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INTRODUCTION: Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. METHODS: We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. RESULTS: Circulating amyloid beta (Aß), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. DISCUSSION: This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. HIGHLIGHTS: Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.
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BACKGROUND: Quantification of cerebral blood flow (CBF) with [15 O]H2 O-positron emission tomography (PET) requires arterial sampling to measure the input function. This invasive procedure can be avoided by extracting an image-derived input function (IDIF); however, IDIFs are sensitive to partial volume errors due to the limited spatial resolution of PET. PURPOSE: To present an alternative hybrid PET/MR imaging of CBF (PMRFlowIDIF ) that uses phase-contrast (PC) MRI measurements of whole-brain (WB) CBF to calibrate an IDIF extracted from a WB [15 O]H2 O time-activity curve. STUDY TYPE: Technical development and validation. ANIMAL MODEL: Twelve juvenile Duroc pigs (83% female). POPULATION: Thirteen healthy individuals (38% female). FIELD STRENGTH/SEQUENCES: 3 T; gradient-echo PC-MRI. ASSESSMENT: PMRFlowIDIF was validated against PET-only in a porcine model that included arterial sampling. CBF maps were generated by applying PMRFlowIDIF and two previous PMRFlow methods (PC-PET and double integration method [DIM]) to [15 O]H2 O-PET data acquired from healthy individuals. STATISTICAL TESTS: PMRFlow and PET CBF measurements were compared with regression and correlation analyses. Paired t-tests were performed to evaluate differences. Potential biases were assessed using one-sample t-tests. Reliability was assessed by intraclass correlation coefficients. Statistical significance: α = 0.05. RESULTS: In the animal study, strong agreement was observed between PMRFlowIDIF (average voxel-wise CBF, 58.0 ± 16.9 mL/100 g/min) and PET (63.0 ± 18.9 mL/100 g/min). In the human study, PMRFlowDIM (y = 1.11x - 5.16, R2 = 0.99 ± 0.01) and PMRFlowPC-PET (y = 0.87x + 3.82, R2 = 0.97 ± 0.02) performed similarly to PMRFlowIDIF, and CBF was within the expected range (eg, 49.7 ± 7.2 mL/100 g/min for gray matter). DATA CONCLUSION: Accuracy of PMRFlowIDIF was confirmed in the animal study with the primary source of error attributed to differences in WB CBF measured by PC MRI and PET. In the human study, differences in CBF from PMRFlowIDIF , PMRFlowDIM , and PMRFlowPC-PET were due to the latter two not accounting for blood-borne activity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.
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Circulação Cerebrovascular , Tomografia por Emissão de Pósitrons , Animais , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Radioisótopos de Oxigênio , Tomografia por Emissão de Pósitrons/métodos , Reprodutibilidade dos Testes , SuínosRESUMO
OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is a general cognitive screening tool that has shown sensitivity in detecting mild levels of cognitive impairment in various clinical populations. Although mood dysfunction is common in referrals to memory clinics, the influence of mood on the MoCA has to date been largely unexplored. METHOD: In this study, we examined the impact of mood dysfunction on the MoCA using a memory clinic sample of individuals with depressive symptoms who did not meet criteria for a neurodegenerative disease. RESULTS: Half of the group with depressive symptoms scored below the MoCA-suggested cutoff for cognitive impairment. As a group, they scored below healthy controls, but above individuals with Alzheimer's disease and frontotemporal dementia. A MoCA subtask analysis revealed a pattern of executive/attentional dysfunction in those with depressive symptoms. CONCLUSIONS: This observed negative impact of depressive symptomatology on the MoCA has interpretative implications for its utility as a cognitive screening tool in a memory clinic setting.
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Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Depressão/complicações , Testes Neuropsicológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disorder resulting in social-cognitive deficits partially attributed to abnormalities processing social cues, such as facial expressions. However, to our knowledge, the functional neuroanatomy of deficient social cue processing in individuals with FTD has not been examined. The objective of this study was to delineate the functional abnormalities under lying altered facial expression processing in individuals with FTD using functional magnetic resonance imaging (fMRI). METHODS: Patients meeting Neary criteria for behavioural variant FTD (bvFTD) with supportive neuroimaging and 18 age-matched healthy controls completed an implicit facial expression task during fMRI. We conducted volumetric brain morphometry to correct functional imaging data for volume differences. RESULTS: We included 20 patients with bvFTD and 18 controls in our study. The results demonstrate emotion-specific functional abnormalities in frontal and limbic regions in patients with bvFTD. Patients also showed decreased activity in posterior ventral visual regions, specifically the fusiform cortex, possibly reflecting reduced afferent input from limbic regions. Finally, bvFTD was associated with increased activity in posterior regions, including the inferior parietal cortex. LIMITATIONS: Autopsy validation of frontotemporal dementia is not yet available for this cohort. CONCLUSION: Together, these findings suggest that fMRI combined with tasks targeting social-cognitive deficits is a powerful technique to objectively measure neural systems involved in emotion processing in individuals with bvFTD. As viewing emotional expressions is known to engage many of the same neural systems that are active when experiencing the emotion itself, fMRI during expression processing provides a novel window into the emotions of patients with FTD.
