The prevalence of frontotemporal dementia

OBJECTIVE: To estimate the prevalence of frontotemporal dementia (FTD) and other degenerative early-onset dementias in a geographically defined population. BACKGROUND: Early-onset dementia (at age <65 years) results in high psychiatric morbidity and caregiver burden. Prevalence figures are available for early-onset AD but not for FTD, a dementia that is almost invariably of early onset. METHODS: Case ascertainment was by review of case records of three specialist clinic databases and inpatient admissions at a university hospital in Cambridge, United Kingdom, for patients with dementia who were <65 years of age, living in Cambridge City or East or South Cambridgeshire (population 326,019) on May 30, 2000. All the relevant health services in the area were also contacted for potential cases. Diagnosis of various dementias was based on published criteria. All patients with potential FTD were examined by the study investigators and underwent structural neuroimaging. The 1998 population estimates for the area were used to calculate age and sex prevalence with confidence intervals for AD, FTD, and other causes of dementia. RESULTS: A total of 108 patients (66 men and 42 women) with dementia with onset before they were 65 years of age were identified, of whom 60 were <65 years on the census date, giving an overall prevalence of 81 (95% CI, 62.8 to 104.5) per 100,000 in the 45- to 64-year age group. The prevalences of early-onset FTD and AD were the same: 15 per 100,000 (8.4 to 27.0) in the 45- to 64-year-old population. The mean age at onset of FTD was 52.8 years and there was a striking male preponderance (14:3). It is possible case ascertainment methods resulted in a relative underrepresentation of some forms of dementia. CONCLUSIONS: Frontotemporal dementia is a more common cause of early-onset dementia than previously recognized and appears to be more common in men.     

The contribution of TMS to frontotemporal dementia variants

Objective – Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions mainly characterized by personality changes and cognitive deficits in language and executive functions; movement disorders have also been associated with FTLD. The present study aimed to measure the primary motor cortex (M1) inhibitory and facilitatory functions in patients affected by FTLD. Materials and methods – The study included 17 FTLD patients, 8 age‐matched healthy controls and 8 Alzheimer’s disease (AD) patients. Transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (ICI) and facilitation (ICF) by using a double‐pulse paradigm. Results – FTLD patients were comparable with controls and AD patients for ICI and ICF. Corticobasal degeneration (CBD) patients presented significant reduced inhibition at ISI3; moreover two out of seven CBD patients had only ipsilateral responses. Discussion – The present study reveals a selective impairment of M1 ICI inhibitory response in CBD, which may help in distinguishing among the FTLD clinical spectrum.     

Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis

Abnormal balance between intracortical inhibitory and excitatory mechanisms has been found to contribute to the genesis of motor cortex hyperexcitability in amyotrophic lateral sclerosis (ALS), but data are lacking on the role of these abnormalities in the pathophysiology of the disease. We evaluated the resting motor threshold (RMT), the cortical silent period (CSP) to single-pulse transcranial magnetic stimulation (TMS), early intracortical inhibition (ICI), early intracortical facilitation (ICF) and late ICI to paired-pulse TMS in 40 patients with ALS. These parameters were correlated with disease duration and clinical features. They were also monitored over time in selected patients.The main abnormal TMS findings were: (a). reduced or even absent early and late ICI; six out of 9 patients, with normal early ICI at the first recording, developed abnormal ICI after several months; (b). reduced cortical silent period duration with increasing TMS intensity. ICF and RMT were not affected. Impairment of early and late ICI correlated significantly with disease duration, the diagnostic categories and the clinical evidence of upper motor neuron involvement.The alteration of different cortical inhibitory functions seems to take place with disease progression, rather than being the primary event in the pathogenesis of ALS. The impaired inhibition is considered as being due to both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss. Clarification of the importance of these factors in the pathogenesis of the disease may have diagnostic and therapeutic implications.     

Frontotemporal dementia: An attempt at clinical characteristics.

