Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study.

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.

Using community-based geographical information system (GIS) to recruit older Asian Americans in an Alzheimer's disease study.

OBJECTIVE: This study aims to show the usefulness of incorporating a community-based geographical information system (GIS) in recruiting research participants for the Asian Cohort for Alzheimer's Disease (ACAD) study for using the subgroup of Korean American (KA) older adults. The ACAD study is the first large study in the USA and Canada focusing on the recruitment of Chinese, Korean and Vietnamese older adults to address the issues of under-representation of Asian Americans in clinical research. METHODS: To promote clinical research participation of racial/ethnic minority older adults with and without dementia, we used GIS by collaborating with community members to delineate boundaries for geographical clusters and enclaves of church and senior networks, and KA serving ethnic clinics. In addition, we used socioeconomic data identified as recruitment factors unique to KA older adults which was analysed for developing recruitment strategies. RESULTS: GIS maps show a visualisation of the heterogeneity of the sociodemographic characteristics and the resources of faith-based organisations and KA serving local clinics. We addressed these factors that disproportionately affect participation in clinical research and successfully recruited the intended participants (N=60) in the proposed period. DISCUSSION: Using GIS maps to locate KA provided innovative inroads to successful research outreach efforts for a pilot study that may be expanded to other underserved populations across the USA in the future. We will use this tool subsequently on a large-scale clinical genetic epidemiology study. POLICY IMPLICATION: This approach responds to the call from the National Institute on Aging to develop strategies to improve the health status of older adults in diverse populations. Our study will offer a practical guidance to health researchers and policymakers in identifying understudied and hard-to-reach specific Asian American populations for clinical studies or initiatives. This would further contribute in reducing the health and research disparity gaps among older minority populations.

Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial.

Importance: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial. Objective: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial. Design, Setting, and Participants: A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019. Interventions: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices. Main Outcomes and Measures: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months. Results: A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment. Conclusions and Relevance: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort. Trial Registration: ClinicalTrials.gov Identifier: NCT01767909.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

IMPORTANCE: Oligomeric amyloid-ß peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. OBJECTIVE: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-ß peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. INTERVENTIONS: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. MAIN OUTCOMES AND MEASURES: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. RESULTS: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. CONCLUSIONS AND RELEVANCE: Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02167256.

BrainWorks: A Comparative Effectiveness Trial to Examine Alzheimer's Disease Education for Community-Dwelling African Americans.

OBJECTIVES: To test a culturally tailored intervention to improve Alzheimer's disease (AD) literacy among African Americans. DESIGN: A 3-arm randomized comparative effectiveness trial. SETTING: Community sites in Los Angeles, CA. PARTICIPANTS: 193 African American community-dwelling adults, ages 45 to 95 years old. INTERVENTION: All groups attended BrainWorks Live, a culturally tailored, 60-minute talk show and received standard printed educational materials on AD. From there: a) the BrainWorks Live group received no further contact until the post-test; b) one intervention group received a 1-month, culturally tailored, unidirectional, daily text-message program; and c) a second intervention group received daily text messages based on the printed educational materials that the general public would receive. AD literacy was measured at baseline and one month post intervention. MEASUREMENTS: Alzheimer's disease literacy and demographic and health covariates. RESULTS: At one month, participants who received culturally tailored text messages had the highest increase in AD literacy levels, followed by those in the BrainWorks Live arm. Participants who received general text messages had a lower overall increase in AD literacy levels compared to the other arms, but had higher mean AD literacy levels than the BrainWorks Live arm. There was a significantly greater increase in AD literacy levels among participants who received culturally tailored text messages compared with those who attended BrainWorks Live only. There were no other statistically significant differences between arms. CONCLUSIONS: AD literacy among African Americans can be improved after only one month through culturally competent, economically feasible educational formats.

White Matter Disruption and Connected Speech in Non-Fluent and Semantic Variants of Primary Progressive Aphasia.

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.

Cognitive and psychosocial function in retired professional hockey players.

