Changes in Digital Speech Measures in Asymptomatic Carriers of Pathogenic Variants Associated With Frontotemporal Degeneration.

BACKGROUND AND OBJECTIVES: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool. We aimed to identify early changes in the natural speech of FTD pathogenic variant carriers before they become symptomatic. METHODS: In this cohort study, speech samples of picture descriptions were collected longitudinally from healthy participants in observational studies at the University of Pennsylvania and Columbia University between 2007 and 2020. Participants were asymptomatic but at risk for familial FTD. Status as "carrier" or "noncarrier" was based on screening for known pathogenic variants in the participant's family. Thirty previously validated digital speech measures derived from automatic speech processing pipelines were selected a priori based on previous studies in patients with FTD and compared between asymptomatic carriers and noncarriers cross-sectionally and longitudinally. RESULTS: A total of 105 participants, all asymptomatic, included 41 carriers: 12 men [30%], mean age 43 ± 13 years; education, 16 ± 2 years; MMSE 29 ± 1; and 64 noncarriers: 27 men [42%]; mean age, 48 ± 14 years; education, 15 ± 3 years; MMSE 29 ± 1. We identified 4 speech measures that differed between carriers and noncarriers at baseline: mean speech segment duration (mean difference -0.28 seconds, 95% CI -0.55 to -0.02, p = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, p = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, p = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, p = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (ß = -0.02, 95% CI -0.03 to -0.004, p = 0.009); total narrative production time in seconds per month (ß = -0.24, 95% CI -0.37 to -0.12, p < 0.001); and total number of words per month (ß = -0.48, 95% CI -0.78 to -0.19, p = 0.002) including in 3 carriers who later converted to symptomatic disease. DISCUSSION: Using automatic processing pipelines, we identified early changes in the natural speech of FTD pathogenic variant carriers in the presymptomatic stage. These findings highlight the potential utility of natural speech as a digital clinical outcome assessment tool in FTD, where objective and quantifiable measures for abnormal behavior and language are lacking.

Verbal and nonverbal fluency in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

Demographic and Symptom Correlates of Initial Idiopathic Psychiatric Diagnosis in Frontotemporal Dementia.

INTRODUCTION: This study aims to measure frequency and correlates of initial idiopathic psychiatric diagnosis in a cohort of 147 patients with Frontotemporal Dementia (FTD)-spectrum disorders. METHODS: Participants were evaluated at the National Institutes of Health in Bethesda, Maryland. Initial participant diagnoses were determined by chart review and patient and informant interviews. Logistic regression was used to assess the relationships between diagnosis and age of symptom onset, gender, education, family history of psychiatric illness, and family history of dementia. Additional exploratory analyses investigated patients' first symptom type. RESULTS: 25% (n=43) of all the patients reviewed were initially misdiagnosed with an idiopathic psychiatric illness, which is less than half the commonly cited 50% rate.3 Depression was the most common misdiagnosis (46.5%). Family history of dementia, family history of mental illness and an exploratory analysis of behavioral first symptoms suggested significant association with a greater likelihood of initial idiopathic psychiatric diagnosis in FTD patients. DISCUSSION: This data confirms patterns of initial idiopathic psychiatric diagnosis in FTD and elucidates potential factors underlying misdiagnosis. Potential implications for patient outcomes, caregiver burden and healthcare costs are discussed.

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample.

BACKGROUND AND OBJECTIVES: This prospective study seeks to examine the utility of subjective cognitive decline (SCD) as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black, and Latinx individuals. Debate surrounds the utility of SCD, the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia. METHODS: Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project if they were cognitively unimpaired, had baseline measurement of SCD, and self-identified as non-Latinx White, non-Latinx Black, or Latinx. SCD was measured as a continuous sum of 10 items assessing cognitive complaints. Competing risk models tested the main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort, and baseline memory test performance with death jointly modelled as a function of race/ethnicity. RESULTS: A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black, and 1,713 Latinx) participants were selected for this study with a mean age of 75 years, 67% women, and with a mean follow-up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (hazard ratio [HR] 1.085, CI 1.047-1.125, p < 0.001) and within Latinx (HR 1.084, CI 1.039-1.130, p < 0.001) and non-Latinx Black individuals (HR 1.099, CI 1.012-1.194, p = 0.024). DISCUSSION: Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. Because models examining the risk of dementia were adjusted for baseline memory test performance, the results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD.

