Polsinelli, Angelina J.

AbstractObjectiveThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodsData from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid‐positive EOAD [n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]).ResultsCognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.ConclusionsWe present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

AbstractBackgroundWe report a group of individuals presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions and positive biomarkers for Alzheimer’s pathophysiology.MethodIn this retrospective review, we report on 55 participants with a clinically defined progressive dysexecutive syndrome with 18F‐fluorodeoxyglucose‐positron emission tomography (FDG) and AD biomarker positivity. A subset of these individuals enrolled in our ADRC were compared to other phenotypic variants of AD.ResultSixty‐two percent were female with a mean of 15.2 years of education. Mean age of symptom onset was 53.8 while mean age at diagnosis was 57.2 years. Multi‐domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently and severely affected. The frontal and/or parietal regions demonstrate clear hypometabolism on positron emission tomography in all cases. Genetic testing for autosomal dominant genes was negative in all 8 participants tested and at least one APOE ε4 allele was present in 14/26. EEG was abnormal in 14/17 cases. CSF and neuroimaging biomarkers (PIB‐PET and Tau‐PET) were consistent with Alzheimer’s disease pathophysiology, although CSF p‐tau was normal in 24% of cases. In two participants that came to autopsy, the hippocampus was relatively spared compared to frontal and parietal cortex. Participants presenting with a progressive dysexecutive syndrome and evidence of AD pathology are labeled dAD. Comparing FDG in dAD relative to other AD phenotypes revealed unique areas of relatively greater hypometabolism in parieto‐frontal cortex and relative sparing of medial temporal (vs typical AD), visual (vs PCA), and left temporal (vs lvPPA) (Figure 1). Controlling for age did not alter patterns of regional differences. This demonstrates regional variability related to clinical phenotype not accountable by variation in age, duration, stage, or severity (Figure 2).ConclusionA progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype. This clinical presentation can be due to Alzheimer’s disease but is not specific for any single etiology (non‐AD cases of progressive dysexecutive syndrome will be discussed). Prominent impairment of executive task performance, young‐age of onset, normal CSF p‐tau, and relative preservation of the hippocampus were commonly encountered in this case series of dAD.

Abstract We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer’s pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer’s disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer’s disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as ‘memory problems’ but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer’s disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer’s disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer’s disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.

Abstract. The present study examined the interpersonal focus within autobiographical memories (AMs) of older and younger adults from the perspective of socioemotional selectivity theory (SST). Specifically, we measured interpersonal focus directly through rater codings (relational vs. individual focus) and social word use, and indirectly through personal pronoun use. Forty-five older ( Mage = 76.76) and 25 younger ( Mage = 18.64) adults recalled positive and negative AMs, which were then coded and processed through computerized text analysis software to obtain word-use counts. Consistent with SST, the positive AMs of older adults were more interpersonally focused compared to negative AMs and younger adults. The results suggest that the positive life experiences of older adults tend to be associated with a high degree of social importance and focus on others.

Abstract Objective The Test of Memory Malingering (TOMM) is widely used to assess performance validity. To improve efficiency, we investigated whether abbreviated administration (i.e., only the first 25 items of Trial 1 [T1]) is possible when effort is very strong (≥49/50 on T1 or T2). Method We collected TOMM scores of 501 consecutive adult patients ranging in cognitive status who underwent standard neuropsychological evaluation at Mayo Clinic, Rochester, MN. Results Receiver Operating Characteristic (ROC) analysis showed excellent area under the curve (AUC) (0.94; CI95% [0.92, 0.97]) and a cutoff of 25/25 had 100% specificity for identifying strong performance. Of the 224 patients who obtained a perfect score on the first 25 items, 197 (88%) obtained ≥49 on T1 and the remaining patients (n = 27) obtained ≥49 on T2. Conclusion A perfect score on the first 25 items of the TOMM predicted overall strong performance 100% of the time, supporting abbreviated administration in select cases in a general outpatient clinical setting.