Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer's disease

OBJECTIVE/BACKGROUND: To determine whether difficulty in the early differentiation between frontotemporal dementia (FTD) and AD may arise from a failure to discriminate between the temporal and frontal variants of FTD. METHODS: Neuropsychological profiles of patients with early dementia of Alzheimer type (DAT; n = 10), the temporal variant of FTD (tv-FTD or semantic dementia; n = 5), and the frontal variant of FTD (fv-FTD; n = 10) were compared to each other and normal controls (n = 10). Structural MRI demonstrated temporal lobe atrophy in the tv-FTD patients and frontal lobe atrophy in the fv-FTD group. RESULTS: Subjects with tv-FTD showed severe deficits in semantic memory with preservation of attention and executive function. Subjects with fv-FTD showed the reverse pattern. Attention and executive function impairment separated the fv-FTD patients from the early DAT subjects, who were densely amnesic. CONCLUSION: The double dissociation in performance on semantic memory and attention/executive function clearly separated the temporal and frontal variants of FTD and aids the early differentiation of FTD from AD. The characteristic cognitive profiles reflect the distribution of pathology within each syndrome and support the putative role of the inferolateral temporal neocortex in semantic memory, the medial temporal lobe structures of the hippocampal complex in episodic memory, and the frontal lobes in executive function.     

Dissociation of social cognition and executive function in frontal variant frontotemporal dementia

In this paper, we adopt a neurodevelopmental stance to examining frontal variant frontotemporal dementia (fv-FTD) by using experimental procedures from the literature on the growth of social behaviour in children to examine the deficits in social reasoning which may underpin behavioural disturbance in fv-FTD. We present the case of a 47-year-old man with a diagnosis of fv-FTD and severe antisocial behaviour. Tests of general neuropsychology and of executive function were performed. In addition, the patient, JM, was assessed on tasks which test theory of mind. Theory of mind develops in distinct stages through childhood and is a core ability to represent the thoughts and feelings of others, independent of the level of intellectual ability. The results indicate relatively intact general neuropsychological and executive function, but extremely poor performance on tasks of theory of mind. This indicates a dissociation of social cognition and executive function suggesting that in psychiatric presentations of fv-FTD there may be a fundamental deficit in theory of mind independent of the level of executive function. The implications of this finding for diagnostic procedures and possible behavioural management are discussed.     

The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia

Verbal fluency tasks are commonly used to explore semantic memory and executive functions. The aim of this study was to gain a better understanding of the cognitive and neural mechanisms underlying verbal fluency impairment in the frontal variant of frontotemporal dementia (fv-FTD) and in semantic dementia (SD). Semantic and phonemic fluency tasks were performed by 36 fv-FTD and SD patients and 18 elderly controls. We also carried out a neuropsychological investigation of semantic memory, working memory and shifting and updating processes. We performed correlative and regression analyses of fluency scores and neuropsychological data. In addition, patients underwent a resting positron emission tomography examination, and statistical parametric mapping was used to establish correlations between resting-state FDG uptake in the whole brain and fluency scores for each patient group. Both patient groups displayed impaired performances on both fluency tasks compared with controls, but with different patterns. While fv-FTD patients scored higher than SD patients on semantic fluency, their performances on the phonemic task did not differ. Correlation and regression analyses clearly demonstrated that the fv-FTD patients’ performances on both fluency tasks depended on their executive abilities, while those of the SD patients were hampered by the impairment of their semantic memory store. Correlations with resting FDG uptake were consistent with the results of the cognitive study. In fv-FTD, both fluency performances were related to the metabolism of the frontal lobes, while we observed significant correlations between performances on both fluency tasks and the left temporal lobe metabolism in SD.     

