Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.

OBJECTIVE: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. METHODS: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). RESULTS: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. CONCLUSION: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

Ecological validity and neuroanatomical correlates of the NIH EXAMINER executive composite score.

Executive functions refer to a constellation of higher-level cognitive abilities that enable goal-oriented behavior. The NIH EXAMINER battery was designed to assess executive functions comprehensively and efficiently. Performance can be summarized by a single score, the "Executive Composite," which combines measures of inhibition, set-shifting, fluency, and working memory. We evaluated the ecological validity of the Executive Composite in a sample of 225 mixed neurological patients and controls using the Frontal Systems Behavior Scale (FrSBe), an informant-based measure of real-world executive behavior. In addition, we investigated the neuroanatomical correlates of the Executive Composite using voxel-based morphometry in a sample of 37 participants diagnosed with dementia, mild cognitive impairment, or as neurologically healthy. The Executive Composite accounted for 28% of the variance in Frontal Systems Behavior Scale scores beyond age. Even after including two widely used executive function tests (Trails B and Stroop) as covariates, the Executive Composite remained a significant predictor of real-world behavior. Anatomically, poorer scores on the Executive Composite were associated with smaller right and left dorsolateral prefrontal volumes, brain regions critical for good executive control. Taken together, these results suggest that the Executive Composite measures important aspects of executive function not captured by standard measures and reflects the integrity of frontal systems.

How I treat CNS lymphomas.

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

Interrater reliability of the new criteria for behavioral variant frontotemporal dementia.

OBJECTIVE: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. RESULTS: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy. CONCLUSIONS: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology.

The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.

Possible lingering effects of multiple past concussions.

Background. The literature on lingering or "cumulative" effects of multiple concussions is mixed. The purpose of this study was to examine whether athletes with a history of three or more concussions perform more poorly on neuropsychological testing or report more subjective symptoms during a baseline, preseason evaluation. Hypothesis. Athletes reporting three or more past concussions would perform more poorly on preseason neurocognitive testing. Study Design. Case-control study. Methods. An archival database including 786 male athletes who underwent preseason testing with a computerized battery (ImPACT) was used to select the participants. Twenty-six athletes, between the ages of 17 and 22 with a history of three or more concussions, were identified. Athletes with no history of concussion were matched, in a case-control fashion, on age, education, self-reported ADHD, school, sport, and, when possible, playing position and self-reported academic problems. Results. The two groups were compared on the four neuropsychological composite scores from ImPACT using multivariate analysis of variance followed by univariate ANOVAs. MANOVA revealed no overall significant effect. Exploratory ANOVAs were conducted using Verbal Memory, Visual Memory, Reaction Time, Processing Speed, and Postconcussion Scale composite scores as dependent variables. There was a significant effect for only the Verbal Memory composite. Conclusions. Although inconclusive, the results suggest that some athletes with multiple concussions could have lingering memory deficits.

Genetic causes of frontotemporal degeneration.

The purpose of this review is to provide a comprehensive update on the genetic causes of frontotemporal lobar degeneration (FTLD). Approximately 40% to 50% of patients diagnosed with FTLD have a family history of a ''related disorder,'' whereas 10% to 40% have an autosomal dominant family history for the disease. At this time, mutations occurring in 2 independent genes located on the same chromosome (MAPT and GRN) have been shown to cause the majority of cases of autosomal dominant FTLD. Specific genetic, molecular, pathological, and phenotypic variations associated with each of these gene mutations are discussed, as well as markers that may help differentiate the 2. In addition, 3 relatively rare, additional genes known to cause familial FTLD are examined in brief. Lastly, genetic counseling issues which may be important to the community clinician are discussed.

Clinical presentation of prodromal frontotemporal dementia.

BACKGROUND: Misrecognition of symptoms in the early stages of frontotemporal dementia (FTD) frequently contributes to diagnostic delay. Three frameworks have been proposed for the clinical identification of prodromal FTD: (1) cognitive profiling, (2) the presence of behavioral/psychiatric symptoms in the absence of memory complaints, and (3) a combined approach of cognitive, behavioral, and neuroimaging features. OBJECTIVE: To evaluate current conceptual frameworks for the clinical recognition of prodromal FTD with current empirical evidence. METHOD: We performed a comprehensive PsychINFO and MEDLINE database search to identify articles investigating the prodromal symptoms of FTD. CONCLUSIONS: The 3 frameworks capture important aspects of the clinical picture of prodromal FTD but require further refinement. The prodromal stage of FTD is characterized by both cognitive and behavioral features. Diagnostic accuracy will likely be improved by considering a combination of cognitive and behavioral features, because some features overlap with prodromes for Alzheimer's disease and vascular dementia.

Putting informed and shared decision making into practice.

OBJECTIVE: To investigate the practice, experiences and views of motivated and trained family physicians as they attempt to implement informed and shared decision making (ISDM) in routine practice and to identify and understand the barriers they encounter. BACKGROUND: Patient involvement in decision making about their health care has been the focus of much academic activity. Although significant conceptual and experimental work has been done, ISDM rarely occurs. Physician attitudes and lack of training are identified barriers. DESIGN: Qualitative analysis of transcripts of consultations and key informant group interviews. SETTINGS AND PARTICIPANTS: Six family physicians received training in the ISDM competencies. Audiotapes of office consultations were made before and after training. Transcripts of consultations were examined to identify behavioural markers associated with each competency and the range of expression of the competencies. The physicians attended group interviews at the end of the study to explore experiences of ISDM. RESULTS: The physicians liked the ISDM model and thought that they should put it into practice. Evidence from transcripts indicated they were able to elicit concerns, ideas and expectations (although not about management) and agree an action plan. They did not elicit preferences for role or information. They sometimes offered choices. They had difficulty achieving full expression of any of the competencies and integrating ISDM into their script for the medical interview. The study also identified a variety of competency-specific barriers. CONCLUSION: A major barrier to the practice of ISDM by motivated physicians appears to be the need to change well-established patterns of communication with patients.