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Encéfalo/fisiopatologia , Emoções/fisiologia , Demência Frontotemporal/psicologia , Idoso , Estudos de Casos e Controles , Sinais (Psicologia) , Discriminação Psicológica/fisiologia , Expressão Facial , Feminino , Demência Frontotemporal/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Processos Mentais/fisiologia , Testes Neuropsicológicos , Estimulação Luminosa , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To specify the presenting symptoms and clinical course of patients with frontotemporal dementia (FTD) and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion. BACKGROUND: The 2011 discovery of the C9ORF72 repeat expansion causing familial FTD and amyotrophic lateral sclerosis has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish carriers of the C9ORF72 mutation from other patients with FTD. Prior reports identified a subset of patients with FTD who had an unusually high prevalence of psychosis, although their specific symptoms had not yet been fully described. METHODS: From a cohort of 62 patients with FTD, we conducted a retrospective chart review of 7 patients who had C9ORF72 mutations on genetic testing, and 1 untested sibling of a C9ORF72 carrier. RESULTS: Detailed histories revealed a higher prevalence of psychosis, including visual and auditory hallucinations and delusions, in the 8 C9ORF72 carriers than in our patients with sporadic FTD. CONCLUSIONS: This cohort confirms and adds clinical details to the reports of a high prevalence of psychotic phenomena in patients who have C9ORF72 mutations as well as FTD or amyotrophic lateral sclerosis.
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Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Alucinações/genética , Mutação , Proteínas/genética , Transtornos Psicóticos/genética , Adulto , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Gânglios da Base/patologia , Proteína C9orf72 , Córtex Cerebral/patologia , Estudos de Coortes , Comorbidade , Expansão das Repetições de DNA , Evolução Fatal , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/patologia , Alucinações/epidemiologia , Heterozigoto , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos Psicóticos/epidemiologia , Estudos Retrospectivos , Substância Negra/patologiaRESUMO
Patients with behavioural variant frontotemporal dementia demonstrate abnormalities in behaviour and social cognition, including deficits in emotion recognition. Recent studies suggest that the neuropeptide oxytocin is an important mediator of social behaviour, enhancing prosocial behaviours and some aspects of emotion recognition across species. The objective of this study was to assess the effects of a single dose of intranasal oxytocin on neuropsychiatric behaviours and emotion processing in patients with behavioural variant frontotemporal dementia. In a double-blind, placebo-controlled, randomized cross-over design, 20 patients with behavioural variant frontotemporal dementia received one dose of 24 IU of intranasal oxytocin or placebo and then completed emotion recognition tasks known to be affected by frontotemporal dementia and by oxytocin. Caregivers completed validated behavioural ratings at 8 h and 1 week following drug administrations. A significant improvement in scores on the Neuropsychiatric Inventory was observed on the evening of oxytocin administration compared with placebo and compared with baseline ratings. Oxytocin was also associated with reduced recognition of angry facial expressions by patients with behavioural variant frontotemporal dementia. Together these findings suggest that oxytocin is a potentially promising, novel symptomatic treatment candidate for patients with behavioural variant frontotemporal dementia and that further study of this neuropeptide in frontotemporal dementia is warranted.
