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Background: People with dementia commonly have impaired social functioning and may not recognize this. This lack of awareness may result in worse outcomes for the person and their family carers., Objective: We aimed to characterize awareness of social functioning in dementia and describe its association with dementia severity., Methods: Multi-center cross-sectional study of people aged >65 years with dementia and family informants recruited from Germany, Japan and the United Kingdom. We used the Social Functioning in Dementia (SF-DEM) scale, assessing "spending time with other people" (domain 1), "communicating with other people" (domain 2), and "sensitivity to other people" (domain 3), and calculated lack of awareness into social functioning as the discrepancy between patient and informant ratings., Results: 108 participants with dementia (50.9% women), mean age = 78.9 years, and mean MMSE score = 22.7. Patient and informant domain 1 ratings did not differ, but patient-rating was higher than carers for domain 2 (11.2 versus 10.1; p = 0.003) and domain 3 (9.7 versus 8.1; p < 0.001). Sixty people with dementia overestimated their overall social functioning, 30 underestimated, and 18 gave ratings congruent with their informant. Performance on the MMSE and its sub-domains was not associated with SF-DEM discrepancy score., Conclusions: We found that awareness of social functioning in dementia was a multidimensional concept, which varies according to subdomains of social functioning. Clinicians should help family members understand and adapt by explaining their relative with dementia's lack of awareness about aspects of their social functioning.

Importance: Although the barriers to dementia care in primary care are well characterized, primary care practitioner (PCP) perspectives could be used to support the design of values-aligned dementia care pathways that strengthen the role of primary care., Objective: To describe PCP perspectives on their role in dementia diagnosis and care., Design, Setting, and Participation: In this qualitative study, interviews were conducted with 39 PCPs (medical doctors, nurse practitioners, and doctors of osteopathic medicine) in California between March 2020 and November 2022. Results were analyzed using thematic analysis., Main Outcomes and Measures: Overarching themes associated with PCP roles in dementia care., Results: Interviews were conducted with 39 PCPs (25 [64.1%] were female; 16 [41%] were Asian). The majority (36 PCPs [92.3%]) reported that more than half of their patients were insured via MediCal, the California Medicaid program serving low-income individuals. Six themes were identified that convey PCPs' perspectives on their role in dementia care. These themes focused on (1) their role as first point of contact and in the diagnostic workup; (2) the importance of long-term, trusting relationships with patients; (3) the value of understanding patients' life contexts; (4) their work to involve and educate families; (5) their activities around coordinating dementia care; and (6) how the care they want to provide may be limited by systems-level constraints., Conclusions and Relevance: In this qualitative study of PCP perspectives on their role in dementia care, there was alignment between PCP perspectives about the core values of primary care and their work diagnosing and providing care for people living with dementia. The study also identified a mismatch between these values and the health systems infrastructure for dementia care in their practice environment.

Objectives: Older immigrants of Latin American descent are disproportionately impacted by dementia, yet little is known about their dementia- and brain health-related knowledge. We explored perspectives on brain health and aging in this population to inform the development of culturally-relevant interventions., Methods: Individual, semi-structured interviews were conducted with 30 Spanish-speaking immigrants over 60. Questions addressed knowledge about the brain, perceptions of healthy and unhealthy aging, ideas of how to take care of one's brain, and where knowledge was acquired. Responses were analyzed using thematic analysis., Results: The following themes emerged: (1) Descriptions of the brain varied, from anatomy, cognition, and psychology to disease. (2) Perceptions of healthy aging included independence, memory, emotions, and orientation. (3) Ideas of how to care for the brain included physical, social, and cognitive engagement. (4) Knowledge was acquired in childhood, communities, healthcare settings, careers, and media., Conclusions: Results showed significant variability in knowledge. Findings may be leveraged to improve interventions that address brain health literacy disparities among older Latin American immigrants., Clinical Implications: Takeaways involve increasing education about the structure and functions of the brain, promoting realistic understandings of what nonnormative brain aging entails, and increasing knowledge of empirically-supported maintenance approaches. Dissemination may be increased via healthcare providers, community centers, churches, and media.

