Kyle B. Womack

Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

BACKGROUND The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimers disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired National Football League Players: A Cross-sectional Study

OBJECTIVES To assess cognitive impairment and depression in aging former professional football (National Football League [NFL]) players and to identify neuroimaging correlates of these dysfunctions. DESIGN We compared former NFL players with cognitive impairment and depression, cognitively normal retired players who were not depressed, and matched healthy control subjects. SETTING Research center in the North Texas region of the United States. PATIENTS Cross-sectional sample of former NFL players with and without a history of concussion recruited from the North Texas region and age-, education-, and IQ-matched controls. Thirty-four retired NFL players (mean age, 61.8 years) underwent neurological and neuropsychological assessment. A subset of 26 players also underwent detailed neuroimaging; imaging data in this subset were compared with imaging data acquired in 26 healthy matched controls. MAIN OUTCOME MEASURES Neuropsychological measures, clinical diagnoses of depression, neuroimaging mea-sures of white matter pathology, and a measure of cerebral blood flow. RESULTS Of the 34 former NFL players, 20 were cognitively normal. Four were diagnosed as having a fixed cognitive deficit; 8, mild cognitive impairment; 2, dementia; and 8, depression. Of the subgroup in whom neuroimaging data were acquired, cognitively impaired participants showed the greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in cognitively impaired and depressed retired players compared with their respective controls. Regional blood flow differences in the cognitively impaired group (left temporal pole, inferior parietal lobule, and superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming, and word finding). CONCLUSIONS Cognitive deficits and depression appear to be more common in aging former NFL players compared with healthy controls. These deficits are correlated with white matter abnormalities and changes in regional cerebral blood flow.

Subscores of the FAB differentiate frontotemporal lobar degeneration from AD

Objective: To determine the clinical utility of the Frontal Assessment Battery (FAB), a short test of frontal lobe functions, in differentiating frontotemporal lobar degeneration (FTLD) from Alzheimer disease (AD). Methods: FAB total scores and subscores for 23 subjects with FTLD and 31 subjects with AD were compared for sensitivity, specificity, and positive predictive value. Concurrent validity of the FAB with the Mini-Mental State Examination (MMSE) and other scales was also assessed. Results: The FAB did not have positive predictive value for FTLD. Total FAB scores did not differ between the FTLD and AD groups. However, three subtests of the FAB (mental flexibility, motor programming, and environmental autonomy) demonstrated significant differences between the two groups. Total FAB scores correlated with scores on the MMSE, a more general test of cognition. Conclusion: The Frontal Assessment Battery did not discriminate subjects with frontotemporal lobar degeneration from those with Alzheimer disease, though certain subtests may be helpful in differential diagnosis.

Depressive symptoms and white matter dysfunction in retired NFL players with concussion history

Objective: To determine whether correlates of white matter integrity can provide general as well as specific insight into the chronic effects of head injury coupled with depression symptom expression in professional football players. Method: We studied 26 retired National Football League (NFL) athletes who underwent diffusion tensor imaging (DTI) scanning. Depressive symptom severity was measured using the Beck Depression Inventory II (BDI-II) including affective, cognitive, and somatic subfactor scores (Buckley 3-factor model). Fractional anisotropy (FA) maps were processed using tract-based spatial statistics from FSL. Correlations between FA and BDI-II scores were assessed using both voxel-wise and region of interest (ROI) techniques, with ROIs that corresponded to white matter tracts. Tracts demonstrating significant correlations were further evaluated using a receiver operating characteristic curve that utilized the mean FA to distinguish depressed from nondepressed subjects. Results: Voxel-wise analysis identified widely distributed voxels that negatively correlated with total BDI-II and cognitive and somatic subfactors, with voxels correlating with the affective component (p < 0.05 corrected) localized to frontal regions. Four tract ROIs negatively correlated (p < 0.01) with total BDI-II: forceps minor, right frontal aslant tract, right uncinate fasciculus, and left superior longitudinal fasciculus. FA of the forceps minor differentiated depressed from nondepressed athletes with 100% sensitivity and 95% specificity. Conclusion: Depressive symptoms in retired NFL athletes correlate negatively with FA using either an unbiased voxel-wise or an ROI-based, tract-wise approach. DTI is a promising biomarker for depression in this population.