Living With Frontotemporal Degeneration: Diagnostic Journey, Symptom Experiences, and Disease Impact.

Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive declines in cognition, behavior, and personality. Hearing directly from individuals living with FTD and their care partners is critical in optimizing care, identifying meaningful clinical trial endpoints, and improving research recruitment and retention. The current paper presents a subset of data from the FTD Insights Survey, chronicling the diagnostic journey, symptoms, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease. Survey respondents included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses. Around half of survey respondents reported seeing three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick's disease. Participating independently in a range of activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the degree to which the lives of these individuals are affected even at the mild and moderate stages of disease. Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop therapies that improve quality of life.

An emotion-eliciting version of the Hayling Sentence Completion Test.

INTRODUCTION: Executive functions comprise a suite of higher-order cognitive processes, which interact with other processes, such as emotion, to drive goal-directed behavior. The Hayling Sentence Completion Test is a widely used standard neuropsychological tool to measure executive functions, namely verbal initiation and suppression. The current studies aimed to establish and validate an emotion-eliciting version of the Hayling Sentence Completion Test, in order to examine the executive processes of initiation and suppression in an emotional context. Study 1 aimed to provide a quantitative evaluation of the emotional content of the Emotional Hayling Test. Study 2 investigated the differences between the Standard and Emotional Hayling Tests, and explored how performance relates to specific emotional properties of the sentences within the Emotional Hayling. METHODS: Study 1 included N = 100 participants, who were asked to rate each Emotional Hayling Sentence stem in terms of valence (pleasant-unpleasant) and arousal (intensity: low-high). Study 2 included N = 204 participants who completed the Emotional Hayling Test, along with other neuropsychological measures of cognitive and affective functioning. RESULTS: As designed, the sentence stimuli in the Emotional Hayling were rated as significantly higher in absolute emotional valence and arousal, compared to the Standard Hayling (Study 1). Overall, initiation and suppression on the Emotional Hayling were significantly poorer than on the Standard Hayling (Study 2). Finally, within the Emotional Hayling, participants made more suppression errors in response to negative sentences compared to positive sentences, and this effect was present in younger but not older adults. CONCLUSIONS: Reduced performance on the Emotional Hayling Test, particularly in response to negative sentences, is consistent with the emotional content placing increased demands on the executive function system. We present the Emotional Hayling Test as a promising clinical tool, with the potential to capture disruptions in emotional processing.

Examining the Role of Aging Perceptions in Subjective Cognitive Decline.

OBJECTIVE: While subjective cognitive decline (SCD) is gaining ground as a "preclinical" risk state for Alzheimer disease, its utility depends on our understanding of the factors linked to SCD. Rarely examined sociocultural factors including perceptions of aging may relate to the subjective experience of cognitive aging. Identifying such associations will help to refine the utility of SCD as an early marker of AD while setting the stage for addressing modifiable factors contributing to SCD. METHODS: The study consisted of N=136 participants (68% female; 73% White; 22% Black race, age mean =74.72; education mean =16.01). Questionnaires assessed SCD, depressive symptoms, and age perceptions (essentialist aging beliefs, subjective age, age group identification, and explicit/implicit age stereotypes). Cognitive functioning was measured with a semantic interference and learning task. RESULTS: SCD was correlated with essentialist aging beliefs, age identification, and depressive symptoms [ rrange =0.18 to 0.22, Prange =0.009 to 0.02, confidence interval (CI) range =0.00-0.39]. Essentialist aging beliefs were correlated with subjective age and age group identification ( rrange =0.22 to 0.42, Prange <0.001 to 0.003, CI range =0.08-0.57). Both age group identification and essentialism were correlated with depressive symptoms ( rrange =0.22, Prange =0.009 to 0.01, CI range =0.04-0.39). In the adjusted regression model including depressive symptoms, age perceptions, and SCD, only SCD was associated with cognition ( b =-0.31, P <0.001). CONCLUSION: Although correlated with SCD, perceptions of aging do not explain the relationship between SCD and performance on a sensitive cognitive test among older adults.

