[18F]Flortaucipir PET Across Various MAPT Mutations in Presymptomatic and Symptomatic Carriers

Objective:To assess the [18F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers.Methods:We compared regional [18F]flortaucipir binding potential(BPND) derived from a 130-minute dynamic [18F]flortaucipir PET scan, in nine (pre)symptomatic MAPT mutation carriers(4 with P301L[1 symptomatic], 2 with R406W[1 symptomatic]; 1 presymptomatic L315R, 1 presymptomatic S320F and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 Alzheimer’s disease patients.Results:[18F]flortaucipir BPND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal and frontal lobe. Elevated medial temporal lobe BPND was observed in a presymptomatic R406W carrier. The single symptomatic and one of the three presymptomatic P301L carriers showed elevated [18F]flortaucipir BPND in the insula, parietal and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BPND, with at neuropathological examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BPND compared to controls. The BPND values of the S320F presymptomatic mutation carrier fell within the range of controls.Conclusion:Presymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [18F]flortaucipir BPND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [18F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies.

Download Full-text

Voxel-based morphometry in Alzheimers disease and mild cognitive impairment: Systematic review of studies addressing the frontal lobe

Dementia & Neuropsychologia ◽

10.1590/s1980-5764-2016dn1002006 ◽

2016 ◽

Vol 10 (2) ◽

pp. 104-112 ◽

Cited By ~ 2

Author(s):

Luís Gustavo Ribeiro ◽

Geraldo Busatto Filho

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Frontal Lobe ◽

Brain Area ◽

Neuropsychiatric Symptoms ◽

Anterior Cingulate ◽

Voxel Based Morphometry ◽

Cognitively Normal ◽

Pubmed Database ◽

Brain Changes

ABSTRACT Voxel-based morphometry (VBM) is a useful approach for investigating neurostructural brain changes in dementia. We systematically reviewed VBM studies of Alzheimer's disease (AD) and mild cognitive impairment (MCI), specifically focusing on grey matter (GM) atrophy in the frontal lobe. Methods: Two searches were performed on the Pubmed database. A set of exclusion criteria was applied to ensure the selection of only VBM studies that directly investigated GM volume abnormalities in AD and/or MCI patients compared to cognitively normal controls. Results: From a total of 46 selected articles, 35 VBM studies reported GM volume reductions in the frontal lobe. The frontal subregions, where most of the volume reductions were reported, included the inferior, superior and middle frontal gyri, as well as the anterior cingulate gyrus. We also found studies in which reduced frontal GM was detected in MCI patients who converted to AD. In a minority of studies, correlations between frontal GM volumes and behavioural changes or cognitive deficits in AD patients were investigated, with variable findings. Conclusion: Results of VBM studies indicate that the frontal lobe should be regarded as an important brain area when investigating GM volume deficits in association with AD. Frontal GM loss might not be a feature specific to late AD only. Future VBM studies involving large AD samples are warranted to further investigate correlations between frontal volume deficits and both cognitive impairment and neuropsychiatric symptoms.

Download Full-text

Early anterior cingulate involvement is seen in presymptomatic MAPT P301L mutation carriers

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00777-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Mica T. M. Clarke ◽

Frédéric St-Onge ◽

Jean-Mathieu Beauregard ◽

Martina Bocchetta ◽

Emily Todd ◽

...

Keyword(s):

Standard Deviation ◽

Mutation Carrier ◽

Anterior Cingulate ◽

Grey Matter Volume ◽

Specific Marker ◽

Brain Scans ◽

Mutation Carriers ◽

P301l Mutation ◽

Negative Controls ◽

And Control

Abstract Background PET imaging of glucose metabolism has revealed presymptomatic abnormalities in genetic FTD but has not been explored in MAPT P301L mutation carriers. This study aimed to explore the patterns of presymptomatic hypometabolism and atrophy in MAPT P301L mutation carriers. Methods Eighteen asymptomatic members from five families with a P301L MAPT mutation were recruited to the study, six mutation carriers, and twelve mutation-negative controls. All participants underwent standard behavioural and cognitive assessment as well as [18F]FDG-PET and 3D T1-weighted MRI brain scans. Regional standardised uptake value ratios (SUVR) for the PET scan and volumes calculated from an automated segmentation for the MRI were obtained and compared between the mutation carrier and control groups. Results The mean (standard deviation) estimated years from symptom onset was 12.5 (3.6) in the mutation carrier group with a range of 7 to 18 years. No differences in cognition were seen between the groups, and all mutation carriers had a global CDR plus NACC FTLD of 0. Significant reduction in [18F] FDG uptake in the anterior cingulate was seen in mutation carriers (mean 1.25 [standard deviation 0.07]) compared to controls (1.36 [0.09]). A similar significant reduction was also seen in grey matter volume in the anterior cingulate in mutation carriers (0.60% [0.06%]) compared to controls (0.68% [0.08%]). No other group differences were seen in other regions. Conclusions Anterior cingulate hypometabolism and atrophy are both apparent presymptomatically in a cohort of P301L MAPT mutation carriers. Such a specific marker may prove to be helpful in stratification of presymptomatic mutation carriers in future trials.