Background: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up., Objective: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation., Methods: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis., Results: We identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations., Conclusion: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

Background: Primary care providers (PCPs) are typically the first to screen and evaluate patients for neurocognitive disorders (NCDs), including mild cognitive impairment and dementia. However, data on PCP attitudes and evaluation and management practices are sparse. Our objective was to quantify perspectives and behaviors of PCPs and neurologists with respect to NCD evaluation and management., Methods: A cross-sectional survey with 150 PCPs and 50 neurologists in the United States who evaluated more than 10 patients over age 55 per month. The 51-item survey assessed clinical practice characteristics, and confidence, perceived barriers, and typical practices when diagnosing and managing patients with NCDs., Results: PCPs and neurologists reported similar confidence and approaches to general medical care and laboratory testing. Though over half of PCPs performed cognitive screening or referred patients for cognitive testing in over 50% of their patients, only 20% reported high confidence in interpreting results of cognitive tests. PCPs were more likely to order CT scans than MRIs, and only 14% of PCPs reported high confidence interpreting brain imaging findings, compared to 70% of specialists. Only 21% of PCPs were highly confident that they correctly recognized when a patient had an NCD, and only 13% were highly confident in making a specific NCD diagnosis (compared to 72 and 44% for neurologists, both p < 0.001). A quarter of all providers identified lack of familiarity with diagnostic criteria for NCD syndromes as a barrier to clinical practice., Conclusions: This study demonstrates how PCPs approach diagnosis and management of patients with NCDs, and identified areas for improvement in regards to cognitive testing and neuroimaging. This study also identified all providers' lack of familiarity with published diagnostic criteria for NCD syndromes. These findings may inform the development of new policies and interventions to help providers improve the efficacy of their decision processes and deliver better quality care to patients with NCDs.

Objective: White matter (WM) microstructural changes are increasingly recognized as a mechanism of age-related cognitive differences. This study examined the associations between patterns of WM microstructure and cognitive performance on the University of California, San Francisco (UCSF) Brain Health Assessment (BHA) subtests of memory (Favorites), executive functions and speed (Match), and visuospatial skills (Line Orientation) within a sample of older adults., Method: Fractional anisotropy (FA) in WM tracts and BHA performance were examined in 84 older adults diagnosed as neurologically healthy (47), with mild cognitive impairment (19), or with dementia (18). The relationships between FA and subtest performances were evaluated using regression analyses. We then explored whether regional WM predicted performance after accounting for variance explained by global FA., Results: Memory performance was associated with FA of the fornix and the superior cerebellar peduncle; and executive functions and speed, with the body of the corpus callosum. The fornix-memory association and the corpus callosum-executive association remained significant after accounting for global FA. Neither tract-based nor global FA was associated with visuospatial performance., Conclusions: Memory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age- and disease-related cognitive decline.

Objective: Self-monitoring is a crucial component of human empathy and necessary for the formation and repair of social relations. Several studies have brought to light possible neuronal substrates associated with self-monitoring, but the information that they have provided is inconclusive. The authors, therefore, studied a large group of patients with dementia to assess what brain structures are necessary for the self-monitoring function. Methods: Seventy-seven patients with dementia of various types were screened using voxel-based morphometry to assess possible volume reduction in the brain structures of patients with self-monitoring problems, and the decrease of socioemotional expressiveness and modification of self-presentation was estimated using the Revised Self-Monitoring Scale. Regression analysis was employed to investigate the correlation between gray matter loss and deficient self-monitoring. Results: The socioemotional expressiveness scores were associated with decreased gray matter volume in the right olfactory cortex, inferior frontal gyrus, superior temporal pole, parahippocampal gyrus, insula, and medial temporal gyrus bilaterally. Self-presentation scores were associated with bilateral gray matter volume reduction in the olfactory cortex, insula, rectus gyrus and inferior frontal gyrus, right superior temporal pole, and parahippocampal gyrus, as well as the left medial temporal gyrus and anterior superior frontal gyrus. Conclusions: These results suggest that patients with dementia present decreased ability of self-monitoring, probably due to impaired insula and orbitofrontal cortex and their disconnection from structures of the salience network.

The neural organization of semantic memory remains much debated. A 'distributed-only' view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.

Objective: We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions., Methods: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI., Results: Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits., Conclusions: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.

