Apathy in frontotemporal dementia: behavioral and neuroimaging correlates.

We investigated the occurrence of goal-directed motivational change in the form of apathy in patients with frontotemporal dementia (FTD), particularly those with behavioral variant social and executive deficits (bvFTD). Standardized behavioral inventory was employed to survey and compare apathy ratings from patients and caregivers. In cases of bvFTD, apathy ratings were further related to measures of social cognition, executive function, and atrophy on brain MRI. Results indicated that caregivers rated bvFTD patients as having significantly elevated apathy scores though patient self-ratings were normal. Caregiver and self-ratings of FTD samples with progressive nonfluent aphasia and semantic dementia did not differ from healthy controls and their informants. In the bvFTD sample, caregiver apathy scores were not correlated with general cognitive screening or depression scores, but were significantly correlated with social cognition and executive function measures. Voxel-based morphometry revealed that apathy ratings in bvFTD were related to prominent atrophy in the right caudate (including the ventral striatum), the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum- anterior insula region. Findings suggest that bvFTD is associated with a significant breakdown in goal-directed motivated behavior involving disruption of cortical-basal ganglia circuits that is also related to social and executive function deficits.

Sentence processing in Lewy body spectrum disorder: the role of working memory.

Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson's disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferior prefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.

Difficulty processing temporary syntactic ambiguities in Lewy body spectrum disorder.

While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb's statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.

The Philadelphia Brief Assessment of Cognition (PBAC): a validated screening measure for dementia.

The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer's disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.

Social cognition, executive functioning, and neuroimaging correlates of empathic deficits in frontotemporal dementia.

The authors investigated aspects of interpersonal sensitivity and perspective-taking in relation to empathy, social cognitions, and executive functioning in 26 frontotemporal dementia (FTD) patients. Behavioral-variant FTD (bvFTD) patients were significantly impaired on caregiver assessments of empathy, although self-ratings were normal. Progressive nonfluent aphasia and semantic-dementia samples were rarely abnormal. In bvFTD, empathy ratings were found to be correlated with social cognition and executive functioning measures, but not depression. Voxel-based morphometry revealed that reduced empathic perspective-taking was related to bifrontal and left anterior temporal atrophy, whereas empathic emotions were related to right medial frontal atrophy. Findings suggest that bvFTD causes multiple types of breakdown in empathy, social cognition, and executive resources, mediated by frontal and temporal disease.

Impaired information integration contributes to communication difficulty in corticobasal syndrome.

OBJECTIVE: To investigate the cognitive and neural correlates of discourse impairment in corticobasal syndrome (CBS). BACKGROUND: Difficulty communicating is a frequent clinical manifestation in patients with CBS. However, the mechanisms underlying this disabling problem are not well understood. METHODS: Twenty patients with CBS and 8 healthy seniors narrated a picture story. Narratives were analyzed for maintenance of the narrative theme, identification of the overall point of the story (global connectedness), and connectedness between consecutive events (local connectedness). Discourse measures were correlated with performance on cognitive tasks and with cortical atrophy as determined by magnetic resonance imaging voxel-based morphometry. RESULTS: Patients with CBS referred to the narrative theme significantly less frequently than controls. Global connectedness was intact in only 6 of 20 CBS patients (30%), but preserved in all controls. Local connectedness was significantly diminished in patients relative to controls. Discourse performance in CBS was related to tasks requiring higher-order integration of visual material, but not to basic visuospatial/visuoperceptual, language, or memory function. Discourse impairment was directly related to atrophy in the right parietal lobe and bilateral dorsolateral prefrontal cortex. CONCLUSIONS: Our findings suggest that impaired information integration in CBS, related to parieto-frontal disease, interferes with patients' ability to narrate a coherent story.

Speech errors in progressive non-fluent aphasia.

The nature and frequency of speech production errors in neurodegenerative disease have not previously been precisely quantified. In the present study, 16 patients with a progressive form of non-fluent aphasia (PNFA) were asked to tell a story from a wordless children's picture book. Errors in production were classified as either phonemic, involving language-based deformations that nevertheless result in possible sequences of English speech segments; or phonetic, involving a motor planning deficit and resulting in non-English speech segments. The distribution of cortical atrophy as revealed by structural MRI scans was examined quantitatively in a subset of PNFA patients (N=7). The few errors made by healthy seniors were only phonemic in type. PNFA patients made more than four times as many errors as controls. This included both phonemic and phonetic errors, with a preponderance of errors (82%) classified as phonemic. The majority of phonemic errors were substitutions that shared most distinctive features with the target phoneme. The systematic nature of these substitutions is not consistent with a motor planning deficit. Cortical atrophy was found in prefrontal regions bilaterally and peri-Sylvian regions of the left hemisphere. We conclude that the speech errors produced by PNFA patients are mainly errors at the phonemic level of language processing and are not caused by a motor planning impairment.