In search of autobiographical memories: A PET study in the frontal variant of frontotemporal dementia

Patients suffering from frontal variant of frontotemporal dementia (fv-FTD) undergo autobiographical amnesia encompassing all time periods. We previously demonstrated in a group of 20 fv-FTD patients that this impairment involved deficits in executive function and semantic memory for all periods as well as new episodic learning and behavioural changes for the most recent period covering the last 12 months [Matuszewski, V., Piolino, P., de la Sayette, V., Lalevée, C., Pélerin, A., Dupuy, B., et al. (2006). Retrieval mechanisms for autobiographical memories: Insights from the frontal variant of frontotemporal dementia, Neuropsychologia, 44, 2386-2397]. The aim of the present study was to unravel the neural bases of this impairment by mapping in a subgroup of patients correlations between resting-state brain glucose utilization measured by FDG-PET and measures of autobiographical memory (AM) using the TEMPau task which is designed to gauge personal event recollection across five life time periods. Like in our previous report, the group of patients was impaired regardless of time periods compared to healthy subjects providing generic memories instead of event specific sensory-perceptual-affective details, i.e., episodic memories. New data showed that the patients were also impaired in sense of reliving and self-perspective during retrieval. The cognitivo-metabolic correlations between the AM score and resting normalized FDG-Uptake were computed using statistical parametric mapping (SPM2) and controlling for age and dementia severity. They revealed that AM deficits were mainly subserved by the dysfunction of left-sided orbitofrontal and also temporal neocortical areas whatever the period. Additional analysis showed that specific memories were associated with left orbitofrontal areas whereas generic memories were mainly associated with the left temporal pole. This study supports the view that fv-FTD patients undergo a breakdown of generative processes which relies regardless of the remoteness on the left orbitofrontal cortex and temporal neocortex to gain access to AM.     

Effects of white matter lesions and lacunes on cortical function

BACKGROUND: Subcortical ischemic vascular dementia has been ascribed to prominent frontal lobe dysfunction secondary to ischemic lesions in frontothalamic circuits.Whether small-vessel disease in fact predominantly affects the frontal lobes is not well documented. OBJECTIVE: To investigate the effects of subcortical lesions (lacunes and white matter lesions [WML]) on cortical function, as reflected in glucose metabolism and cognitive function, in elderly individuals. DESIGN: Cross-sectional analyses of case series. SETTING: Multicenter, university-based study of subcortical vascular dementia. PATIENTS: Persons with normal cognition, mild cognitive impairment, or dementia and with and without lacunes on magnetic resonance images. MAIN OUTCOME MEASURES: Regional cerebral glucose metabolism, normalized regional metabolic activity, and neuropsychological test scores. Major hypotheses were that volume of lacunes and WML correlate selectively with hypometabolism of prefrontal cortex and failure of executive cognitive ability. RESULTS: Lacunes correlated with metabolic rates in dorsolateral frontal cortex (DLF); WML substantially reduced metabolic rates throughout cortex, most strongly so in DLF. When regional metabolic activity was normalized to whole brain activity, lacunes remained correlated with DLF activity, whereas the WML effect was no longer found, probably because of its general distribution. Regional cerebral glucose metabolism and normalized activity in DLF also correlated with cortical atrophy. Metabolic activity in DLF correlated with executive function, memory, and global cognitive function, while activity in middle temporal gyrus correlated with memory and global function but not executive function. CONCLUSIONS: The metabolic effects of lacunes and WML are most apparent in DLF, but the effects of WML are generalized and frontal hypometabolism correlates with memory and global impairment, cognitive as well as executive function. The effects of subcortical cerebrovascular disease appear to converge on the frontal lobes but are diffuse, complex, and of modest magnitude.     

Measuring and modifying abnormal social cognition in frontal variant frontotemporal dementia

We describe a 57-year-old man (MW) with frontal variant frontotemporal dementia (fv-FTD) who presented with a long history of drinking problem and marital disharmony followed by gradual changes in personality with disinhibition, stereotypic checking, overeating and a decline in self-care. Structural MRI imaging confirmed marked frontal atrophy involving particularly the ventromedial region. Performance on standard tests of frontal executive function was largely unremarkable and MW obtained a perfect score on the Mini-Mental State Examination (MMSE). In contrast, an experimental battery of tasks designed to evaluate theory of mind (ToM) revealed marked deficits. MW's challenging and disruptive behaviours, notably obsessive checking of car suspension by rocking, and wandering, responded to behavioural modification regimes adapted from the neurorehabilitation literature. In conclusion, deficits in ToM may underline the gross abnormalities in social conduct, which characterise fv-FTD; ToM appears to dissociate from frontal executive function; and behavioural modification approaches can be of benefit in this disorder.     