We performed a longitudinal anatomical study to map the progression of gray matter atrophy in anatomically defined predominantly left (LTLV) and right (RTLV) temporal lobe variants of semantic dementia (SD). T1-weighted MRI scans were obtained at presentation and one-year follow-up from 13 LTLV, 6 RTLV, and 25 control subjects. Tensor-based morphometry (TBM) in SPM2 was applied to derive a voxel-wise estimation of regional tissue loss over time from the deformation field required to warp the follow-up scan to the presentation scan in each subject. When compared to controls, both LTLV and RTLV showed significant progression of gray matter atrophy not only within the temporal lobe most affected at presentation, but also in the controlateral temporal regions (p<0.05 FWE corrected). In LTLV, significant progression of volume loss also involved the ventromedial frontal and the left anterior insular regions. These results identified the anatomic substrates of the previously reported clinical evolution of LTLV and RTLV into a unique 'merged' clinical syndrome characterized by semantic and behavioral deficits and bilateral temporal atrophy.

Frontotemporal lobar degeneration (FTLD) represent a constellation of disorders that may be overlooked or misdiagnosed, despite being fairly common presenile neurodegenerative diseases. Although the cognitive disorder can be difficult to document, particularly early in the dementia course, neuropsychological evaluation can assist in the diagnosis. Neuropsychologists are in an excellent position to draw from related disciplines like personality theory and social psychology to better assess the types of changes that characterize the prodromal and early phases of the disease. This review summarizes the current state of the field in the diagnosis of FTLD and discusses the emerging role of neuropsychology in elucidating the brain organization of complex processes including empathy, behavioral control and inhibition, reward systems, appetitive behaviors, emotional regulation, and goal-orientation. As this review underscores, frontotemporal dementia remains a powerful model for studying brain-behavior relationships.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by progressive behavioural abnormalities and frontotemporal atrophy. Here we used tensor based morphometry (TBM) to identify regions of longitudinal progression of gray matter atrophy in FTD compared to controls. T1-weighted MRI images were acquired at presentation and 1-year follow-up from 12 patients with mild to moderate FTD and 12 healthy controls. Using TBM as implemented in SPM2, a voxel-wise estimation of regional tissue volume change was derived from the deformation field required to warp a subject's late to early anatomical images. A whole brain analysis was performed, in which a level of significance of p<0.05 corrected for multiple comparisons (family wise error-FWE) was accepted. Based on prior studies, a region of interest (ROI) analysis was also performed, including in the search area bilateral medial and orbital frontal regions, anterior cingulate gyrus, insula, amygdala and hippocampus. Within this ROI a level of significance of p<0.001 uncorrected was accepted. In the whole brain analysis, the anterior cingulate/paracingulate gyri were the only regions that showed significant atrophy change over 1 year. In the ROI analysis, the left ventro-medial frontal cortex, right medial superior frontal gyrus, anterior insulae and left amygdala/hippocampus showed significant longitudinal changes. In conclusion, limbic and paralimbic regions showed detectable gray matter contraction over 1 year in FTD, confirming the susceptibility of these regions to the disease and the consistency with their putative role in causing typical presenting behaviours. These results suggest that TBM might be useful in tracking progression of regional atrophy in FTD.

Objective: To characterize dementia-induced changes in visual art production., Background: Although case studies show altered visual artistic production in some patients with neurodegenerative disease, no case-controlled studies have quantified this phenomenon across groups of patients., Method: Forty-nine subjects [18 Alzheimer disease, 9 frontotemporal dementia (FTD), 9 semantic dementia (SD), 15 healthy older controls (NC)] underwent formal neuropsychologic testing of visuospatial, perceptual, and creative functioning, and produced 4 drawings. Subjective elements of drawings were rated by an expert panel that was blind to diagnosis., Results: Despite equal performance on standard visuospatial tests, dementia groups produced distinct patterns of artistic features that were significantly different from NCs. FTDs used more disordered composition and less active mark-making (P<0.05). Both FTDs and SDs drawings were rated as more bizarre and demonstrated more facial distortion than NCs (P<0.05). Also, SDs drastically failed a standardized test of divergent creativity. Alzheimer disease artwork was more similar to controls than to FTDs or SDs, but showed a more muted color palette (P<0.05) and trends toward including fewer details, less ordered compositions, and occasional facial distortion., Conclusions: These group differences in artistic style likely resulted from disease-specific focal neurodegeneration, and elucidate the contributions of particular brain regions to the production of visual art.