The clinical recognition of frontotemporal dementia (FTD) depends on its differentiation from Alzheimer's disease (AD). From 212 patients primarily diagnosed as probable AD, 24 cases with mild dementia, absence of disturbances the presence of which would have prevented a full neuropsychological assessment, and brain CT with detailed visualization of hippocampus atrophy were chosen. On the basis of neuropsychological examination the patients were divided into two groups: 11 cases with predominant deficit in frontal system tasks (FTD group) and 13 cases with changes in cognitive functions typical of AD (AD group). Age at onset, duration, behavioral changes, psychotic symptoms, depression, speech disorders, neurologic deficit and hippocampal atrophy were analyzed in both groups. Statistically significant differences for behavioral disturbances and hippocampal atrophy were found. Early behavioral changes and lack of early hippocampal atrophy on CT may be useful features for differentiating between FTD and AD, especially when SPECT is not available.     

Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis.

OBJECTIVES: Different physiological approaches demonstrated motor system hyperexcitability in amyotrophic lateral sclerosis (ALS), probably reflecting excitotoxic mechanisms. Transcranial magnetic stimulation (TMS) showed that both increased excitability of corticomotoneurons and reduced intracortical inhibition (ICI) contribute to motor cortex hyperexcitability, but the importance of these factors in inducing this cortical dysfunction is unknown. The aim of the study was to establish how different mechanisms interact to promote motor system hyperexcitability in ALS in relation to clinical features. METHODS: The resting motor threshold (RMT), the motor evoked potential (MEP) recruitment curve and the cortical silent period (CSP) to single-pulse TMS were evaluated in 35 patients with ALS. Early ICI and intracortical facilitation (ICF) and late ICI were evaluated by paired TMS. RESULTS: The main abnormal TMS findings were: (a) a steeper MEP recruitment curve associated with a lowering of the RMT; (b) reduced or even absent early and late ICI; (c) reduced CSP lengthening with increasing TMS intensity. ICF was not affected. RMT increased and the MEP recruitment curve became less steep with longer disease duration, but they did not correlate with the motor deficit, the type of motoneuron affection and the decrease of ICI. Impairment of early and late ICI were significantly correlated to each other, to disease severity and to clinical evidence of upper motor neuron involvement. CONCLUSIONS: Different and partially independent mechanisms contribute to motor cortex hyperexcitability in ALS. The increased gain in MEP recruitment with a lowering of the RMT appears to be a primary event reflecting an increase in the strength of corticospinal projections, probably related to changes in the ion-channel permeability of the neuronal membrane. On the other hand, inhibitory functions linked to multiple neurotransmitter systems decline with disease progression. Both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss have been considered to account for the impaired inhibition. The clarification of the importance of these factors in the pathogenesis of ALS may have diagnostic and therapeutic implications.     

Analogous corticocortical inhibition and facilitation in ipsilateral and contralateral human motor cortex representations of the tongue.

How the human brain controls activation of the ipsilateral part of midline muscles is unknown. We studied corticospinal and corticocortical network excitability of both ipsilateral and contralateral motor representations of the tongue to determine whether they are under analogous or disparate inhibitory and facilitatory corticocortical control. Motor evoked potentials (MEPs) to unilateral focal transcranial magnetic stimulation (TMS) of the tongue primary motor cortex were recorded simultaneously from the ipsilateral and contralateral lingual muscles. Single-pulse TMS was used to assess motor threshold (MT) and MEP recruitment. Paired-pulse TMS was used to study intracortical inhibition (ICI) and intracortical facilitation (ICF) at various interstimulus intervals (ISIs) between the conditioning stimulus (CS) and the test stimulus (TS), and at different CS and TS intensities, respectively. Focal TMS invariably produced MEPs in both ipsilateral and contralateral lingual muscles. MT was lower and MEP recruitment was steeper when recorded from the contralateral muscle group. ICI and ICF were identical in the ipsilateral and contralateral representations, with inhibition occurring at short ISIs (2 and 3 ms) and facilitation occurring at longer ISIs (10 and 15 ms). Moreover, changing one stimulus parameter regularly produced analogous changes in MEP size bilaterally, revealing strong linear correlations between ipsilateral and contralateral ICI and ICF (P < 0.0001). These findings indicate that the ipsilateral and contralateral representations of the tongue are under analogous inhibitory and facilitatory control, possibly by a common intracortical network.     