Download Full-text

Differentiating Between Healthy Control Participants and Those with Mild Cognitive Impairment Using Volumetric MRI Data

Journal of the International Neuropsychological Society ◽

10.1017/s135561771900047x ◽

2019 ◽

Vol 25 (08) ◽

pp. 800-810 ◽

Cited By ~ 2

Author(s):

Renée DeVivo ◽

Lauren Zajac ◽

Asim Mian ◽

Anna Cervantes-Arslanian ◽

Eric Steinberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Frontal Cortex ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Temporal Cortex ◽

Anterior Cingulate ◽

Cognitively Normal

AbstractObjective:To determine whether volumetric measures of the hippocampus, entorhinal cortex, and other cortical measures can differentiate between cognitively normal individuals and subjects with mild cognitive impairment (MCI).Method:Magnetic resonance imaging (MRI) data from 46 cognitively normal subjects and 50 subjects with MCI as part of the Boston University Alzheimer’s Disease Center research registry and the Alzheimer’s Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical, subcortical, and hippocampal subfield volumes were generated from each subject’s MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to identify subjects as control or MCI.Results:A model containing regions of interest (superior temporal cortex, caudal anterior cingulate, pars opercularis, subiculum, precentral cortex, caudal middle frontal cortex, rostral middle frontal cortex, pars orbitalis, middle temporal cortex, insula, banks of the superior temporal sulcus, parasubiculum, paracentral lobule) fit the data best (R2= .7310, whole model test chi-square = 97.16,p< .0001).Conclusions:MRI data correctly classified most subjects using measures of selected medial temporal lobe structures in combination with those from other cortical areas, yielding an overall classification accuracy of 93.75%. These findings support the notion that, while volumes of medial temporal lobe regions differ between cognitively normal and MCI subjects, differences that can be used to distinguish between these two populations are present elsewhere in the brain.

Download Full-text

Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000509585 ◽

2021 ◽

pp. 19-25

Author(s):

Lynn Marie Trotti ◽

Donald L. Bliwise ◽

Glenda L. Keating ◽

David B. Rye ◽

William T. Hu

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cholinesterase Inhibitor ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Cognitively Normal ◽

Dementia Patients ◽

Sleep Questionnaires ◽

Sleep Alterations ◽

Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

Download Full-text

The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00865-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Hannah D. Franklin ◽

Lucy L. Russell ◽

Georgia Peakman ◽

Caroline V. Greaves ◽

Martina Bocchetta ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Medial Temporal Lobe ◽

Social Cognitive ◽

Early Stage ◽

Self Monitoring ◽

Self Presentation ◽

Genetic Groups ◽

Mutation Carriers ◽

Large Patient ◽

Weighted Magnetic Resonance Imaging

Abstract Background Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. Methods We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. Results The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. Conclusions The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.

Download Full-text

Impaired Conflict Adaptation in an Emotional Task Context following Rostral Anterior Cingulate Cortex Lesions in Humans

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_00266 ◽

2012 ◽

Vol 24 (10) ◽

pp. 2070-2079 ◽

Cited By ~ 29

Author(s):

Martin E. Maier ◽

Giuseppe di Pellegrino

Keyword(s):

Emotional Expression ◽

Anterior Cingulate ◽

Conflict Adaptation ◽

Task Context ◽

Imaging Studies ◽

Control Groups ◽

Rostral Anterior Cingulate Cortex ◽

Competing Response ◽

Context Specific ◽

Normal Controls

Recent brain imaging studies have implicated the rostral ACC (rACC) in the resolution of conflict between competing response tendencies in emotional task contexts, but not in neutral task contexts. This study tested the hypothesis that the rACC is necessary for such context-specific conflict adaptation. To this end, a group of patients with lesions of the rACC, a group of brain-damaged controls, and a group of normal controls classified the emotional expression (emotional task context) or the gender (neutral task context) of faces while ignoring congruent and incongruent words written across the faces. In all three groups, performance was worse with incongruent as compared with congruent stimuli in both task contexts. In the two control groups, this congruency effect was reduced following incongruent trials in both task contexts. By contrast, the rACC group displayed such conflict adaptation only in the neutral, but not in the emotional, task context. These results show that the rACC is necessary for conflict adaptation in emotional but not in neutral task contexts and suggest that the regulation of behavior is context specific.

Download Full-text

Social and emotional functions in three patients with medial frontal lobe damage including the anterior cingulate cortex

Cognitive Neuropsychiatry ◽

10.1080/13546800444000245 ◽

2006 ◽

Vol 11 (4) ◽

pp. 369-388 ◽

Cited By ~ 32

Author(s):

Amee Baird ◽

Bonnie‐Kate Dewar ◽

Hugo Critchley ◽

Ray Dolan ◽

Tim Shallice ◽

...