Objectives: To test if arterial spin labeling (ASL) MRI could detect a pattern of hypoperfusion in frontotemporal dementia (FTD) vs cognitively normal (CN) control subjects; to determine the regional difference of perfusion between FTD and Alzheimer disease (AD); and to determine whether hypoperfusion in FTD correlates with cognitive impairment., Methods: We included 21 patients with FTD, 24 patients with AD, and 25 CN subjects in this cross-sectional MRI study. All subjects had MRI scans including T1-weighted structural images and ASL-MR images., Results: ASL-MRI detected a pattern of hypoperfusion in right frontal regions in patients with FTD vs CN subjects, similar to PET and SPECT. FTD had higher perfusion than AD in the parietal regions and posterior cingulate. Frontal hypoperfusion in FTD correlated with deficits in judgment and problem solving. Adding frontal perfusion to gray matter (GM) atrophy significantly improved the classification of FTD from normal aging to 74%, and adding parietal perfusion to GM atrophy significantly improved the classification of FTD from AD to 75%. Combining frontal and parietal lobe perfusion further improved the classification of FTD from AD to 87%., Conclusion: Frontotemporal dementia and Alzheimer disease display different spatial distributions of hypoperfusion on arterial spin labeling MRI. With further development and evaluation, arterial spin labeling MRI could contribute to the differential diagnosis between frontotemporal dementia and Alzheimer disease.

Deficits in the ability to suppress automatic behaviors lead to impaired decision making, aberrant motor behavior, and impaired social function in humans with frontal lobe neurodegeneration. We have studied patients with different patterns of frontal lobe dysfunction resulting from frontotemporal lobar degeneration or Alzheimer's disease, investigating their ability to perform visually guided saccades and smooth pursuit eye movements and to suppress visually guided saccades on the antisaccade task. Patients with clinical syndromes associated with dorsal frontal lobe damage had normal visually guided saccades but were impaired relative to other patients and control subjects in smooth pursuit eye movements and on the antisaccade task. The percentage of correct antisaccade responses was correlated with neuropsychological measures of frontal lobe function and with estimates of frontal lobe gray matter volume based on analyses of structural magnetic resonance images. After controlling for age, gender, cognitive status, and potential interactions between disease group and oculomotor function, an unbiased voxel-based morphometric analysis identified the volume of a segment of the right frontal eye field (FEF) as positively correlated with antisaccade performance (less volume equaled lower percentage of correct responses) but not with either pursuit performance or antisaccade or visually guided saccade latency or gain. In contrast, the volume of the presupplementary motor area (pre-SMA) and a portion of the supplementary eye fields correlated with antisaccade latency (less volume equaled shorter latency) but not with the percentage of correct responses. These results suggest that integrity of the presupplementary motion area/supplementary eye fields is critical for supervisory processes that slow the onset of saccades, facilitating voluntary saccade targeting decisions that rely on the FEF.

Background: Loss of insight is a core diagnostic criterion for frontotemporal dementia (FTD), whereas failure to recognise cognitive deficits and unawareness of disease (anosognosia) are well established findings in Alzheimer's disease (AD). However, self awareness of personality has not been quantified in these patient groups., Methods: Twenty two patients (12 with frontal variant FTD; 10 with early AD) and 11 older adult normal controls completed self report questionnaires (the Interpersonal Adjectives Scales) describing their current personality. First degree relative informants completed two questionnaires, one describing the subject's current personality, the other retrospectively describing the subject's personality before disease onset. Differences between subject and informant reports of current personality were used to measure the accuracy of self awareness., Results: Discriminant function analysis showed significant differences in self awareness among the three groups, with those in the FTD group showing the greatest magnitude of error in the largest number of personality dimensions (dominance, submissiveness, cold heartedness, introversion, and ingenuousness). Despite personality changes over time, patients with AD showed accurate self awareness in all personality dimensions except submissiveness and extraversion. Normal controls showed a pattern of underestimating positive qualities, whereas patients with FTD exaggerated positive qualities and minimised negative qualities. For the personality facets showing impaired insight, the self reports of patients with FTD and AD most closely matched their premorbid personalities, suggesting a failure to update their self image after disease onset., Conclusions: This study operationalises research criteria for loss of insight in FTD.