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Sintomas Comportamentais/tratamento farmacológico , Cognição/efeitos dos fármacos , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/fisiopatologia , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Comportamento/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Expressão Facial , Humanos , Testes Neuropsicológicos , Placebos , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
BACKGROUND: Clinical diagnosis of frontotemporal dementia (FTD) remains a challenge due to the overlap of symptoms among FTD subtypes and with other psychiatric disorders. Perfusion imaging by arterial spin labeling (ASL) is a promising non-invasive alternative to established PET techniques; however, its sensitivity to imaging parameters can hinder its ability to detect perfusion abnormalities. PURPOSE: This study evaluated the similarity of regional hypoperfusion patterns detected by ASL relative to the gold standard for imaging perfusion, PET with radiolabeled water (15O-water). METHODS AND MATERIALS: Perfusion by single-delay pseudo continuous ASL (SD-pCASL), free-lunch Hadamard encoded pCASL (FL_TE-pCASL), and 15O-water data were acquired on a hybrid PET/MR scanner in 13 controls and 9 FTD patients. Cerebral blood flow (CBF) by 15O-water was quantified by a non-invasive approach (PMRFlow). Regional hypoperfusion was determined by comparing individual patients to the control group. This was performed using absolute (aCBF) and CBF normalized to whole-brain perfusion (rCBF). Agreement was assessed based on the fraction of overlapping voxels. Sensitivity and specificity of pCASL was estimated using hypoperfused regions of interest identified by 15O-water. RESULTS: Region of interest (ROI) based perfusion measured by 15O-water strongly correlated with SD-pCASL (R = 0.85 ± 0.1) and FL_TE-pCASL (R = 0.81 ± 0.14). Good agreement in terms of regional hypoperfusion patterns was found between 15O-water and SD-pCASL (sensitivity = 70%, specificity = 78%) and between 15O-water and FL_TE-pCASL (sensitivity = 71%, specificity = 73%). However, SD-pCASL showed greater overlap (43.4 ± 21.3%) with 15O-water than FL_TE-pCASL (29.9 ± 21.3%). Although aCBF and rCBF showed no significant differences regarding spatial overlap and metrics of agreement with 15O-water, rCBF showed considerable variability across subtypes, indicating that care must be taken when selecting a reference region. CONCLUSIONS: This study demonstrates the potential of pCASL for assessing regional hypoperfusion related to FTD and supports its use as a cost-effective alternative to PET.
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Demência Frontotemporal , Circulação Cerebrovascular/fisiologia , Demência Frontotemporal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Marcadores de Spin , Tomografia Computadorizada por Raios X , ÁguaRESUMO
BACKGROUND: Advances in the understanding of the pathophysiology of frontotemporal dementia (FTD) and related disorders, along with the development of novel candidate disease modifying treatments, have stimulated the need for tools to assess the efficacy of new therapies. While perfusion imaging by arterial spin labeling (ASL) is an attractive approach for longitudinal imaging biomarkers of neurodegeneration, sources of variability between sessions including arterial transit times (ATT) and fluctuations in resting perfusion can reduce its sensitivity. Establishing the magnitude of perfusion changes that can be reliably detected is necessary to delineate longitudinal perfusion changes related to disease processes from the effects of these sources of error. PURPOSE: To assess the feasibility of ASL for longitudinal monitoring of patients with FTD by quantifying between-session variability of perfusion on a voxel-by-voxel basis. METHODS AND MATERIALS: ASL data were collected in 13 healthy controls and 8 patients with FTD or progressive supra-nuclear palsy. Variability in cerebral blood flow (CBF) by single delay pseudo-continuous ASL (SD-pCASL) acquired one month apart were quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Additionally, CBF by SD-pCASL and ATT by low-resolution multiple inversion time ASL (LowRes-pCASL) were compared to Hadamard encoded sequences which are able to simultaneously measure CBF and ATT with improved time-efficiency. RESULTS: Agreement of grey-matter perfusion between sessions was found for both patients and controls (CV = 10.8% and 8.3% respectively) with good reliability for both groups (ICC > 0.6). Intensity normalization to remove day-to-day fluctuations in resting perfusion reduced the CV by 28%. Less than 5% of voxels had ATTs above the chosen post labelling delay (2 s), indicating that the ATT was not a significant source of error. Hadamard-encoded perfusion imaging yielded systematically higher CBF compared to SD-pCASL, but produced similar transit-time measurements. Power analysis revealed that SD-pCASL has the sensitivity to detect longitudinal changes as low as 10% with as few as 10 patient participants. CONCLUSION: With the appropriate labeling parameters, SD-pCASL is a promising approach for assessing longitudinal changes in CBF associated with FTD.
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Demência Frontotemporal , Circulação Cerebrovascular/fisiologia , Demência Frontotemporal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Perfusão , Reprodutibilidade dos Testes , Marcadores de SpinRESUMO
BACKGROUND: Changes in financial judgement and skills can herald a neurodegenerative dementia and are a common reason for referral for cognitive neurologic assessment. However, patients with neurodegenerative diseases affecting the frontal or temporal lobes may perform well on standard cognitive tests, complicating clinical determinations about their diagnosis and financial capacity. METHODS: Forty-five patients with possible or probable FTD or Alzheimer's disease and 22 healthy controls completed two financial assessment batteries, the FACT and the FCAI. Patients' performance was compared to study partner estimates of patients' financial abilities. RESULTS: All three patient groups performed worse than controls on both the FACT and the FCAI. Study partners over-estimated the performance of patients with Alzheimer's disease. CONCLUSIONS: These initial findings suggest that accurate clinical assessment of financial skills and judgement in patients with possible neurodegenerative dementias requires performance-based assessment.