Keyword(s):

Anterior Cingulate Cortex ◽

Frontal Lobe ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Social And Emotional ◽

Frontal Lobe Damage

Download Full-text

Neuropsychological performance of adults with attention deficit hyperactivity disorder (ADHD): Diagnostic classification estimates for measures of frontal lobe/executive functioning

Journal of the International Neuropsychological Society ◽

10.1017/s1355617799533055 ◽

1999 ◽

Vol 5 (3) ◽

pp. 222-233 ◽

Cited By ~ 88

Author(s):

DAVID W. LOVEJOY ◽

J.D. BALL ◽

MATTHEW KEATS ◽

MICHAEL L. STUTTS ◽

EDWARD H. SPAIN ◽

...

Keyword(s):

Executive Functioning ◽

Frontal Lobe ◽

Classification Accuracy ◽

Predictive Power ◽

Diagnostic Classification ◽

Neuropsychological Measures ◽

Hyperactivity Disorder ◽

Good Classification ◽

Summary Index ◽

Normal Controls

ADHD adults (N = 26) were compared to normal controls (N = 26) on 6 neuropsychological measures believed sensitive to frontal lobe–executive functioning. MANOVA analyses and subsequent univariate tests indicated that most of the neuropsychological measures discriminated between the two groups. To address clinical significance, diagnostic classification rates were also generated for each measure individually, and for the battery as a whole. Levels of positive predictive power (PPP) for each of the 6 measures (83–100%) indicated that abnormal scores on these tests were good predictors of ADHD. However, estimates of negative predictive power (NPP) suggested that normal scores poorly predicted the absence of ADHD. When classification rates were calculated for the overall battery classification accuracy improved substantially. Thus, neuropsychological tests can differentiate adults suffering from ADHD from adults without ADHD, while also providing good classification accuracy. Finally, the pattern of neurobehavioral impairments exemplified through the Summary Index scores was interpreted as consistent with conceptualizations of ADHD depicting mild neurologic dysfunction in networks associated with the frontal lobes. (JINS, 1999, 5, 222–233.)

Download Full-text

The Correlations Between Plasma Fibrinogen With Amyloid-Beta and Tau Levels in Patients With Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2020.625844 ◽

2021 ◽

Vol 14 ◽

Author(s):

Dong-Yu Fan ◽

Hao-Lun Sun ◽

Pu-Yang Sun ◽

Jie-Ming Jian ◽

Wei-Wei Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Fibrinogen ◽

Cognitively Normal ◽

Amyloid Aβ ◽

And Gender ◽

T Tau ◽

The Relationship ◽

Phosphorylated Tau 181 ◽

Normal Controls

Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer’s disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.

Download Full-text

Combining Visual Rating Scales for Medial Temporal Lobe Atrophy and Posterior Atrophy to Identify Amnestic Mild Cognitive Impairment from Cognitively Normal Older Adults: Evidence Based on Two Cohorts

Journal of Alzheimer s Disease ◽

10.3233/jad-200016 ◽

2020 ◽

Vol 77 (1) ◽

pp. 323-337

Author(s):

Can Sheng ◽

Yu Sun ◽

Min Wang ◽

Xiaoni Wang ◽

Yi Liu ◽

...

Keyword(s):

Medial Temporal Lobe ◽

Rating Scales ◽

Rating Scale ◽

Discriminative Power ◽

Medial Temporal Lobe Atrophy ◽

Cognitively Normal ◽

Visual Rating ◽

Visual Rating Scale ◽

Visual Assessments ◽

Lobe Atrophy

Background: Visual rating scales for medial temporal lobe atrophy (MTA) and posterior atrophy (PA) have been reported to be useful for Alzheimer’s disease diagnosis in routine clinical practice. Objective: To investigate the efficacy of combined MTA and PA visual rating scales to discriminate amnestic mild cognitive impairment (aMCI) patients from healthy controls. Methods: This study included T1-weighted MRI images from two different cohorts. In the first cohort, we recruited 73 patients with aMCI and 48 group-matched cognitively normal controls for training and validation. Visual assessments of MTA and PA were carried out for each participant. Global gray matter volume and density were estimated using voxel-based morphometry analysis as the objective reference. We investigated the discriminative power of a single visual rating scale and the combination of the MTA and PA rating scales for identifying aMCI. The second cohort, consisting of 33 aMCI patients and 45 controls, was used to verify the reliability of the visual assessments. Results: Compared with the single visual rating scale, the combination of the MTA and PA exhibited the best discriminative power, with an AUC of 0.818±0.041, which was similar to the diagnostic accuracy of the gray matter volumetric measures. The discriminative power of the combined MTA and PA was verified in the second cohort (AUC 0.824±0.058). Conclusion: The combined MTA and PA rating scales demonstrated practical diagnostic value for distinguishing aMCI patients from controls, suggesting its potential to serve as a convenient and reproducible method to assess the degree of atrophy in clinical settings.

Download Full-text