Objective: To examine the relationship between empathy and cognition in frontotemporal lobar degeneration (FTLD)., Background: Theoretical models suggest empathy has multiple cognitive and affective subcomponents, and recent studies suggest that performance on specific cognitive tests may predict empathy. Qualitative behavioral studies of patients with FTLD suggest empathy loss may occur directly as a result of damage to frontal and temporal structures., Method: First-degree relatives used the Interpersonal Reactivity Index (IRI), a measure of cognitive and emotional empathy, to rate 18 patients with frontotemporal dementia (FTD), 19 patients with semantic dementia (SD), 16 patients with Alzheimer disease (AD), and 10 age-matched healthy control subjects (NC). Subjects also underwent cognitive testing., Results: Both FTD and SD groups showed significantly lower levels of empathy than either ADs or NCs. SDs showed disruption of both emotional and cognitive empathy, whereas FTDs showed only disruption of cognitive empathy. Regressions controlling for general cognitive impairment showed 32% of the variance in Perspective Taking score was predicted by Category Fluency (P < 0.001), and 25% of the variance in Fantasy score was accounted for by Phonemic Fluency (P < 0.001)., Conclusions: Although cognitive empathy is at least partly reliant on frontal structures, the emotional components of empathy are likely mediated by structures in the temporal lobes.

Semantic dementia (SD) is a clinical variant of frontotemporal lobar degeneration (FTLD) characterized by progressive deterioration of semantic memory with relative sparing of other cognitive functions. It is associated with mainly left anterior temporal atrophy, and is also referred to as "left-temporal lobe variant" of FTLD. Recently, patients with mainly right-sided atrophy, or "right-temporal lobe variant"(RTLV), have been described. While some authors have reported that the initial and most significant deficit in these right-sided cases is a difficulty in recognizing famous people, others have observed that major behavioral abnormalities are the presenting symptoms. Here we report a detailed neuropsychological, language, behavioral and neuroimaging assessment of JT, a case of right temporal lobe variant of FTLD. JT showed early and prominent behavioral changes accompanied by a severe impairment in recognizing foods by their look, flavor or name. Later she also developed a difficulty in recognizing familiar people and objects. Standardized caregiver questionnaires of JT's pre- and post-morbid personality and interpersonal functioning showed that she went from being a flexible, dominant, extraverted, person to showing rigid, submissive and introverted behaviors. Her levels of neuroticism significantly increased, while her scores on agreeableness and cognitive and emotional empathy dropped. Voxel-based morphometry (VBM) showed most significant atrophy in the right amygdala/anterior hippocampal complex and collateral sulcus, extending to the right insula. We discuss the atypical cognitive and behavioral features of this case of RTLV of FTLD and stress the importance of behavioral changes and atypical semantic deficits for early diagnosis.

We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E epsilon4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.

Background: Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP tau) and is associated with neuronal or glial tau inclusions., Objectives: To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family., Design: A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made., Setting: Family study., Patients: San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members do not have a MAP tau coding or splice regulatory sequence mutation, and the MAP tau is genetically excluded., Main Outcome Measures: Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS)., Results: The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and alpha-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform., Conclusion: The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.

Recent investigations of the neuroanatomy of complex social behaviors suggest that the underlying brain circuits involve multiple cortical and subcortical structures. The neuroanatomic origins of agreeableness have not yet been clearly elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic alterations in agreeableness arising from frontal and temporal lobe damage. Based on previous research, we hypothesized that agreeableness would be negatively correlated with left medial orbitofrontal cortex size and positively correlated with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed according to the Lund-Manchester criteria) were asked to fill out the NEO-Five Factor Inventory to assess the patients' current level of agreeableness, a construct comprised of the facets trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness. These patients underwent T(1)-weighted MRI imaging, and gray matter volumes for right and left orbitofrontal lobes and amygdalas were derived via segmentation and region of interest tracing, normalizing for total intracranial volume. Regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (beta = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (beta = -0.638) was negatively correlated with agreeableness (p < 0.01). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness. This finding partly replicates a previous study that used a different measure of social functioning, the Interpersonal Adjective Scale, to delineate a left frontal-right amygdala circuit for agreeableness. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving both hemispheres., (Copyright 2004 S. Karger AG, Basel)