Towards Defining the Neuroanatomical Basis of Late-Onset Psychiatric Symptoms.

Psychiatric symptoms, including changes in emotional processing, are a common feature of many neurodegenerative disorders, such as Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, and Huntington's disease. However, the neuroanatomical basis of emotional symptoms is not well defined; this stands in contrast to the relatively well-understood neuroanatomical correlates of cognitive and motor symptoms in neurodegenerative disorders. Furthermore, psychiatric diagnostic categories, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Statistical Classification of Diseases and Related Health Problems (ICD), may have limited applicability in patients with late-onset psychiatric symptoms in the context of neurodegenerative disorders. In this clinical review, we suggest that early-onset and late-onset psychiatric symptoms have distinct etiologies, and that late-onset changes in emotional processing are likely underpinned by neurodegenerative disease. Furthermore, we suggest that an improved understanding of the neuroanatomical correlates of emotional changes in neurodegenerative disease may facilitate diagnosis and future treatment development. Finally, we propose a novel clinical approach, in a preliminary attempt to incorporate late-onset emotional symptoms alongside cognitive and motor symptoms into a clinical "algorithm," with a focus on the neuroanatomy implicated when particular combinations of emotional, cognitive, and motor features are present. We anticipate that this clinical approach will assist with the diagnosis of neurodegenerative disorders, and our proposed schema represents a move towards integrating neurologic and psychiatric classification systems.

Subjective Cognitive Decline Is More Accurate When Metamemory Is Better.

Objective: Subjective cognitive decline (SCD) has emerged as one of the first manifestations of Alzheimer's disease (AD). However, discrepancies in its relationship with tests of memory and other cognitive abilities have hindered SCD's diagnostic utility. Inter-individual heterogeneity in metamemory, or memory awareness, and the use of clinical measures of cognition lacking sensitivity to early cognitive dysfunction, may contribute to these discrepancies. We aimed to assess if the relationship between SCD and markers of early cognitive dysfunction is moderated by metamemory abilities. Methods: The sample included 79 cognitively healthy older adults (77% female, 68% White, and 32% Black participants) with a mean age of 74.4 (SD = 6.1) and 15.9 (SD = 2.7) years of education. Metamemory was assessed using an episodic Feeling of Knowing test with four 5-item trials. Outcome measures included a resolution metric defined as a gamma correlation reflecting the accuracy of item-level predictions ("Will you know the correct answer?"). Early cognitive dysfunction was measured through the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) and the Short-Term Memory Binding Test (STMB), measures sensitive to preclinical AD. SCD was assessed with a 20-item questionnaire that asked participants to compare themselves to others their age on a 7-point Likert scale. Regression analyses examined whether a potential relation between SCD and early cognitive dysfunction was moderated by metamemory. Results: Subjective cognitive decline was associated with susceptibility to semantic proactive interference such that greater complaints were associated with increased susceptibility to semantic proactive interference (b = -0.30, p = 0.003) only. Metamemory moderated the association between SCD and susceptibility to and recovery of semantic proactive interference such that those with more accurate metamemory showed a stronger association between increased complaints and susceptibility to semantic proactive interference (b = -0.71, p = 0.005; b = -0.62, p = 0.034). Metamemory, however, did not moderate the association of SCD with retroactive semantic interference nor short term memory binding. Discussion: The accuracy of an individual's metamemory, specifically their ability to adjust moment to moment predictions in line with their performance, can influence the extent to which SCD maps onto objective cognition. Such self-referential assessment should be considered when interpreting SCD.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

Idea selection for propositional language production.

The ability to select an idea from an array of competing options is critical for successful propositional language production, and deficient idea selection contributes to propositional language impairments in clinical populations. We investigate whether three clinical idea selection tasks are sensitive to selection demands in neurologically unimpaired adults, and whether performance relates to age. 154 neurologically normal adults aged 18-89 years completed a neuropsychological baseline and three  idea selection tasks. Stimuli either activated a dominant response or multiple competing response options. All three idea selection tasks were sensitive to selection demands in terms of reaction times but not errors. Older age was associated with greater effects of selection demands on Sentence Completion task performance only. Exploratory analyses revealed a potential role of executive functioning. Overall, we demonstrate that clinical idea selection tasks are sensitive to idea selection demands in a non-clinical sample, and show some age-related differences in performance.

