Michael Tierney

A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment

Article abstract-Given the relationship between the presence of ApoE epsilon 4 and Alzheimers disease (AD), we studied whether knowledge of epsilon 4 status would predict which memory-impaired patients would develop AD over time. One hundred seven patients who presented with memory impairment but not dementia were referred to the study by their family physicians. These patients were followed prospectively over a 2-year period. Twenty-nine patients developed AD, while 78 did not develop dementia. We found that ApoE genotype was a reliable prognostic indicator of who developed AD in this group only when memory test performance was included in the predictive model. These findings indicate the limitations of ApoE genotyping in isolation as a prognostic indicator of AD. Because this study included prospectively selected patients who were followed longitudinally, our findings are likely to have more relevance in the clinical setting than those obtained from currently available retrospective studies. NEUROLOGY 1996;46: 149-154

Damage to the Fronto-Polar Cortex Is Associated with Impaired Multitasking

Background A major question in understanding the functional organization of the brain is to delineate the functional divisions of the prefrontal cortex. Of particular importance to the cognitive capacities that are uniquely human is the fronto-polar cortex (Brodmanns area 10), which is disproportionally larger in humans relative to the rest of the brain than it is in the apes brain. The specific function of this brain region remains poorly understood, but recent neuroimaging studies have proposed that it may hold goals in mind while exploring and processing secondary goals. Principal Findings Here we show that the extent of damage to the fronto-polar cortex predicts impairment in the management of multiple goals. This result reveals that the integrity of the fronto-polar cortex is necessary to perform tasks that require subjects to maintain a primary goal in mind while processing secondary goals, an ability which is crucial for complex human cognitive abilities. Conclusion/Significance These results provide important new insights concerning the cerebral basis of complex human cognition such as planning and multitasking.

Executive dysfunction in frontotemporal dementia and corticobasal syndrome

Objective: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses. Method: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction. Results: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD. Conclusions: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making.

Characteristics of frontotemporal dementia patients with a Progranulin mutation.

Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.

FUS and TDP43 genetic variability in FTD and CBS.

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.

Screening for C9ORF72 repeat expansion in FTLD

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimers disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.

Genetic variability in CHMP2B and frontotemporal dementia.

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72-associated amyotrophic lateral sclerosis. Homing in on poly(GP) proteins A mutation in the C9ORF72 gene causes amyotrophic lateral sclerosis (ALS) through the accumulation of G4C2 RNA. Therapeutics that target G4C2 RNA are thus being developed. Testing these therapeutics in patients with “c9ALS” will depend on finding a marker to monitor the effect of treatments on G4C2 RNA. Gendron et al. demonstrate that poly(GP) proteins produced from G4C2 RNA are present in cerebrospinal fluid from c9ALS patients. Furthermore, using patient cell models and a mouse model of c9ALS, they report that poly(GP) proteins correlate with G4C2 RNA, suggesting that poly(GP) could be used to test potential treatments for c9ALS in upcoming clinical trials. There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA–mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA–based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Neural Correlates of Caregiver Burden in Cortical Basal Syndrome and Frontotemporal Dementia

Aims: To determine areas of atrophy in patients that are associated with caregiver burden. Methods: We measured caregiver burden, dementia and neuropsychiatric scores in 22 patients with corticobasal syndrome (CBS) and 25 with frontotemporal dementia (FTD), and in 14 healthy controls. We used voxel-based morphometry to correlate caregiver burden with gray matter loss. Results: Increased dementia and behavioral disturbances contributed to higher burden scores in CBS patients, while behavioral disturbances alone significantly affected burden scores in frontal-variant FTD (FTD-fv) patients. In CBS patients, caregiver burden scores correlated with atrophy in left inferior and middle temporal gyri. Conclusions: Caregivers of FTD-fv patients had significantly higher burden scores than caregivers of CBS patients. Damage to areas important in semantic knowledge appears critical in increased burden for CBS caregivers.

White Matter Tract Damage in the Behavioral Variant of Frontotemporal and Corticobasal Dementia Syndromes

The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these disorders.