Objective: To assess the ability of a brief neuropsychological bedside screening battery to discriminate between Alzheimer disease, frontotemporal dementia, and semantic dementia., Methods: Subjects were 21 patients with frontotemporal dementia, 14 patients with semantic dementia, and 30 patients with Alzheimer disease comparable in terms of Mini Mental Status Examination score, age, and education. Frontotemporal dementia and semantic dementia diagnoses were made clinically using the consensus criteria of Neary et al. 1 Subjects were administered a brief neuropsychological screening assessing episodic memory, working memory, executive function, naming, spatial ability, abstract reasoning, and calculations., Results: Both the Alzheimer disease and semantic dementia groups were significantly impaired relative to the frontotemporal dementia group on verbal memory, whereas only the Alzheimer disease group was impaired on visual memory. Frontotemporal dementia patients performed significantly worse on backward digit span and made significantly more executive errors than Alzheimer disease and semantic dementia patients. Semantic dementia patients were more impaired than Alzheimer disease and frontotemporal dementia patients on confrontation naming. Discriminant function analyses identified the 5 most discriminating variables that correctly classified 89.2% of cases., Conclusions: Frontotemporal dementia, semantic dementia, and Alzheimer disease are associated with distinct neuropsychological profiles that classify these dementia syndromes with considerable success. The neuropsychological profiles highlight the distinctiveness between the 3 syndromes, are consistent with the known loci of neuropathology in these conditions, and can potentially serve as an adjunct to the current clinical criteria.

Background: Progressive brain atrophy is associated with Alzheimer disease (AD) and other dementias. Regional differences in brain atrophy may reflect clinical features of disease., Objective: To identify regions of cerebral atrophy that are associated with AD vs other dementias., Setting: University hospital dementia clinic., Participants: Eleven patients with AD and 11 with semantic dementia (SD), matched for age, sex, education, and degree of overall cognitive impairment and 15 normal controls., Methods: Voxel-based morphometry was used to compare patterns of gray matter loss, measured on T1-weighted magnetic resonance images, between patients with AD or SD, a subtype of frontotemporal lobar degeneration, and controls. Statistically significant differences in regional gray matter concentration, after multiple-comparisons correction, between groups of subjects were identified., Results: Patients with AD were more impaired than those with SD on tests of visuospatial function and on simple calculations. Consistent with these neuropsychological deficits, the most significant area of atrophy in the AD group was the left parietal cortex vs controls (z = 5.0; P =.04). Compared with SD, AD was associated with more atrophy in the left parietal lobe (z = 5.6; P =.04) and bilaterally in the posterior cingulate/precuneus (z = 5.1; P =.04). A discriminant function analysis demonstrated that the degree of atrophy of right posterior cingulate, left parietal lobe, right amygdala, and right anterior temporal lobe structures correctly classified 96% of the patients., Conclusion: Alzheimer disease is associated with a specific pattern of cortical atrophy compared with SD.

Background: Efforts to characterize changes in social functioning in frontotemporal dementia (FTD) have failed to elicit clear dissociation between frontal and temporal variants of the disease based on behavioral measures., Methods: This study obtained premorbid and current first-degree relative ratings using an established measure of interpersonal functioning, the Interpersonal Adjectives Scales, to measure personality change in 16 patients with frontal variant (FLV) and 13 with temporal variant (TLV) FTD, and in a control group of 16 patients with AD., Results: All three groups showed significant change over time in multiple domains, including increased introversion (FG) and submissiveness (HI). However, patients with both FTD subtypes evidenced significantly greater increases in overall interpersonal pathology vector length [VL] than did patients with AD, who remained within the normal range on all scores. Patients with FLV showed a 2 SD increase in submissiveness (HI), but their cold-heartedness (DE) change scores were not significantly different from those of patients with AD. Conversely, the TLV cold-heartedness (DE) score increased 2 SD compared to minimal change for the AD and FLV groups, yet change in submissiveness (HI) did not differentiate between AD and TLV groups., Conclusions: The Interpersonal Adjectives Scales differentiated both FTD groups from patients with AD on the basis of both degree and direction of personality change. Also, the two subtypes of FTD showed distinctly different patterns of change in social functioning: patients with temporal variant shifted toward severe interpersonal coldness with mild loss of dominance, whereas patients with frontal variant showed the opposite pattern.

IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.