A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia

OBJECTIVES: To validate a simple bedside test battery designed to detect mild dementia and differentiate AD from frontotemporal dementia (FTD). METHODS: Addenbrooke's Cognitive Examination (ACE) is a 100-point test battery that assesses six cognitive domains. Of 210 new patients attending a memory clinic, 139 fulfilled inclusion criteria and comprised dementia (n = 115) and nondementia (n = 24) groups. The composite and the component scores on the ACE for the two groups were compared with those of 127 age- and education-matched controls. Norms and the probability of diagnosing dementia at different prevalence rates were calculated. To evaluate the ACE's ability to differentiate early AD from FTD, scores of the cases diagnosed with dementia with a Clinical Dementia Rating < or = 1 (AD = 56, FTD = 24, others = 20) were compared. RESULTS: Two cut-off values for the ACE composite score (88 and 83) were of optimal utility depending on the target population. The ACE had high reliability, construct validity, and sensitivity (93%, using 88 as cut-off). Using the lower cut-off of 83, the ACE had a higher sensitivity (82%) and predictive value than the Mini-Mental State Examination for a wide range of dementia prevalence. The ACE differentiated AD from FTD, and the VLOM ratio (derived using component scores: [verbal fluency + language]/[orientation + memory]) of <2.2 for FTD and >3.2 for AD was highly discriminating. CONCLUSION: The ACE is a brief and reliable bedside instrument for early detection of dementia, and offers a simple objective index to differentiate AD and FTD in mildly demented patients.     

<Emphasis Type="SmallCaps">l-</Emphasis>dopa modulates motor cortex excitability in Alzheimer’s disease patients

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have shown abnormalities of motor cortical excitability, such as a decreased intra-cortical inhibition (ICI) and changes in resting motor threshold (rMT). We studied the effects of L-dopa on rMT and ICI in a cohort of moderate AD patients after paired-pulse TMS. Results were compared with a control group of healthy subjects. As expected, AD patients showed a significant reduction in ICI and a lower rMT. L-dopa administration (soluble form, melevodopa 200 mg) promptly reversed the ICI impairment up to normalization. This effect was specific, since it was not mimicked in control subjects. These results indicate a possible role of dopamine in modulating AD cortical excitability, thus suggesting an interaction between dopaminergic ascending pathways and endogenous intracortical transmitters. In addition, considering that L-dopa showed a pharmacological profile similar to the one of cholinomimetics, L-dopa might represent a reliable tool to study new therapeutic perspective and strategies for AD.     

Working memory, attention, and executive function in Alzheimer's disease and frontotemporal dementia

Working memory deficits are a recognised feature of Alzheimer's disease (AD). They are commonly ascribed to central executive impairment and assumed to relate to frontal lobe dysfunction. Performance failures on standard tests of attention and executive function reinforce this interpretation. Nevertheless, early-onset AD patients do not show the frank behavioural changes indicative of frontal lobe dysfunction, and the characteristic functional neuroimaging changes are in posterior hemispheres rather than frontal lobes. We explored this anomaly through a comparison of working memory, attention and executive test performance in patients with AD (a 'typical' early-onset group with deficits in memory, language and perceptuospatial function and an 'amnesic' group) and frontotemporal dementia (FTD). Typical-AD and FTD patients both showed impaired performance, whereas amnesic-AD patients performed well. Despite similar quantitative performance measures, typical-AD and FTD patients showed qualitatively distinct performance profiles. Impairments in FTD patients were interpreted in 'frontal' executive terms as deficits in attention, set shifting and response inhibition. AD patients' performance appeared to be influenced by information load and was interpreted in terms of working memory capacity. In keeping with these different interpretations, neuroimaging showed characteristic frontal lobe abnormalities in FTD and temporoparietal change in typical-AD. The findings highlight the importance of the posterior hemispheres in working memory and point to a need for caution in the automatic attribution of working memory, attention and executive test failures to frontal lobe failure. They underline also the phenotypic variation within AD.     