BACKGROUND AND OBJECTIVE: The relationship between repeated concussions and neurodegenerative disease has received significant attention, particularly research in postmortem samples. Our objective was to characterise retired professional ice hockey players' cognitive and psychosocial functioning in relation to concussion exposure and apolipoprotein ε4 status. METHODS: Alumni athletes (N=33, aged 34-71 years) and an age-matched sample of comparison participants (N=18) were administered measures of cognitive function and questionnaires concerning psychosocial and psychiatric functioning. RESULTS: No significant group differences were found on neuropsychological measures of speeded attention, verbal memory or visuospatial functions, nor were significant differences observed on computerised measures of response speed, inhibitory control and visuospatial problem solving. Reliable group differences in cognitive performance were observed on tests of executive and intellectual function; performance on these measures was associated with concussion exposure. Group differences were observed for cognitive, affective and behavioural impairment on psychosocial questionnaires and psychiatric diagnoses. There was no evidence of differential effects associated with age in the alumni athletes. Possession of an apolipoprotein ε4 allele was associated with increased endorsement of psychiatric complaints, but not with objective cognitive performance. CONCLUSIONS: We found only subtle objective cognitive impairment in alumni athletes in the context of high subjective complaints and psychiatric impairment. Apolipoprotein ε4 status related to psychiatric, but not cognitive status. These findings provide benchmarks for the degree of cognitive and behavioural impairment in retired professional athletes and a point of comparison for future neuroimaging and longitudinal studies.

Lack of Frank Agrammatism in the Nonfluent Agrammatic Variant of Primary Progressive Aphasia.

BACKGROUND/AIMS: Frank agrammatism, defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors, is variably reported in patients with nonfluent variant primary progressive aphasia (nfPPA). This study addressed whether frank agrammatism is typical in agrammatic nfPPA patients when this feature is not required for diagnosis. METHOD: We assessed grammatical production in 9 patients who satisfied current diagnostic criteria. Although the focus was agrammatism, motor speech skills were also evaluated to determine whether dysfluency arose primarily from apraxia of speech (AOS), instead of, or in addition to, agrammatism. Volumetric MRI analyses provided impartial imaging-supported diagnosis. RESULTS: The majority of cases exhibited neither frank agrammatism nor AOS. CONCLUSION: There are nfPPA patients with imaging-supported diagnosis and preserved motor speech skills who do not exhibit frank agrammatism, and this may persist beyond the earliest stages of the illness. Because absence of frank agrammatism is a subsidiary diagnostic feature in the logopenic variant of PPA, this result has implications for differentiation of the nonfluent and logopenic variants, and indicates that PPA patients with nonfluent speech in the absence of frank agrammatism or AOS do not necessarily have the logopenic variant.

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

OBJECTIVE: This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. DESIGN: 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. RESULTS: The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. CONCLUSIONS AND RELEVANCE: This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

Amyloid deposition in semantic dementia: a positron emission tomography study.

BACKGROUND: Pittsburgh compound B ([11C]-PIB) identifies amyloid-ß (Aß) deposition in vivo. Asymptomatic Aß deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aß deposition. OBJECTIVE: Comparison of Aß deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. METHODS: Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. RESULTS: The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. CONCLUSIONS: Aß deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aß deposition. Copyright © 2016 John Wiley & Sons, Ltd.

Trajectories of Behavioural Disturbances Across Dementia Types.

OBJECTIVE: To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias. METHODS: Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups. RESULTS: The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias. CONCLUSIONS: A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.

Grey matter atrophy in mild cognitive impairment / early Alzheimer disease associated with delusions: a voxel-based morphometry study.

OBJECTIVES: Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions. METHODS: We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline. RESULTS: Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions. CONCLUSION: Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

Lifetime History of Depression Predicts Increased Amyloid-ß Accumulation in Patients with Mild Cognitive Impairment.

Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimer's disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-ß (Aß) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Aß accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Aß deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD (n = 39) had significantly higher 18F-Florbetapir standardized uptake value ratios, a surrogate measure of Aß deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Aß in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Aß predicts future conversion into AD in this population.

Emotional evaluation and memory in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) affects emotional evaluation, but less is known regarding the patients' ability to remember emotional stimuli. Here, bvFTD patients and age-matched controls studied positive, negative, and neutral pictures followed by a recognition memory test. Compared to controls, bvFTD patients showed a reduction in emotional evaluation of negative scenes, but not of positive or neutral scenes. Additionally, the patients showed an overall reduction in recognition memory accuracy, due to impaired recollection in the face of relatively preserved familiarity. These results show that bvFTD reduces the emotional evaluation of negative scenes and impairs overall recognition memory accuracy and recollection.

