Showing papers by "Katherine P. Rankin published in 2012"

Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion

Abstract: Background Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD ‘phenocopies’ or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. Methods 384 patients with an FTD clinical spectrum and Alzheimer9s disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Results Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. Conclusions C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features.

Abstract: Objective: To describe the phenotype of patients with C9FTD/ALS ( C9ORF72 ) hexanucleotide repeat expansion. Methods: A total of 648 patients with frontotemporal dementia (FTD)–related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD–motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS). Results: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. Conclusions: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.

Tracking Emotional Valence: The Role of the Orbitofrontal Cortex

Abstract: Successful navigation of the social world requires the ability to recognize and track emotions as they unfold and change dynamically. Neuroimaging and neurological studies of emotion recognition have primarily focused on the ability to identify the emotion shown in static photographs of facial expressions, showing correlations with the amygdala as well as temporal and frontal brain regions. In the current study we examined the neural correlates of continuously tracking dynamically-changing emotions. Fifty-nine patients with diverse neurodegenerative diseases used a rating dial to track continuously how positive or how negative the character in a film clip felt. Tracking accuracy was determined by comparing participants’ ratings with the ratings of 10 normal control participants. The relationship between tracking accuracy and regional brain tissue content was examined using voxel-based morphometry. Low tracking accuracy was primarily associated with gray matter loss in the right lateral orbitofrontal cortex (OFC). Our finding that the right OFC is critical to the ability to track dynamically-changing emotions is consistent with previous research showing right OFC involvement in both socioemotional understanding and modifying responding in changing situations.

COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures

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

Clinical characterization of bvFTD due to FUS neuropathology.

Abstract: In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social-emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social- emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and diminished capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD.

BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease.

Abstract: Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimer's disease (AD). However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with cognitive tests and patterns of brain atrophy using voxelbased morphometry. We found small negative correlations between BDNF serum concentrations and some of the cognitive tests assessing learning, information processing speed and cognitive control in complex situations, however, BDNF did not predict disease group membership despite adequate power. These findings suggest that BDNF serum concentration may not be a reliable diagnostic biomarker to distinguish among neurodegenerative diseases.

Neuropsychiatric Features of C9ORF72 Mutation-Associated bvFTD and FTD-ALS (IN9-2.003)

Abstract: Objective: To characterize neuropsychiatric features associated with C9ORF72 mutations in behavioral variant frontotemporal dementia (bvFTD) and FTD-amyotrophic lateral sclerosis (FTD-ALS). Background Hexanucleotide repeat expansions in the C9ORF72 gene may be the most common genetic cause of bvFTD and FTD-ALS, but the neuropsychiatric features associated with C9ORF72 mutations remain largely uncharacterized. Design/Methods: Four hundred and sixteen patients with FTD or related disorders and asymptomatic family members evaluated at UCSF were tested for C9ORF72 expansion (C9+: N=37). Eighty-six cases (C9+/bvFTD=12; C9-/bvFTD=47; C9+/FTD-ALS=11; C9-/FTD-ALS=16) underwent blinded chart review to identify first reported neuropsychiatric symptoms. Neuropsychiatric Inventory (NPI) scores at first evaluation were analyzed for all C9+ cases and a subset of C9-/bvFTD controls matched for disease severity according by MMSE and CDR-SB. Results:First neuropsychiatric symptoms: In C9+/bvFTD, delusions and aggression were more frequently reported as presenting symptoms (p=0.04). In C9+/FTD-ALS, more rash/careless actions (p=0.04) and greater disinhibition were seen (p=0.13), whereas apathy, anxiety and depression were less frequently reported (p=0.09, 0.12 and 0.12) compared to C9-/FTD-ALS patients. By first evaluation: On the NPI, C9+/bvFTD cases had less disinhibition (p=0.04), aberrant motor (p=0.03) and eating behaviors (p=0.08), but higher anxiety (p=0.12) than C9- bvFTDs. In FTD-ALS, C9+ and C9- NPI scores did not differ. Total NPI scores did not differ by genotype in either group. Conclusions: In bvFTD, C9ORF72 mutation carriers9 first neuropsychiatric symptoms are more frequently delusions and aggression. Later they develop greater anxiety than non-carriers with bvFTD but show less disinhibition or aberrant eating/motor behaviors. In FTD-ALS, C9ORF72 mutation carriers display greater disinhibition as their first symptom, but later become neuropsychiatrically indistinct from non-carriers with FTD-ALS. Further investigation in larger samples will improve differentiation of the neuropsychiatric features caused by C9ORF72 mutations. Supported by: In part by M01-RR0079 General Clinical Research Center; the National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; the State of California, Alzheimer9s Disease Research Center of California (ARCC) grant 03-7527. NIH grants R01AG038791, R01AG031278. Disclosure: Dr. Takada has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Rankin has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Fong has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis. Dr. Boxer has received personal compensation for activities with BMS, Plexxikon and Phloronol as a consultant. Dr. Boxer has received research support from Elan, Forest, Genentech, Medivation, BMS, Janssen and Pfizer Pharmaceuticals. Dr. Miller has received personal compensation for activities with Allon Therapeutics, Inc. and TauRx Therapeutics, Ltd. Dr. Miller has received research support from Novartis.