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Status Econômico , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/psicologia , Julgamento , Competência Mental/psicologia , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões/fisiologia , Feminino , Humanos , Julgamento/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). METHODS: We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. RESULTS: All 3 doses of intranasal oxytocin were safe and well tolerated. CONCLUSIONS: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory.
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Demência Frontotemporal/tratamento farmacológico , Ocitocina/administração & dosagem , Administração Intranasal , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Emoções , Empatia , Feminino , Demência Frontotemporal/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Ocitocina/efeitos adversos , Resultado do TratamentoRESUMO
Descriptions of extrapyramidal (EP) involvement in Pick's disease (renamed recently as FTD) appeared 80 years ago. CBD pathology was confirmed as a common substrate for primary progressive aphasia (PPA). We suggested that CBD and PPA should be included with frontal lobe dementia as Pick complex. PSP was prototype for "subcortical dementia", and aphasia and apraxia, considered unusual for PSP, are now seen as a rule. The overlap of PSP and CBD is considerable. We recently reviewed our cohort with EPS in FTD and identified 22 patients with the movement disorder as a first syndrome and another larger group of 48 patients who developed EPS after an initial onset with a cognitive disorder: aphasic, behavioral or both. All cognitive onset CBD/PSP patients and all but two with motor onset developed aphasia during the course of their illness. General cognitive and behavioral measures are similar for each presentation, but language scores are worse in cognitive onset cases, reflecting the frequency of aphasic presentations. Anomic patients become non-fluent, logopenic, agrammatic and mute. Using the Frontal Behavioral Inventory (FBI), a questionnaire specifically designed for the spectrum of apathy and disinhibition displayed by patients with FTD, we have documented the behavior change in CBD/PSP with motor and cognitive onsets. The significant personality changes consisted of apathy, disinhibition, perseveration and inattention, some of the core symptoms of FTD. In 18 autopsied cases, 15 had tau pathology. The overlap of CBD/PSP with PPA and bvFTD suggests a spectrum of related entities and predicts tau-positive pathology. Cross-sectional studies without significant follow-up may not observe the subsequent development language or behavior deficit, or the evolution from PPA and/or FTD-bv to CBD/PSP.
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Doença de Pick/patologia , Doença de Pick/fisiopatologia , Afasia Primária Progressiva/patologia , Afasia Primária Progressiva/fisiopatologia , Estudos de Coortes , Estudos Transversais , Humanos , Testes Neuropsicológicos , Síndrome , Proteínas tau/metabolismoRESUMO
OBJECTIVES: To describe a large, clinically defined cohort of patients with semantic dementia (SD) that highlights important, sometimes overlooked features and to compare it with similar entities. DESIGN: Cohort study. SETTING: A cognitive neurology clinic. PATIENTS: A population of 48 patients clinically diagnosed with SD was contrasted with 52 patients with progressive nonfluent aphasia, 42 patients with a behavioral variety of frontotemporal dementia, and 105 patients with Alzheimer disease on speech output characteristics, comprehension, naming, and repetition subtests of the Western Aphasia Battery, the Frontal Behavioral Inventory, and other cognitive tests. Neuroimaging was visually analyzed, and 6 patients with SD had autopsy. RESULTS: Of 37 patients with probable SD, 48.6% had semantic jargon; 21.6%, excessive garrulous output; and 75.7%, some pragmatic disturbance. Semantic substitutions were frequent in SD (54.1%) but phonological errors were absent, in contrast to progressive nonfluent aphasia with the opposite pattern. All but 3 patients with probable SD questioned the meaning of words. Patients with SD had significantly lower naming and comprehension scores, and their fluency was between progressive nonfluent aphasia and Alzheimer disease or behavioral frontotemporal dementia. Behavior was abnormal in 94.6% of patients with probable SD. CONCLUSIONS: Semantic dementia is distinguishable from other presentations of frontotemporal dementia and Alzheimer disease, not only by fluent speech and impaired comprehension without loss of episodic memory, syntax, and phonology but also by empty, garrulous speech with thematic perseverations, semantic paraphasias, and poor category fluency. Questioning the meaning of words (eg, "What is steak?") is an important diagnostic clue not seen in other groups, and behavior change is prevalent.