Reliability and validity of the Japanese version of the Frontal Assessment Battery in patients with the frontal variant of frontotemporal dementia

Patients with the frontal variant of frontotemporal dementia (fv-FTD) exhibit deficits of executive functions. However, no single executive function task that might be used to detect the executive function deficits in fv-FTD patients has been established as yet. The frontal assessment battery (FAB) devised by Dubois et al. (2000) has been reported to be a quick and simple bedside screening test that is sensitive for differentiating between FTD and Alzheimer's disease (AD). The present study was conducted with the aim of ascertaining the reliability and validity of the Japanese version of the FAB among Japanese patients with fv-FTD. The Japanese version of FAB was given to patients with mild fv-FTD (n = 18) and those with AD (n = 18). The test-retest reliability was evaluated after a 3-week interval by the same interviewer. Data from the Wisconsin Card Sorting Test (Keio version: KWCST) were also collected to ascertain the validity of the FAB. The Japanese version of the FAB exhibited good internal reliability (Cronbach's alpha: 0.70, 95% confidence interval [CI] = 0.50-0.84) and good test-retest reliability (intraclass correlation coefficient: 0.89, 95%CI = 0.77-0.95). Significant correlations were observed between the total FAB score and the category achieved (r = 0.454, P < 0.05) and number of perseveration errors (number of errors that were perseverations; r = 0.719, P < 0.01) in the KWCST. A cut-off of 10 for the total FAB score yielded the highest sensitivity (85%) and specificity (92%) for discriminating between patients with fv-FTD and AD with the highest positive likelihood (12.0, 95%CI = 2.6-55.4). The Japanese version of the FAB offers promise as an easy and quick bedside screening test to distinguish fv-FTD from AD.     

Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, -24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, -22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD.     

Dissociation of decisions in ambiguous and risky situations in obsessive–compulsive disorder

Patients with obsessive–compulsive disorder (OCD) often show deficits in everyday decision-making, a phenomenon which is leading to a growing research interest in neuropsychological aspects of decision-making in OCD. Previous investigations of OCD patients demonstrated deficits in the Iowa Gambling Task (IGT), a decision-making task with implicit rules. Results were interpreted as reflecting orbitofrontal cortex dysfunctions observed in OCD. The aim of the present study is to investigate OCD patients' performance on the Game of Dice Task (GDT), a decision-making task with explicit and stable rules. For this purpose, 23 patients with OCD and 22 healthy comparison subjects were examined with the GDT and the IGT as well as with tests of executive functioning. While patients performed worse than comparison subjects on the IGT, they were unimpaired on the GDT and executive functioning tasks. Results further emphasize dysfunctions of the orbitofrontal cortex, but indicate intact functioning of the dorsolateral prefrontal cortex in patients with OCD.     

Do visuospatial and constructional disturbances differentiate frontal variant of frontotemporal dementia and Alzheimer's disease? An experimental study of a clinical belief

BACKGROUND: In recent years several attempts have been made to distinguish frontotemporal dementia (FTD) from Alzheimer's disease (AD) on neuropsychological grounds; in particular, it has been suggested that FTD patients show spared spatial abilities with respect to AD patients. OBJECTIVE: We aimed at verifying whether patients with the frontal variant of frontotemporal dementia (fv-FTD) and AD patients perform differently on visuospatial and constructional tasks. METHODS: We assessed a wide range of visuospatial abilities and provided a qualitative analysis of constructional performances in 14 fv-FTD patients and 11 AD patients, matched for general cognitive abilities. RESULTS: The two groups of patients achieved similar scores on two copying tasks, presented similar drawing procedures in copying Rey complex figure and made a similar quantitative and qualitative pattern of errors in copying simple geometrical drawings. Moreover, no significant difference was found between fv-FTD and AD patients on a specific battery for visuospatial abilities. CONCLUSIONS: Our data and a review of the literature suggest that basic visuospatial and constructional skills cannot be taken as a reliable diagnostic criterion for distinguishing fv-FTD and AD at a mild to moderate disease stage and that the clinical belief of spared spatial abilities in fv-FTD has to be referred to the lack of topographic disorientation in comparison to AD.     

Perfusion abnormalities and decision making in cocaine dependence.

