Frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau (FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.

BACKGROUND AND OBJECTIVE: Individuals with biomarker evidence of ß-amyloid (Aß) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aß-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. METHODS: Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aß PET positivity was defined based on ADNI cutpoints. We identified all Aß-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aß PET (amyloid with low tau [ALT] group) and all Aß-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aß Centiloid, and hippocampal volume. RESULTS: We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aß Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aß Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. DISCUSSION: Aß-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aß cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.

Uptake of AV-1451 in meningiomas.

AIM: AV-1451 is an imaging agent labeled with the positron-emitting radiolabel Fluorine-18. 18F-AV-1451 binds paired helical filament tau (PHF-tau), a pathology related to Alzheimer's disease. In our study of AV-1451 uptake in the brains of cognitively normal subjects, we noted a case of a meningioma with visually significant uptake of AV-1451. OBJECTIVE: We initiated the present retrospective study to further examine cases of meningioma that underwent AV-1451 imaging. METHODS: We searched the patient records of 650 patients who had undergone AV-1451 at our institution for the keyword "meningioma" to identify potential cases. PET/CT and MRI results were visually reviewed and semi-quantitative analysis of PET was performed. A paired student's t test was run between background and tumor standard uptake values. Fisher's exact test was used to examine the association between AV-1451 uptake and presence of calcifications on CT. RESULTS: We identified 12 cases of meningioma, 58% (7/12) of which demonstrated uptake greater than background using both visual analysis and tumor-to-normal cortex ratios (T/N + 1.90 ± 0.83). The paired student's t test revealed no statistically significant difference between background and tumor standard uptake values (p = 0.09); however, cases with a T/N ratio greater than one showed statistically higher uptake in tumor tissue (p = 0.01). A significant association was noted between AV-1451 uptake and presence of calcifications (p = 0.01). CONCLUSION: AV-1451 PET imaging should be reviewed concurrently with anatomic imaging to prevent misleading interpretations of PHF-tau distribution due to meningiomas.

Brain tau deposition linked to systemic causes of death in normal elderly.

The relationship between causes of death and 4 major neurodegenerative brain proteins (beta-amyloid, tau, alpha-synuclein, and the TAR DNA-binding protein of 43 kDa (TDP-43) were assessed in 94 cognitively normal elderly participants that died without a neurodegenerative disease. There was an association between tau and causes of death (p = 0.01). Tau in the brain was associated with a reduced likelihood of dying from systemic cancers (p = 0.046), and with an increased likelihood of dying from pulmonary (p = 0.03) and gastrointestinal (p = 0.049) diseases. There were no associations between beta-amyloid, alpha-synuclein, or TDP-43 and causes of death. Tau deposition in the brain may have a relationship with systemic causes of death, including cancer, in the cognitively normal elderly.

Coprophagia in neurologic disorders.

We report on the unusual behavior of coprophagia (eating one's own feces) in neurologic disorders. The Mayo Clinic Health Sciences-computerized clinical database was queried for all patients evaluated at our institution between 1995 and 2015 in which coprophagia was documented in the medical records. Twenty-six patients were identified of which 17 had coprophagia. Of the 17 patients, five were excluded due to age at onset less than 10 years, leaving 12 adult patients for this study. The median age at onset of coprophagia in the 12 patients was 55 years (range 20-88 years), and half were female. Additional behaviors were common including scatolia (fecal smearing), hypersexuality, aggression, and pica (eating objects of any kind). Coprophagia was associated with neurodegenerative dementia in six patients, developmental delay in two, and one each with seizures, steroid psychosis, frontal lobe tumor, and schizoaffective disorder. Brain imaging in the six patients with dementia showed moderate-to-severe medial temporal lobe atrophy, as well as mild frontal lobe atrophy. Autopsy examination was performed in one patient and revealed frontotemporal lobar degeneration pathology. Many different behavioral and pharmacologic therapies were implemented, yet only haloperidol was associated with discontinuation of the behavior. Coprophagia is associated with different neurologic disorders, particularly neurodegenerative dementias. The behavior may be related to medial temporal lobe atrophy, similar to the Klüver-Bucy syndrome. Haloperidol appears to be effective in treating the behavior, at least in some patients.

Neuroimaging in frontotemporal lobar degeneration--predicting molecular pathology.

Frontotemporal lobar degeneration (FTLD) encompasses a group of diseases characterized by neuronal loss and gliosis of the frontal and temporal lobes. Almost all cases of FTLD can be classified into three categories on the basis of deposition of one of three abnormal proteins: the microtubule-associated protein tau, TAR DNA-binding protein 43, or fused in sarcoma. The specific diagnoses within each of these three categories are further differentiated by the distribution and morphological appearance of the protein-containing inclusions. Future treatments are likely to target these abnormal proteins; the clinical challenge, therefore, is to be able to predict molecular pathology during life. Clinical diagnosis alone has had variable success in helping to predict pathology, and is particularly poor in the diagnosis of behavioral variant frontotemporal dementia, which can be associated with all three abnormal proteins. Consequently, other biomarkers of disease are needed. This Review highlights how patterns of atrophy assessed on MRI demonstrate neuroanatomical signatures of the individual FTLD pathologies, independent of clinical phenotype. The roles of these patterns of atrophy as biomarkers of disease, and their potential to help predict pathology during life in patients with FTLD, are also discussed.

Focal brain atrophy in gastric bypass patients with cognitive complaints.

Recently, we have identified a series of patients presenting with cognitive complaints after gastric bypass, without any identifiable etiology. We aimed to determine if focal brain atrophy could account for the complaints. A retrospective case series was performed to identify patients with cognitive complaints following gastric bypass who had a volumetric MRI. Voxel-based morphometry was used to assess patterns of grey matter loss in all 10 patients identified, compared to 10 age and gender-matched controls. All patients had undergone Roux-en-Y gastric bypass surgery at a median age of 54 (range: 46-64). Cognitive complaints developed at a median age of 57 (52-69). Formal neuropsychometric testing revealed only minor deficits. No nutritional abnormalities were identified. Voxel-based morphometry demonstrated focal thalamic atrophy in the gastric bypass patients when compared to controls. Patients with cognitive complaints after gastric bypass surgery may have focal thalamic brain atrophy that could result in cognitive impairment.

VBM signatures of abnormal eating behaviours in frontotemporal lobar degeneration.

The brain bases of specific human behaviours in health and disease are not well established. In this voxel-based morphometric (VBM) study we demonstrate neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption, or hyperphagia) in individuals with frontotemporal lobar degeneration (FTLD). Sixteen male patients with FTLD were assessed using the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia and classified according to the presence or absence of abnormal eating behaviours. Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol. Compared with healthy controls, the FTLD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTLD group, grey matter changes associated with different abnormal behaviours were assessed independently using a covariate-only model. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral OFC bilaterally (Brodmann area 11). In accord with emerging evidence in humans and other species, our findings implicate distinct components of a multi-component brain network in the control of specific aspects of eating behaviour.