Verb production in the nonfluent and semantic variants of primary progressive aphasia: the influence of lexical and semantic factors.

Differential patterns of impairment with respect to noun and verb production have been observed in the nonfluent and semantic variants of primary progressive aphasia. However, the factors influencing this discrepancy remain unclear. The present study evaluates verb retrieval in primary progressive aphasia using a naming task and a story completion task. Findings indicate that patients with the semantic variant are influenced by familiarity, frequency, and age of acquisition in both object and action naming, whereas patients with the nonfluent variant are not. Surprisingly, there were no differences in either group between object and action naming, presumably because the lists were well matched on pertinent variables. In the story completion task, greater impairment in semantically heavier than in semantically lighter verbs was observed for the semantic variant, and grammaticality and verb tense agreement was significantly lower in the nonfluent variant. The present findings suggest that lexicosemantic attributes affect verb production in the semantic variant, whereas both lexicosemantic and syntactic attributes affect verb production in the nonfluent variant.

Early neuropsychological characteristics of progranulin mutation carriers.

Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature.

Salience network resting-state activity: prediction of frontotemporal dementia progression.

IMPORTANCE: Noninvasive measures of activity within intrinsic brain networks may be clinically relevant, providing a marker of neurodegenerative disease and predicting clinical behaviors. OBJECTIVE: To correlate baseline resting-state measures within the salience network and changes in behavior among patients with frontotemporal dementia. DESIGN: Baseline resting-state functional magnetic resonance imaging data and longitudinal clinical measures were obtained from prospectively accrued patients during 8 weeks. SETTING: Tertiary academic care center specializing in the assessment and management of patients with neurodegenerative disease. PARTICIPANTS: Fifteen patients with clinically diagnosed frontotemporal dementia (5 behavioral variant and 10 semantic dementia). MAIN OUTCOMES AND MEASURES: Baseline resting-state functional magnetic resonance imaging data measured within regions of interest were regressed on serial behavioral measures from prospectively accrued patients with frontotemporal dementia to determine the ability of baseline resting-state activity to account for changes in behavior. RESULTS: Low-frequency fluctuations in the left insula significantly predicted changes in Frontal Behavioral Inventory scores (standard ß = 0.51, P = .049), accounting for 28% of the change variance. The trend was driven by changes in measures of apathy independent of dementia severity. CONCLUSION AND RELEVANCE: Baseline measures of salience network connectivity involving the left insula may predict behavioral changes in patients with frontotemporal dementia.

Development of supportive services for frontotemporal dementias through community engagement.

The effect of early onset frontotemporal dementias (FTD) on spouses and children is profound, requiring different types of support services from pre-existing Alzheimer's disease interventions already in place. This article explores how the needs of families living with FTD resulted in three programme initiatives developed at Baycrest (an academic health sciences centre focused on ageing, in Toronto, Canada) to meet the needs of this population. These included an Internet-based videoconferencing support group for spouses, a website that provides support and counsel for children and their parents, and an adult day programme designed for FTD patients. The strength of these interventions is that services were developed with involvement of stakeholders in FTD care from the start, to deal with gaps in services in a sustainable way.

Incorporating new diagnostic schemas, genetics, and proteinopathy into the evaluation of frontotemporal degeneration.

PURPOSE OF REVIEW: Within the continuously growing body of knowledge in the field of dementia, frontotemporal degeneration stands out in importance as the second most common cause of early-onset dementia after Alzheimer disease. Neurologists, neuropsychologists, and speech pathologists are particularly involved in the diagnosis and recognition of etiologies for patients with deficits in frontal lobe function and language. RECENT FINDINGS: The recent discovery of a novel mutant gene (C9ORF72) and the new nomenclature adopted for subclassification have significantly promoted our understanding of this disorder. SUMMARY: This article relates the most recent consensus criteria for diagnosis of the two forms of frontotemporal degeneration (ie, behavioral and primary progressive aphasia variants) to basic neurologic principles and remind clinicians of the neuropsychiatric and neuroradiologic components that clarify frontotemporal degeneration diagnoses and guide management.