BACKGROUND: Previous studies have shown that cocaine abusers have cerebral perfusion deficits that may diminish cognitive functioning. This study examined whether cocaine-dependent patients have perfusion abnormalities associated with poor decision-making ability as measured by the Iowa Gambling Task (IGT). METHODS: Seventeen abstinent cocaine-dependent patients were administered the IGT after completion of resting 99mTc-HMPAO single-photon emission computed tomography (SPECT). RESULTS: Better IGT performance was negatively correlated with perfusion within the anterior cingulate gyrus, middle frontal gyrus, medial frontal gyrus, and superior frontal gyrus. The time to complete card selections was positively correlated with the severity of impairment. CONCLUSIONS: Resting hyperperfusion in brain regions previously implicated in decision making and response inhibition was associated with worse IGT scores. Impaired performance was related to a greater amount of time taken for card selections, suggesting that reduced ability was due to cognitive factors other than an impulsive response pattern.     

Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study

We describe three sibling patients with autosomal dominantly inherited sensory neuropathy, sensorineural hearing loss and dementia. The features of cognitive-behavioral deficits in the patients, including executive dysfunction, apathy, indifference and inattention, were consistent with a frontal lobe dysfunction. Magnetic resonance imaging showed a diffuse brain atrophy. A fluorodeoxyglucose positron emission tomography in one patient and a single photon emission computed tomography in another demonstrated a glucose hypometabolism or a hypoperfusion in the medial frontal and thalamic regions. Primary frontal involvement or frontal dysfunction secondary to thalamic lesions may contribute to the nature of dementia in these patients.     

Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer’s disease

Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer’s disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.     

Frontal Behavioural Inventory in the differential diagnosis of dementia

Objective –  To evaluate diagnostic properties of the Frontal Behavioural Inventory (FBI) in patients suffering from different forms of dementia.
Methods –  The FBI was administered with other psychometric tests investigating cognitive performances and behavioral scales to the caregivers of 35 patients with the frontal variant of frontotemporal dementia (fv-FTD), 22 patients with Alzheimer's disease (AD) and 15 with vascular dementia (VaD). All patients were comparable for degree of dementia severity and level of executive impairment.
Results –  The FBI showed high concurrent validity, internal consistency and good inter-rater and test–retest reliability. The discriminant validity was also very high. A new FBI cut-off score of 23 gave 97% sensitivity and 95% specificity in distinguishing fv-FTD from non-FTD patients. Conversely, the Neuropsychiatic Inventory (NPI) score was unable to differentiate fv-FTD from AD.
Conclusions –  The FBI is a neurobehavioral tool suitable to distinguish fv-FTD from other forms of dementia also when data from cognitive testing or other behavioral scales fail to support the differential diagnosis.     

Discrepancy between social and nonsocial decision-making under uncertainty following prefrontal lobe damage: the impact of an interactionist approach

Deficits in decision-making are thought to contribute significantly to socio-behavioral impairments of patients with frontal lobe damage. The purpose of this study was to test the hypothesis of whether the inappropriate social behavior of patients with frontal lesions can be viewed as the product of a general failure of decision-making ability or as the result of socio-cognitive impairment. We studied a group of patients with prefrontal lesions (FL patients, n = 15) and a group of matched healthy controls (n = 30) on the Iowa Gambling task (IGT) of nonsocial decision-making, environmental dependency phenomena (EDP) during social interaction, and the “reading the mind in the eyes” and “character intention task” of theory of mind (TOM) tasks. The FL patients were impaired in both TOM and EDP protocols but, surprisingly, they behaved appropriately in the IGT. In addition, FL patients with EDP did not differ in executive functioning, IGT and TOM measures from those who did not demonstrate these behavioral disorders. The right orbitofrontal cortex was associated with social decision-making deficits. By adopting an interactionist approach, this study raises the possibility of identifying components of social and nonsocial decision-making, which could be helpful in understanding the behavioral disorders of FL patients.     

Decisions under ambiguity and decisions under risk: correlations with executive functions and comparisons of two different gambling tasks with implicit and explicit rules

We conducted two experiments with healthy subjects to investigate the possible relationships between Iowa Gambling Task (IGT) performance and executive functions as well as IGT performance and decision-making in a task with explicit rules, the Game of Dice Task (GDT). Results indicated that only the last trials of the IGT were correlated with executive functions and GDT performance. We suggest that the IGT taps into two mechanisms of decision-making: decisions under ambiguity in the first trials and decisions under risk in the latter trials. Results have impact on the interpretation of deficient IGT performance in patients with frontal lobe dysfunctions.     