An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration

There are currently no Food and Drug Administration-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition, and function. Forty-three individuals who met clinical criteria for FTLD [21 with frontotemporal dementia (FTD), 13 with semantic dementia (SD), and 9 with progressive nonfluent aphasia (PA)] received 26 weeks of open-label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the Mini Mental State Examination, Alzheimers Disease Assessment Scale-Cognitive (ADAS-cog), clinical dementia rating-sum of boxes, Neuropsychiatric Inventory (NPI), Frontal Behavior Inventory, Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale, and Unified Parkinsons Disease Rating Scale-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, Frontal Behavior Inventory, NPI, TFLS, and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and TFLS, but declined on the UPDRS. Memantine was well-tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.

Do phosphatidylinositides modulate vertebrate phototransduction

Mammalian rod cyclic nucleotide gated (CNG) channels (i.e., α plus β subunits) are strongly inhibited by phosphatidylinositol 4,5-bisphosphate (PIP2) when they are expressed in Xenopus oocytes and studied in giant membrane patches. Cytoplasmic Mg-ATP inhibits CNG currents similarly, and monoclonal antibodies to PIP2 reverse the effect and hyperactivate currents. When α subunits are expressed alone, PIP2 inhibition is less strong; olfactory CNG channels are not inhibited. In giant patches from rod outer segments, inhibition by PIP2 is intermediate. Other anionic lipids (e.g., phosphatidyl serine and phosphatidic acid), a phosphatidylinositol-specific phospholipase C, and full-length diacylglycerol have stimulatory effects. Although ATP also potently inhibits cGMP-activated currents in rod patches, the following findings indicate that ATP is used to transphosphorylate GMP, generated from cGMP, to GTP. First, a phosphodiesterase (PDE) inhibitor, Zaprinast, blocks inhibition by ATP. Second, inhibition can be rapidly reversed by exogenous regulator of G-protein signaling 9, suggesting G-protein activation by ATP. Third, the reversal of ATP effects is greatly slowed when cyclic inosine 5′-monophosphate is used to activate currents, as expected for slow inosine 5′ triphosphate hydrolysis by G-proteins. Still, other results remain suggestive of regulatory roles for PIP2. First, the cGMP concentration producing half-maximal CNG channel activity (K1/2) is decreased by PIP2 antibody in the presence of PDE inhibitors. Second, the activation of PDE activity by several nucleotides, monitored electrophysiologically and biochemically, is reversed by PIP2 antibody. Third, exogenous PIP2 can enhance PDE activation by nucleotides.

Temporoparietal Hypometabolism in Frontotemporal Lobar Degeneration and Associated Imaging Diagnostic Errors

OBJECTIVE To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomographic scans with fludeoxyglucose F 18 (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and patients with Alzheimer disease (AD). DESIGN Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere-frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex, and posterior cingulate cortex. Results were compared with neuropathological diagnoses. SETTING Academic medical centers. PATIENTS Forty-five patients with pathologically confirmed FTLD (n=14) or AD (n=31). RESULTS Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27 of 31 patients [87%]) than in patients with FTLD (7 of 14 patients [50%]) (P=.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 scans lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD. CONCLUSIONS Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism but rather must take into account the relative hypometabolism of all brain regions.

Imaging Correlates of Memory and Concussion History in Retired National Football League Athletes

