ADAD) since the 1990s. Approximately 75% of these individuals are cognitively-unimpaired and are not genetically predisposed to develop ADAD. We conducted a retrospective study on neuropsychological evaluations from 2,673 cognitively unimpaired individuals (56% female), with ages ranging from 18 to 86 years and education from 1 to 25 years. Neuropsychological measures included the Consortium to Establish a Registry for Alzheimer's Disease-Colombia, and other multidomain Spanish tests. We examined associations between age, education, and sex with cognitive performance. Norms stratified by age and education are presented. Cognitive performance showed small associations with age and education and was unrelated to sex. We provided population-based norms for Spanish tests targeting multiple cognitive domains using a large Colombian sample. These normative data may be helpful for the neuropsychological characterization of Spanish speakers from Latin America in clinical and research settings.

Association Between Visual Memory and In Vivo Amyloid and Tau Pathology in Preclinical Autosomal Dominant Alzheimer's Disease.

OBJECTIVE: Visual memory (ViM) declines early in Alzheimer's disease (AD). However, it is unclear whether ViM impairment is evident in the preclinical stage and relates to markers of AD pathology. We examined the relationship between ViM performance and in vivo markers of brain pathology in individuals with autosomal dominant AD (ADAD). METHODS: Forty-five cognitively unimpaired individuals from a Colombian kindred with the Presenilin 1 (PSEN1) E280A ADAD mutation (19 carriers and 26 noncarriers) completed the Rey-Osterrieth Complex Figure immediate recall test, a measure of ViM. Cortical amyloid burden and regional tau deposition in the entorhinal cortex (EC) and inferior temporal cortex (IT) were measured using 11C-Pittsburgh compound B positron emission tomography (PET) and 11F-flortaucipir PET, respectively. RESULTS: Cognitively unimpaired carriers and noncarriers did not differ on ViM performance. Compared to noncarriers, carriers had higher levels of cortical amyloid and regional tau in both the EC and IT. In cognitively unimpaired carriers, greater cortical amyloid burden, higher levels of regional tau, and greater age were associated with worse ViM performance. Only a moderate correlation between regional tau and ViM performance remained after adjusting for verbal memory scores. None of these correlations were observed in noncarriers. CONCLUSIONS: Results suggest that AD pathology and greater age are associated with worse ViM performance in ADAD before the onset of clinical symptoms. Further investigation with larger samples and longitudinal follow-up is needed to examine the utility of ViM measures for identifying individuals at high risk of developing dementia later in life.

The Latin American Spanish version of the Face-Name Associative Memory Exam is sensitive to cognitive and pathological changes in preclinical autosomal dominant Alzheimer's disease.

BACKGROUND: To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer's disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-ß and regional tau burden in mutation carriers. METHODS: A total of 35 cognitively intact mutation carriers (age range 26-41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27-44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-ß and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-ß and tau accumulation. RESULTS: Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-ß (r = - .436, p = .018) and regional tau in the entorhinal (r = - .394, p = .031) and inferior temporal cortex (r = - .563, p = .001) were associated with lower LAS-FNAME Total Scores. CONCLUSIONS: Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.