Quantitative proton magnetic resonance spectroscopy detects abnormalities in dorsolateral prefrontal cortex and motor cortex of patients with frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease of the frontal and temporal neocortex. The single most common pathology underlying FTLD is neuronal degeneration with ubiquitin-positive but tau-negative inclusions consisting of Tar DNA binding proteins (TDP-43). Inclusions containing TDP-43 in neurons are also the most common pathology underlying motor neuron disease (MND). The present study tested the hypothesis that abnormal metabolite patterns within the dorsolateral prefrontal cortex (DLPFC) as well as the motor cortex (MC) may be observed in FTLD patients without motor disorders, using proton magnetic resonance spectroscopy ((1)H MRS). Twenty-six FTLD patients with cognitive damage and ten controls underwent multivoxel (1)H MRS. Absolute concentrations of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) were measured from the DLPFC, the MC and the parietal cortex (PC, an internal control). Statistical analyses were performed for group differences between FTLD patients and controls. Comparisons were also made across brain regions (PC and DLPFC; PC and MC) within FTLD patients. Significant reductions in NAA and Cr along with increased Cho and mI were observed in the DLPFC of FTLD patients compared to controls. Significantly lower NAA and higher Cho were also observed in the MCs of patients as compared to controls. Within the FTLD patients, both the MC and the DLPFC exhibited significantly decreased NAA and elevated Cho compared to the PC. However, only the DLPFC had significantly lower Cr and higher mI. Abnormal metabolite pattern from the MC supports the hypothesis that FTLD and MND may be closely linked.

Longitudinal patterns of semantic and episodic memory in frontotemporal lobar degeneration and Alzheimer's disease.

The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer's disease (AD, n = 128) and with frontotemporal lobar degeneration (FTLD, n = 108), including patients with a social comportment/dysexecutive (SOC/EXEC) disorder, progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.

Neuropsychological patterns in magnetic resonance imaging-defined subgroups of patients with degenerative dementia.

We hypothesized that specific neuropsychological deficits were associated with specific patterns of atrophy. A magnetic resonance imaging volumetric study and a neuropsychological protocol were obtained for patients with several frontotemporal lobar dementia phenotypes including a social/dysexecutive (SOC/EXEC, n = 17), progressive nonfluent aphasia (n = 9), semantic dementia (n = 7), corticobasal syndrome (n = 9), and Alzheimer's disease (n = 21). Blinded to testing results, patients were partitioned according to pattern of predominant cortical atrophy; our partitioning algorithm had been derived using seriation, a hierarchical classification technique. Neuropsychological test scores were regressed versus these atrophy patterns as fixed effects using the covariate total atrophy as marker for disease severity. The results showed the model accounted for substantial variance. Furthermore, the "large-scale networks" associated with each neuropsychological test conformed well to the known literature. For example, bilateral prefrontal cortical atrophy was exclusively associated with SOC/EXEC dysfunction. The neuropsychological principle of "double dissociation" was supported not just by such active associations but also by the "silence" of locations not previously implicated by the literature. We conclude that classifying patients with degenerative dementia by specific pattern of cortical atrophy has the potential to predict individual patterns of cognitive deficits.

Neuropsychological decline in frontotemporal lobar degeneration: a longitudinal analysis.

Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer's disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in 'animal' fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.

Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration.

OBJECTIVE: To investigate the neural basis for the behavioral symptoms of frontotemporal lobar degeneration (FTLD) that cause the greatest caregiver distress. BACKGROUND: FTLD is a progressive neurodegenerative disease associated with behavioral disturbances. Group studies have related these behaviors to volume loss on MRI. METHODS: Forty caregivers of patients with the clinical diagnosis of FTLD completed the Neuropsychiatric Inventory. Twelve neuropsychiatric symptoms and the associated caregiver distress were assessed. Optimized voxel-based morphometry identified significant atrophy in subgroups of FTLD patients with isolated behavioral symptoms corresponding to the most distressing behaviors, and we correlated cortical atrophy directly with these distressing behavioral disorders in an unbiased group analysis. RESULTS: The greatest stressors for caregivers were apathy and disinhibition (p < 0.005 for both contrasts). Partially distinct areas of cortical atrophy were associated with these behaviors in both individual patients with these symptoms and group-wide analyses, including the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex in apathetic patients, and the medial orbital frontal cortex in disinhibited patients. CONCLUSIONS: Caregiver stress in families of FTLD patients is due in large part to apathy and disinhibition. The anatomic distribution of cortical loss corresponding to these distressing social behaviors includes partially distinct areas within the frontal lobe.

Non-Fluent Speech in Frontotemporal Lobar Degeneration.