IMPORTANCE To our knowledge, this is the first study to show an association between concussion, cognition, and anatomical structural brain changes across the age spectrum in former National Football League athletes. OBJECTIVE To assess the relationship of hippocampal volume, memory performance, and the influence of concussion history in retired National Football League athletes with and without mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study assessed differences between groups, mean hippocampal volumes, and memory performance by computing age quintiles based on group-specific linear regression models corrected for multiple comparisons for both athletes and control participants. The study was conducted starting in November 2010 and is ongoing at a research center in the northern region of Texas. This current analysis was conducted from October 9, 2013, to August 21, 2014. Participants included 28 retired National Football League athletes, 8 of whom had MCI and a history of concussion, 21 cognitively healthy control participants, and 6 control participants with MCI without concussion. MAIN OUTCOMES AND MEASURES Hippocampal volume, age, California Verbal Learning Test scores, and the number of grade 3 (G3) concussions. In addition, the number of games played was examined as an objective variable pertaining to football history. RESULTS The mean (SD) age was 58.1 (13) years for the 28 former athletes and 59.0 (12) years for the 27 control participants. Retired athletes with concussion history but without cognitive impairment had normal but significantly lower California Verbal Learning Test scores compared with control participants (mean [SD], 52.5 [8] vs 60.24 [7]; P = .002); those with a concussion history and MCI performed worse (mean [SD], 37 [8.62]) compared with both control participants (P < .001) and athletes without memory impairment (P < .001). Among the athletes, 17 had a G3 concussion and 11 did not. Older retired athletes with at least 1 G3 concussion had significantly smaller bilateral hippocampal volumes compared with control participants at the 40th age percentile (left, P = .04; right, P = .03), 60th percentile (left, P = .009; right, P = .01), and 80th percentile (left, P = .001; right, P = .002) and a smaller right hippocampal volume compared with athletes without a G3 concussion at the 40th percentile (P = .03), 60th percentile (P = .02), and 80th percentile (P = .02). Athletes with a history of G3 concussion were more likely to have MCI (7 of 7) compared with retired athletes without a history of G3 concussion (1 of 5) older than 63 years (P = .01). In addition, the left hippocampal volume in retired athletes with MCI and concussion was significantly smaller compared with control participants with MCI (P = .03). CONCLUSION AND RELEVANCE Prior concussion that results in loss of consciousness is a risk factor for increased hippocampal atrophy and the development of MCI. In individuals with MCI, hippocampal volume loss appears greater among those with a history of concussion.

Effects of Donepezil on Verbal Memory After Semantic Processing in Healthy Older Adults

ObjectiveTo learn if acetylcholinesterase inhibitors alter verbal recall by improving semantic encoding in a double-blind randomized placebo-controlled trial. BackgroundCholinergic supplementation has been shown to improve delayed recall in adults with Alzheimer disease. With functional magnetic resonance imaging, elderly adults, when compared with younger participants, have reduced cortical activation with semantic processing. There have been no studies investigating the effects of cholinergic supplementation on semantic encoding in healthy elderly adults. MethodTwenty elderly participants (mean age 71.5, SD±5.2) were recruited. All underwent memory testing before and after receiving donepezil (5 mg, n=11 or 10 mg, n=1) or placebo (n=8) for 6 weeks. Memory was tested using a Levels of Processing task, where a series of words are presented serially. Subjects were either asked to count consonants in a word (superficially process) or decide if the word was “pleasant” or “unpleasant” (semantically process). ResultsAfter 6 weeks of donepezil or placebo treatment, immediate and delayed recall of superficially and semantically processed words was compared with baseline performance. Immediate and delayed recall of superficially processed words did not show significant changes in either treatment group. With semantic processing, both immediate and delayed recall performance improved in the donepezil group. ConclusionsOur results suggest that when using semantic encoding, older normal subjects may be aided by anticholinesterase treatment. However, this treatment does not improve recall of superficially encoded words.

Semantic memory retrieval circuit: role of pre-SMA, caudate, and thalamus.

We propose that pre-supplementary motor area (pre-SMA)-thalamic interactions govern processes fundamental to semantic retrieval of an integrated object memory. At the onset of semantic retrieval, pre-SMA initiates electrical interactions between multiple cortical regions associated with semantic memory subsystems encodings as indexed by an increase in theta-band EEG power. This starts between 100-150 ms after stimulus presentation and is sustained throughout the task. We posit that this activity represents initiation of the object memory search, which continues in searching for an object memory. When the correct memory is retrieved, there is a high beta-band EEG power increase, which reflects communication between pre-SMA and thalamus, designates the end of the search process and resultant in object retrieval from multiple semantic memory subsystems. This high beta signal is also detected in cortical regions. This circuit is modulated by the caudate nuclei to facilitate correct and suppress incorrect target memories.