Changes in dietary or eating behavior in frontotemporal dementia versus Alzheimer's disease

BACKGROUND: Changes in dietary or eating behavior are common in dementia and may help distinguish between different dementing illnesses. Objective: To evaluate and characterize differences in dietary and eating behavior among patients with early frontotemporal dementia (FTD) versus Alzheimer's disease (AD). METHODS: This study administered the Food-Related Problems Questionnaire (FRPQ) to caregivers of 16 patients with FTD and 16 comparable patients with AD. The FRPQ was evaluated at initial presentation when patients presented for a diagnostic evaluation. RESULTS: Compared with the AD patients, the FTD patients had significantly more changes on the FRPQ. Subscale analysis indicated that the FTD patients showed impairment of observed satiety, improper taking of food, and inappropriate responses when food was not available. CONCLUSIONS: The use of food-related questionnaires, such as the FRPQ, can help distinguish FTD patients, early in their course, from those with AD and can further characterize the altered dietary and eating behavior.     

The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia

Transcranial magnetic stimulation (TMS) is emerging as a promising tool to non-invasively assess specific cortical circuits in neurological diseases. A number of studies have reported the abnormalities in TMS assays of cortical function in dementias. A PubMed-based literature review on TMS studies targeting primary and secondary dementia has been conducted using the key words “transcranial magnetic stimulation” or “motor cortex excitability” and “dementia” or “cognitive impairment” or “memory impairment” or “memory decline”. Cortical excitability is increased in Alzheimer’s disease (AD) and in vascular dementia (VaD), generally reduced in secondary dementias. Short-latency afferent inhibition (SAI), a measure of central cholinergic circuitry, is normal in VaD and in frontotemporal dementia (FTD), but suppressed in AD. In mild cognitive impairment, abnormal SAI may predict the progression to AD. No change in cortical excitability has been observed in FTD, in Parkinson’s dementia and in dementia with Lewy bodies. Short-interval intracortical inhibition and controlateral silent period (cSP), two measures of gabaergic cortical inhibition, are abnormal in most dementias associated with parkinsonian symptoms. Ipsilateral silent period (iSP), which is dependent on integrity of the corpus callosum is abnormal in AD. While single TMS measure owns low specificity, a panel of measures can support the clinical diagnosis, predict progression and possibly identify earlier the “brain at risk”. In dementias, TMS can be also exploited to select and evaluate the responders to specific drugs and, it might become a rehabilitative tool, in the attempt to restore impaired brain plasticity.     

Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia

OBJECTIVES: The study aimed to increase understanding of behavioural changes in frontotemporal dementia (FTD) and identify features that best differentiate FTD from Alzheimer's disease (AD) and cerebrovascular dementia (CvD). METHODS: A semi-structured questionnaire was administered to carers of 30 FTD, 75 AD and 34 CvD patients. RESULTS: Behavioural changes that strongly discriminated FTD from AD and to a lesser extent CvD were loss of emotions and insight, selfishness, disinhibition, personal neglect, gluttony and sweet food preference, wandering, motor and verbal stereotypies, loss of pain, echolalia and mutism. Irritability, hyposexuality and hypersomnia did not discriminate. Emotional, eating and stereotyped behaviours correctly classified 95% of patients using regression analysis. CONCLUSIONS: Behavioural characteristics accurately differentiate FTD from AD and CvD. The findings highlight the particular importance of affective change in FTD, and underline the role of the frontotemporal lobes in emotion.     