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders.

INTRODUCTION: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. METHODS: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. RESULTS: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. DISCUSSION: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults.

Cardiovacular disease (CVD) is the leading cause of death among older adults and is often accompanied by functional decline. It is unclear what is driving this co-occurrence, but it may be behavioral, environmental and/or genetic. We used a family-based study to estimate the phenotypic and shared genetic correlation between CVD risk factors and physical and cognitive functional measures. Participants (n = 1,881) were from the Long Life Family Study, which enrolled families based on their exceptional longevity (sample mean age = 69.4 years, 44% female). Cardiovascular disease risk factors included carotid vessel measures [intima-media thickness and inter-adventitial diameter], obesity [body mass index (BMI) and waist circumference], and hypertension [systolic and diastolic blood pressures]. Function was measured in the physical [gait speed, grip strength, chair stand] and cognitive [digital symbol substitution test, retained and working memory, semantic fluency, and trail making tests] domains. We used SOLAR to estimate the genetic, environmental, and phenotypic correlation between each pair adjusting for age, age2, sex, field center, smoking, height, and weight. There were significant phenotypic correlations (range |0.05-0.22|) between CVD risk factors and physical and cognitive function (all P < 0.05). Most significant genetic correlations (range |0.21-0.62|) were between CVD risk factorsand cognitive function, although BMI and waist circumference had significant genetic correlation with gait speed and chair stand time (range |0.29-0.53|; all P < 0.05). These results suggest that CVD risk factors may share a common genetic-and thus, biologic-basis with both cognitive and physical function. This is particularly informative for research into the genetic determinants of chronic disease.

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Verbal Adynamia and Conceptualization in Partial Rhombencephalosynapsis and Corpus Callosum Dysgenesis.

Verbal adynamia is characterized by markedly reduced spontaneous speech that is not attributable to a core language deficit such as impaired naming, reading, repetition, or comprehension. In some cases, verbal adynamia is severe enough to be considered dynamic aphasia. We report the case of a 40-year-old, left-handed, male native English speaker who presented with partial rhombencephalosynapsis, corpus callosum dysgenesis, and a language profile that is consistent with verbal adynamia, or subclinical dynamic aphasia, possibly underpinned by difficulties selecting and generating ideas for expression. This case is only the second investigation of dynamic aphasia in an individual with a congenital brain malformation. It is also the first detailed neuropsychological report of an adult with partial rhombencephalosynapsis and corpus callosum dysgenesis, and the only known case of superior intellectual abilities in this context.

Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction.

BACKGROUND: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. OBJECTIVE: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. METHODS: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). RESULTS: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (ß= -0.22, p = 0.040, CI = -0.45, -0.01), associative memory (ß= -0.26, p = 0.018, CI = -0.45, -0.06), and list learning (ß= -0.31, p = 0.002, CI = -0.51, -0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (ß= -0.25, p = 0.012, CI = -0.44, -0.06; ß= -0.29, p = 0.003, CI = -0.47, -0.10) and list learning only (ß= -0.25, p = 0.014, CI = -0.45, -0.05; ß= -0.28, p = 0.004, CI = -0.48, -0.09). CONCLUSION: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study.

BACKGROUND: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. OBJECTIVE: To test whether APOE genotype is associated with change of cognitive function in older adults. METHODS: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. RESULTS: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOEɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (-0.31 points, 95% CI: -0.57, -0.05) and delayed (-0.37 points, 95% CI: -0.64, -0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. CONCLUSION: The APOEɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOEɛ2 allele was not significantly associated with any of the cognitive test scores.

Subthalamic deep brain stimulation identifies frontal networks supporting initiation, inhibition and strategy use in Parkinson's disease.

Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS.

Frontal Pole Hypometabolism Linked to Reduced Prosocial Sexual Behaviors in Frontotemporal Dementia and Corticobasal Syndrome.

BACKGROUND: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. OBJECTIVE: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. METHODS: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. RESULTS: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p = 0.026] and NC [p < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p < 0.01. Hypometabolism in Brodmann's Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr) <0.05, k = 44]. No anatomical associations were found with other sexual changes. CONCLUSION: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction.