Background

Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients' behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable.

Methods

To examine the accuracy of community clinicians' diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted.

Results

60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer's, Parkinson's or Huntington's disease, or progressive aphasia.

Conclusion

These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD.

Objective

To describe psychiatric presentations in individuals with genetic mutations causing frontotemporal dementia (FTD).

Design

Case descriptions from five carriers of FTD-related gene mutations with symptoms associated with non-neurodegenerative psychiatric disease.

Setting

A comprehensive research program investigating genetic and non-genetic FTD at the University of California, San Francisco Memory and Aging Center.

Participants

Three proband and two non-proband gene carriers.

Measurements

Medical history and neurological examination, neuropsychological testing, magnetic resonance and/or positron emission tomography imaging, and a genetic analysis to screen for dementia-related mutations. Genetic status was unknown at the time of initial evaluation.

Results

The chosen cases are illustrative of the variety of presentations of psychiatric symptoms in FTD gene carriers. In some cases, a non-neurodegenerative psychiatric illness was diagnosed based on specific symptoms, but the diagnosis may have been inappropriate based on the overall syndrome. In other cases, symptoms closely resembling those seen in non-neurodegenerative psychiatric illness did occur, in some cases immediately preceding the development of dementia, and in other cases developing a decade prior to dementia symptoms.

Conclusions

Psychiatric symptoms in FTD gene carriers can be very similar to those seen in non-neurodegenerative psychiatric illness. Psychiatric symptoms with atypical features (e.g., late-life onset, insidiously worsening course) should prompt careful assessment for neurodegenerative disease. Guidelines for such an assessment should be established.

In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this "speech production network" is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain-behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior-dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases.

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

Importance

Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians' ability to predict disease course and to design targeted management strategies.

Objective

To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches.

Design, setting and participants

In this retrospective observational study, 90 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD underwent evaluation at the Memory and Aging Center of the Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurologic examination, neuropsychological bedside testing, and socioemotional assessments. All patients underwent structural magnetic resonance imaging at their earliest evaluation at the memory clinic. From each patient's structural imaging scans, the mean volumes of 18 regions of interest (ROI) constituting the functional networks specifically vulnerable in bvFTD, including the salience network (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the semantic appraisal network (SAN), anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Data were collected from from June 19, 2002, to January 13, 2015.

Main outcomes and measures

Evaluation of brain morphology and other clinical features, including presenting symptoms, neurologic examination signs, neuropsychological performance, rate of dementia progression, and socioemotional function, in each patient cluster.

Results

Ninety patients (54 men [60%]; 36 women [40%]; mean [SD] age at evaluation, 55.1 [9.7] years) were included in the analysis. Four subgroups of patients with bvFTD with distinct anatomic patterns of network degeneration were identified, including 2 salience network-predominant subgroups (frontal/temporal [SN-FT] and frontal [SN-F]), a semantic appraisal network-predominant group (SAN), and a subcortical-predominant group. Subgroups demonstrated distinct patterns of cognitive, socioemotional, and motor symptoms, as well as genetic compositions and estimated rates of disease progression.

Conclusions and relevance

Divergent patterns of vulnerability in specific functional network components make an important contribution to the clinical heterogeneity of bvFTD. The data-driven anatomic classification identifies biologically meaningful anatomic phenotypes and provides a replicable approach to disambiguate the bvFTD syndrome.