Intra- and inter-cortical motor excitability in Alzheimer’s disease

Transcranial magnetic stimulation (TMS) provides evidence for facilitatory and inhibitory motor dysfunctions in Alzheimer's disease (AD). The corpus callosum (CC) is affected in AD already at early stages consistent with the hypothesis that AD patients exhibit alterations in transcallosally mediated motor inhibition (ipsilateral silent period, iSP). Therefore, here we aimed at investigating the integrity not only of intra-, but also of inter-hemispheric mechanisms of cortical motor excitability in AD. We determined the iSP, the resting motor threshold (RMT), and the amplitude of motor evoked potentials (MEP) in 19 AD patients and 19 healthy controls using single-pulse TMS. Furthermore, we used paired-pulse TMS to study the intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF). All subjects underwent comprehensive neuropsychologic, clinical, and laboratory testing, and neuroimaging to exclude significant co-morbidity. In AD patients, the RMT was significantly reduced (Oneway-ANOVA). An analysis of covariance (ANCOVA) revealed a strong group specific interaction of the inhibitory interstimulus intervals (p = 0.005) with a reduced ICI in AD. Furthermore, we found a significantly prolonged iSP-latency (p = 0.003) in AD compared to controls, whereas the iSP-duration was not different. The iSP-latency correlated significantly with the ICI (ANCOVA) (p = 0.02). The ICF did not differ significantly between groups. Our data suggest comprehensive but still subclinical dysfunctions of motor cortical inhibition in mild to moderate clinical stages of AD with strong interactions of intra- and inter-hemispheric inhibitory phenomena. Future studies are needed to show the potential prognostic relevance of these findings for the further course of the disease.     

Frontotemporal dementia: a clinically complex diagnosis

OBJECTIVE: To compare the time taken to establish a clinical diagnosis of Frontotemporal dementia (FTD) relative to a diagnosis of early onset Alzheimer's dementia (AD). METHODS: The data came from 89 patients under the age of 65 years, 52 of whom met the Manchester-Lund criteria for Frontotemporal dementia; 20 of these came from Lund University Hospital in Sweden. The other 32 patients with FTD along with 37 subjects who fulfilled the ICD-10 criteria for early onset Alzheimer's disease were recruited from four memory clinics and two neurology departments in Norway. RESULTS: For FTD patients in Norway it took 59.2 months (SD 36.1) from the onset of illness until a clinical FTD diagnosis was made. The corresponding time period for FTD patients in Sweden is 49.5 months (SD 24.5) and for AD patients in Norway 39.1 months (SD 19.9). The time from the first visit to a medical doctor until a diagnosis was made for the FTD patients in Norway was 34.5 months (SD 22.6), for the Swedish FTD patients 23.1 months (SD 22.4) and for the AD patients 25.9 months (SD 13.1). In all, 71% of FTD patients and 30% of AD patients initially received a non-dementia diagnosis. CONCLUSION: More knowledge about early presenting cognitive and behavioural signs of FTD is needed in both primary and secondary health care to reduce the time period needed to establish a clinical diagnosis of FTD.     

The apolipoprotein E ε4 allele is not a significant risk factor for frontotemporal dementia

Frontotemporal dementia (FTD) is the most common early-onset non-Alzheimer's dementia (non-AD). Although the role of the ε4 allele of apolipoprotein E (ApoE) has been well established in AD, studies of ApoE allele distribution in patients with FTD have produced variable results. We studied 33 rigorously diagnosed FTD patients, including several who wre pathologically confirmed, and compared the fequency of the ε4 allele in patients with FTD with the frequency in those with early-onset AD (EOAD), in those with late-onset AD (LOAD), and in non-demented elderly controls. The frequency of ApoE ε4 was 21% in patients with FTD, significantly less than the ApoE ε4 frequency in those patients with EOAD (38%) and those with LOAD (40%), but not significantly different from the ApoE ε4 frequency in elderly controls (13%).     

Behavioral quantitation is more sensitive than cognitive testing in frontotemporal dementia

OBJECTIVE: To compare behavioral and cognitive testing in the clinical diagnosis of frontotemporal dementia (FTD). METHODS: A clinically defined cohort of FTD (n = 52) is compared with 52 Alzheimer disease (AD) patients on a Frontal Behavioral Inventory (FBI) and cognitive tests (e.g., Mini-Mental State Examination, Mattis Dementia Rating Scale, Western Aphasia Battery, Wechsler Intelligence Scale, Wechsler Memory Scale). Fourteen patients with FTD had autopsy confirmation, and their tests are also compared with the rest of the FTD population. RESULTS: The FTD and AD groups were matched in sex, duration, and severity of dementia. The total scores on the FBI showed the largest difference. Mini-Mental State Examination and Mattis Dementia Rating Scale total scores did not discriminate between the two groups. Memory subscores were lower in the AD group, and conceptualization and language-related scores were worse in the FTD group. Milder and earlier affected patients, who could carry on a large battery of neuropsychological tests, were much better distinguished by the FBI scores on discriminant function analysis. In contrast to 78% by the cognitive tests, 98% of the FTD and AD patients were differentiated by the FBI. CONCLUSIONS: Although memory scores were lower in AD and language scores in the FTD population, many of the cognitive tests do not distinguish between FTD and AD. On the other hand, a behavioral inventory is a useful adjunct in the diagnosis of FTD. Postmortem validation was carried out in a sizeable subset of the population, showing similar behavioral and cognitive data.     

Qualitative aspects of learning, recall, and recognition in dementia

Objective:

To determine whether learning and serial position effect (SPE) differs qualitatively and quantitatively among different types of dementia and between dementia patients and controls; we also wished to find out whether interference affects it.

Materials and Methods:

We administered the Malayalam version of the Rey Auditory Verbal Learning Test (RAVLT) to 30 cognitively unimpaired controls and 80 dementia patients [30 with Alzheimer''s disease (AD), 30 with vascular dementia (VaD), and 20 with frontotemporal dementia (FTD)] with mild severity on the Clinical Dementia Rating Scale.

Results:

All groups were comparable on education and age, except the FTD group, who were younger. Qualitatively, the learning pattern and SPE (with primacy and recency being superior to intermediate) was retained in the AD, VaD, and control groups. On SPE in free recall, recency was superior to intermediate in the FTD group (P < 0.01 using Bonferroni correction). On recognition, the AD and VaD groups had more misses (P < 0.01), while the FTD group had more false positives (P < 0.01).

Conclusion:

Quantitative learning is affected by dementia. The pattern of qualitative learning remains unaltered in dementia in the early stages.     

Quantitative and qualitative analyses of clock drawing in frontotemporal dementia and Alzheimer's disease.

The clock drawing test (CDT) is a widely used cognitive screening test. It is useful in identifying focal lesions and cognitive deficits in dementia groups. Lately, several studies attempted its use to differentiate between dementia subtypes. Although many studies have examined the CDT in dementia populations, research into the use of clock drawing in frontotemporal dementia (FTD) is limited. We examined quantitative (global) and qualitative (specific error type) differences on the CDT between FTD (n = 36) and Alzheimer's disease (AD; n = 25) patients and controls without dementia (n = 25). Results showed significantly lower overall scores in the dementia groups compared to the control group, whereas FTD patients scored significantly higher than the AD group. On qualitative analysis, the FTD group had fewer stimulus bound responses, conceptual deficits, and spatial or planning errors compared to the AD group. In conclusion, both global and error analysis of the CDT helped discriminate the FTD group from controls and AD patients.     

Self awareness and personality change in dementia

BACKGROUND: Loss of insight is a core diagnostic criterion for frontotemporal dementia (FTD), whereas failure to recognise cognitive deficits and unawareness of disease (anosognosia) are well established findings in Alzheimer's disease (AD). However, self awareness of personality has not been quantified in these patient groups. METHODS: Twenty two patients (12 with frontal variant FTD; 10 with early AD) and 11 older adult normal controls completed self report questionnaires (the Interpersonal Adjectives Scales) describing their current personality. First degree relative informants completed two questionnaires, one describing the subject's current personality, the other retrospectively describing the subject's personality before disease onset. Differences between subject and informant reports of current personality were used to measure the accuracy of self awareness. RESULTS: Discriminant function analysis showed significant differences in self awareness among the three groups, with those in the FTD group showing the greatest magnitude of error in the largest number of personality dimensions (dominance, submissiveness, cold heartedness, introversion, and ingenuousness). Despite personality changes over time, patients with AD showed accurate self awareness in all personality dimensions except submissiveness and extraversion. Normal controls showed a pattern of underestimating positive qualities, whereas patients with FTD exaggerated positive qualities and minimised negative qualities. For the personality facets showing impaired insight, the self reports of patients with FTD and AD most closely matched their premorbid personalities, suggesting a failure to update their self image after disease onset. CONCLUSIONS: This study operationalises research criteria for loss of insight in FTD.     

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.