Cognition and amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsychologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life.     

Rate of cognitive change measured by neuropsychologic test performance in 3 distinct dementia syndromes

Progressive decline in cognition is a hallmark feature of dementia, and the rate and profile of cognitive decline has been well characterized in Alzheimer disease (AD). Less is known about decline in cognition over time in other forms of dementia such as the behavioral variant of frontotemporal dementia (FTD) and primary progressive aphasia (PPA). The present study examined rate of cognitive decline across domains of memory, language, and executive function measured by neuropsychologic tests, in AD (n=84), FTD (n=66), and PPA (n=44). Patients were in the mild stages of dementia, with comparable duration of illness at the baseline evaluation. A best linear unbiased predictor (BLUP) analysis was used in which the slope of the relationship between a cognitive measure and time was estimated for each person. AD subjects demonstrated a floor effect on measures of memory at baseline and a decline on measures of language and executive functioning over time. FTD showed the greatest decline over time on the Mini-Mental State Examination, executive functioning, and naming. PPA patients demonstrated prominent decline on language measures, verbal memory measures, and attention. Results suggest that the profile of rate of change over time has unique features on the basis of the type of dementia syndrome. However, there is overlap in the profiles of decline likely influenced by the overlap in cognitive constructs measured by neuropsychologic tests. The comparison of the rate of decline in FTD and PPA may also reflect the neuroanatomic overlap in these syndromes over time.     

The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia

Structural brain imaging and neuropsychological data implicate the orbital aspects of prefrontal cortex in the developing neuropathology of fvFTD. Damage to this region is associated with deficient performance on laboratory tasks assessing theory of mind (ToM) and affective decision-making (DM), but the relationship between these two capacities in patients with prefrontal cortex dysfunction is unclear. We studied a group of patients with early/mild fvFTD (n=20) and a group of matched normal controls (n=10) on the Iowa gambling task (IGT) of affective decision-making, and the "reading the mind in the eyes" (MIE) and "faux pas" (FP) tests of ToM. The fvFTD group was impaired in both ToM tasks and the IGT. While performance measures from the two ToM tasks were significantly correlated, they were not associated with IGT performance. This suggests that whilst similar prefrontal circuitry is implicated in ToM and DM tasks, these cognitive domains may be independent. In clinical settings, the IGT may be useful as a complementary tool to the frontal test battery for patients with early/mild fvFTD. Deficits in decision-making and ToM observed in this study have distinct but additive effects upon the development of social behaviour in patients with prefrontal dysfunction.     

The role of decision-making ability in HIV/AIDS: Impact on prospective memory

Background: Prospective memory (ProM), a form of episodic memory related to execution of future intentions, is important for everyday functioning. Among persons living with HIV (PLWH), executive dysfunction is implicated in ProM impairments. However, specific subcomponents of executive functioning involved in ProM deficits remain poorly understood. Unlike more “traditional” neurocognitive (NC) measures of executive functioning associated with dorsolateral prefrontal cortex (i.e., conceptual reasoning, abstraction), those associated with medial orbitofrontal/ventromedial prefrontal (mOF/vmP) cortex (i.e., decision making, inhibitory control, goal-oriented behavior) have yet to be examined in ProM. Method: This study characterized ProM ability in a sample of 89 HIV-seropositive adults and examined the unique role of decision-making ability in ProM. Participants completed a standard NC battery, the Iowa Gambling Task (IGT; a decision-making measure), and the Memory for Intentions Screening Test (MIST; a ProM measure). Results: Correlational analyses revealed that both traditional executive functioning measures and the IGT were associated with ProM. Regression analyses revealed that the IGT significantly predicted ProM, even after accounting for NC measures. Among all NC measures, only executive functioning significantly contributed to ProM. Discussion: Further examination of mOF/vmP-sensitive executive dysfunction within this population is needed as PLWH may require more tailored treatment recommendations due to specific decision-making difficulties that can impact medication management.