We investigated the cognitive and neural bases of impaired speech fluency, a central feature of primary progressive aphasia. Speech fluency was assessed in 35 patients with frontotemporal lobar degeneration (FTLD) who presented with progressive non-fluent aphasia (PNFA, n=11), semantic dementia (SemD, n=12), or a social and executive disorder without aphasia (SOC/EXEC, n=12). Fluency was quantified as the number of words per minute in an extended, semi-structured speech sample. This was related to language characteristics of the speech sample and to neuropsychological measures. PNFA patients were significantly less fluent than controls and other FTLD patients. Fluency correlated with grammatical expression but not with speech errors or executive difficulty. SemD and SOC/EXEC patients were also less fluent than controls. In SemD, fluency was associated with semantically limited content. In SOC/EXEC, fluency was associated with executive limitations. Voxel-based morphometry analyses of high-resolution MRI related fluency to gray matter volume in left inferior frontal, insula, and superior temporal regions for the entire cohort of FTLD patients. This region overlapped partially distinct atrophic areas in each FTLD subgroup. It thus appears to play a crucial role in speech fluency, which can be interrupted in different ways in different FTLD subgroups.

Medial temporal lobe involvement in an implicit memory task: evidence of collaborating implicit and explicit memory systems from FMRI and Alzheimer's disease.

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.

Sentence comprehension and voxel-based morphometry in progressive nonfluent aphasia, semantic dementia, and nonaphasic frontotemporal dementia.

To investigate the basis for impaired sentence comprehension in patients with frontotemporal dementia (FTD) we assessed grammatical comprehension and verbal working memory in 88 patients with three distinct presentations: progressive nonfluent aphasia (PNFA), semantic dementia (SD), and nonaphasic patients with a disorder of social comportment and executive processing (SOC/EXEC). We related sentence comprehension and working memory performance to regional cortical volume in a subgroup of 29 patients with structural MRI scans using voxel-based morphometry. PNFA patients exhibited the greatest difficulty with sentence comprehension and were especially impaired with grammatically complex sentences, which correlated with atrophy in left inferior frontal cortex. Working memory performance in these same patients correlated with a proximal but distinct left inferior frontal region. SD patients' sentence comprehension scores correlated with left inferolateral temporal lobe damage, which we hypothesize and reflect impairments in lexical processing. We did not observe any consistent relationship between cortical atrophy and sentence comprehension impairment in SOC/EXEC patients, suggesting the deficits in this subgroup may be due to more variable declines in executive resources.

Distinct antemortem profiles in patients with pathologically defined frontotemporal dementia.

BACKGROUND: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases. OBJECTIVE: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease. DESIGN: Retrospective clinical-pathologic survey. SETTING: Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease. MAIN OUTCOME MEASURES: Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI). RESULTS: Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy. CONCLUSION: Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.

Screening for frontotemporal dementias and Alzheimer's disease with the Philadelphia Brief Assessment of Cognition: a preliminary analysis.

BACKGROUND: A neuropsychological screening instrument sensitive to neuropsychological deficits associated with Alzheimer's disease (AD) and patients with frontotemporal dementia (FTD) would be valuable for diagnostic evaluation. METHODS: The Philadelphia Brief Assessment of Cognition (PBAC) assesses working memory/executive control, language, visuospatial operations, verbal/visual episodic memory, and behavior/social comportment and can be administered and scored in 15-20 min. Participants included 149 patients with AD and four groups of FTD patients - i.e., patients with a decline in social comportment, personality, and executive functioning (SOC/EXEC), semantic dementia (SemD), progressive nonfluent aphasia (PNFA), and corticobasal syndrome (CBS). RESULTS: The total PBAC score correlated with the Mini-Mental State Examination. Between-group analysis of PBAC subscales and the results of logistic regression analyses produced substantial between-group differences, emphasizing the sensitivity of the test to differentiate dementia subtypes. AD patients were impaired on tests of episodic memory, SOC/EXEC patients were impaired on a measure of social comportment/behavioral disturbance, PNFA patients obtained low scores on tests of working memory/executive control, SemD patients obtained lower scores on language-mediated measures, and CBS patients were impaired on visuospatial/visual memory tests. CONCLUSION: These data support the usefulness of the PBAC as a relatively brief screening test of overall dementia severity across a wide range of dementia patients.

TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions.

BACKGROUND: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). OBJECTIVE: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. Patients Twenty-three patients with histopathologically proven FTLD-U. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits. CONCLUSION: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.

Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.

BACKGROUND: Patients with frontotemporal dementia due to mutation of progranulin may have a distinct phenotype. OBJECTIVE: To identify distinct clinical and pathologic features of patients with frontotemporal dementia who have mutations of progranulin (GRN). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. PATIENTS: Twenty-eight patients with frontotemporal dementia, including 9 with GRN mutations (4 autopsy cases and 5 with only clinical information) and 19 with the identical pathologic diagnosis--frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (FTLD-U)--and no GRN mutations. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: Patients with and without a GRN mutation have similar demographic features, although family history is significantly more common in patients with frontotemporal dementia and a GRN mutation. Both patient groups have frequent social and personality complaints. Neuropsychological evaluation reveals a significant recognition memory deficit in patients with a GRN mutation but a significant language deficit only in patients without a GRN mutation. At autopsy, the semiquantitative burden of ubiquitin abnormality is relatively modest in both groups of patients. CONCLUSION: Patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation.