Deficits In Frontotemporal Dementia Research Articles

Social-semantic knowledge in frontotemporal dementia and after anterior temporal lobe resection

Abstract Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural-variant FTD (bvFTD). Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialised for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance to that on matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL-damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared to non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non-social-semantic tests. Our transdiagnostic approach included bvFTD, semantic dementia and “mixed” intermediate cases to capture the FTD clinical spectrum, as well as age-matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy (TLE) were also recruited to assess how selective damage to the left or right ATL impacts social- and non-social-semantic knowledge. Social- and non-social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left vs. right differences in social-semantic knowledge or general semantic processing, and with only naming showing a greater deficit following left vs. right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing: (1) FTD severity, (2) semantic memory and (3) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non-social-semantic knowledge degrade in FTD (semantic dementia and bvFTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally-implemented, functionally-unitary semantic hub in the ATLs. Our results also highlight the value of a transdiagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD.

Facial expression recognition deficits in frontotemporal dementia and Alzheimer's disease: a meta-analytic investigation of effects of phenotypic variant, task modality, geographical region and symptomatic specificity.

Deficits in social cognition may be present in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Here, we conduct a qualitative synthesis and meta-analysis of facial expression recognition studies in which we compare the deficits between both disorders. Furthermore, we investigate the specificity of the deficit regarding phenotypic variant, domain-specificity, emotion category, task modality, and geographical region. The results reveal that both FTD and AD are associated with facial expression recognition deficits, that this deficit is more pronounced in FTD compared to AD and that this applies for the behavioral as well as for language FTD-variants, with no difference between the latter two. In both disorders, overall emotion recognition was most frequently impaired, followed by recognition of anger in FTD and by fear in AD. Verbal categorization was the most frequently used task, although matching or intensity rating tasks may be more specific. Studies from Oceania revealed larger deficits. On the other hand, non-emotional control tasks were more impacted by AD than by FTD. The present findings sharpen the social cognitive phenotype of FTD and AD, and support the use of social cognition assessment in late-life neuropsychiatric disorders.

Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

BackgroundNeurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. MethodsIn the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. ResultsIn prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). ConclusionsThis study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

Von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion.

The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9). von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia

Background: Deficits in instrumental activities of daily living (ADLs) may be more prominent in behavioral variant frontotemporal dementia (bvFTD) than in nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) or semantic variant primary progressive aphasia (svPPA). It is uncertain whether frontotemporal dementia (FTD) subgroups exhibit different patterns and/or predictors of functional impairment. Methods: We examined data from participants diagnosed with bvFTD (n = 607), svPPA (n = 132), and nfvPPA (n = 155) who were included in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and assessed with the Functional Activities Questionnaire (FAQ). Stepwise multiple linear regression analyses were performed to identify associations between FAQ scores and cognitive/behavioral deficits using the NACC UDS neuropsychological testing battery and the Neuropsychiatric Inventory Questionnaire. Results: FAQ scores were higher in bvFTD than svPPA or nfvPPA. Functional deficits across FTD subtypes differed in severity, but not pattern, and were driven by executive dysfunction and behavioral symptoms. Conclusion: Executive dysfunction and behavioral symptoms underlie instrumental ADL deficits in FTD, which are most prominent in bvFTD.

SEROTONERGIC DRUGS FOR MANAGEMENT OF BEHAVIOURAL SYMPTOMS OF FRONTOTEMPORAL DEMENTIA: A SYSTEMATIC REVIEW

ObjectiveIn the last 2 decades, data from neuroimaging and post-mortem studies has consistently demonstrated that postsynaptic receptor deficits in Frontotemporal dementia (FTD) specifically affect the serotonergic system. This contrasts with...

Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.

Many neurodegenerative diseases, such as frontotemporal dementia (FTD), are associated with behavioral deficits, but the anatomical and molecular bases remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to imbalance between Ca2+-permeable and -impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA (miR-124), whose abundance was markedly decreased in the superficial layers of cerebral cortex of FTD mice. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and iPSC-derived neurons of subjects with behavioral variant FTD. Moreover, miR-124 expression in the medial prefrontal cortex decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of Gria2 also alleviated social impairments in FTD mice. Our results identify a novel mechanism involving miR-124 and AMAPRs in regulating social behavior in FTD and suggest a potential therapeutic avenue.

Olfactory Deficits in Frontotemporal Dementia as Measured by the Alberta Smell Test

The study of olfaction in neurodegeneration has primarily focused on Alzheimer's disease. Research of olfaction in frontotemporal dementia (FTD) has generally not been empirically studied. The current study compared olfaction in FTD to major depressive disorder (MDD) using the Alberta Smell Test (AST). Independent-samples t test results suggested olfaction in FTD was impaired when compared with participants diagnosed with MDD. The AST Total score (out of 20 trials) significantly predicted the diagnostic group and accounted for 40% of the variance in diagnostic group status with an odds ratio of 20.08. Results suggested that a cutoff of ≤2/20 differentiated FTD from MDD with 94% accuracy (91% sensitivity, 97% specificity) and a cutoff of ≤1/20 differentiated the groups with a 95.5% hit rate (91% sensitivity, 100% specificity). Results confirmed olfactory identification deficits in FTD and suggested that the AST is an effective tool for the demarcation of FTD from MDD. This is especially important due to the potential for significant overlap in the behavioral/emotional phenotype and cognitive deficits between the two disorders when presented with early stages of FTD.

My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer’s disease

Theory of mind reasoning-the ability to understand someone else's mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else's mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer's disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else's mental perspective requires two distinct processes: inferring someone else's belief and inhibiting one's own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer's disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer's disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimer's disease had a predominant deficit in inferring someone else's belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting one's own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone else's beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia.

Apathy in frontotemporal dementia and Alzheimer's disease: are there distinct profiles?

To find out if distinct clinical profiles of apathy can be distinguished in frontotemporal dementia (FTD) and Alzheimer's disease (AD). 13 outpatients with the frontal variant of DFT, 36 with AD and 29 control subjects. The scores of the Apathy evaluation scale, AES (Marin), filled in by close relatives, were compared to a) cognitives measures, including global ratings (Mini mental state, Dementia rating scale), and specific assessments for memory (Selective reminding test), inhibition (Stroop test) and planification (6 elements); b) affective measures for depression (Montgomery and Asberg, and Hamilton depression rating scales), emotional disturbances (Abrams and Taylor scale, ATS; Depression mood scale, DMS), assessment of valence and intensity of affective reactions by the International affective picture system, IAPS), dimensions of personality (NEO PI-R, Defensive style questionnaire, DSQ); c) functional assessment: Self-maintenance physical scale (ADL) and Instrumental activities of daily living (Lawton), Social activities scale (Katz and Lyerly), and Disability assessment for dementia, DAD. Apathy was also assessed by the Neuropsychiatric Inventory (NPI) and a new tool, the Goal-directed activities scale (GDAS), which allows a quantitative assessment of 32 goal-directed activities and a qualitative evaluation of 4 causal attributions: E = related to external factors; M = disease related; C = affective disturbance related; and D = lack of motivation. A close relationship was found between AES scores and global cognitive deficits in FTD and AD, but only in AD for the memory and executive tests. No relationship was found with the depression scales or dimensions of personality. A significant relationship was found both in FDT and AD with blunted affect as assessed by ATS, but not with direct assessment by the DMS or reactions to the IAPS. Functional activities were closely related to AES scores in all evaluations, except for ADL score in FTD. Causal attributions were mainly related to lack of motivation in FTD (60% of cases according to the patients, and 85% according to the spouses), and both to affective disturbances (respectively in 36 and 48% of cases) and lack of motivation (33% and 45%) in AD. No distinct cognitive or emotional profiles of apathy could be found in FTD and AD. Apathy was constant, more severe, and mainly related to lack of motivation in FTD, less constant, less severe in AD, and related both to affective disturbances and lack of motivation.

Episodic memory in frontotemporal dementia: a critical review

This review offers a critical appraisal of the literature on episodic memory performance in frontotemporal dementia. Historically, description of patients diagnosed with what was then known as Pick's disease included the presence of memory deficits and an underlying amnestic syndrome was noted in some of these patients. Over the last 20 years, however, the clinical view has been that episodic memory processing is relatively intact in the frontotemporal dementia syndrome. In particular, patients with the subtypes of behavioural variant frontotemporal dementia and progressive non-fluent aphasia are reported to perform within normal limits on standard memory tests. In the third clinical presentation of frontotemporal dementia, semantic dementia, relatively intact episodic memory against a significantly impaired semantic memory was regarded as the hallmark. This position was instrumental in the development of clinical diagnostic criteria for frontotemporal dementia in which amnesia was explicitly listed as an exclusion criterion for the disease. The relative intactness of episodic memory, therefore, appeared to be a useful diagnostic marker to distinguish early frontotemporal dementia from Alzheimer's disease, in which early episodic memory disturbance remains the most common clinical feature. We argue that recent evidence questions the validity of preserved episodic memory in frontotemporal dementia, particularly in behavioural variant frontotemporal dementia. In semantic dementia, a complex picture emerges with preservation of some components of episodic memory, notably recognition-based visual memory and recall of recent autobiographical events. We propose a critical synthesis of recent neuropsychological evidence on retrograde and anterograde memory in light of neuroimaging and neuropathological findings, demonstrating involvement of medial temporal structures in frontotemporal dementia, structures known to be critical for episodic memory processing. We further argue that the multifactorial nature of most memory tests commonly used clinically fail to capture the memory deficits in frontotemporal dementia and that sensitive assessment tools of memory are needed. Together, recent clinical and experimental findings and the historical evidence represent a strong case for a re-evaluation of the importance of memory disturbance in the clinical diagnosis of frontotemporal dementia.

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.

Standardised measurement of self-awareness deficits in FTD and AD

BackgroundDiminished ability to perceive one's own impairments, whether cognitive or social, is common in dementia, in particular frontotemporal dementia (FTD), where ‘lack of insight’ is listed as a core diagnostic...

P3-125: Inter-rater reliability of speech and language deficits in frontotemporal dementia

P3-125: Inter-rater reliability of speech and language deficits in frontotemporal dementia

Odor identification deficits in frontotemporal dementia: A preliminary study

Multiple neurodegenerative disorders (e.g. Alzheimer's disease, Dementia with Lewy bodies, Parkinson's disease, and Huntington's disease) show olfactory deficits. Olfactory functioning has not been well studied in frontotemporal dementia (FTD). In the current study, individuals with FTD, Alzheimer's disease (AD), and healthy elderly controls were compared using an odor identification task. Results showed significant differences in odor identification between individuals with FTD and the healthy elderly control group. There were no differences between the FTD and AD groups. Using a cut score of 8/12, discriminant function analysis showed that the overall classification rate for the FTD and control groups was 71.4%, with a sensitivity rate of 87.5% and a specificity rate of 65%. This preliminary research demonstrates olfactory deficits in FTD, which appear to be similar in magnitude to the olfactory deficits seen in AD.

Loss of insight in frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy

Loss of insight is one of the core features of frontal/behavioural variant frontotemporal dementia (FTD). FTD shares many clinical and pathological features with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The aim of this study was to investigate awareness of cognitive deficits in FTD, CBD and PSP using a multidimensional approach to assessment, which examines metacognitive knowledge of the disorders, online monitoring of errors (emergent awareness) and ability to accurately predict performance on future tasks (anticipatory awareness). Thirty-five patients (14 FTD, 11 CBD and 10 PSP) and 20 controls were recruited. Results indicated that loss of insight was a feature of each of the three patient groups. FTD patients were most impaired on online monitoring of errors compared to the other two patient groups. Linear regression analysis demonstrated that different patterns of neuropsychological performance and behavioural rating scores predicted insight deficits across the three putative awareness categories. Furthermore, higher levels of depression were associated with poor anticipatory awareness, reduced empathy was related to impaired metacognitive awareness and impaired recognition of emotional expression in faces was associated with both metacognitive and anticipatory awareness deficits. The results are discussed in terms of neurocognitive models of awareness and different patterns of neurobiological decline in the separate patient groups.

Pin1 protein associates with neuronal lipofuscin: Potential consequences in age-related neurodegeneration

Pin1 protein is a peptidyl-prolyl cis-trans isomerase that modulates the activity of a range of proteins involved in cell function. We and others have demonstrated neuronal Pin1 deficits in Alzheimer's disease (AD) and have shown similar deficits in frontotemporal dementia and in aging. Pin1 may, in fact, be a susceptibility factor; others have shown that Pin1 depletion causes apoptosis in HeLa cells. Further, patterns of AD pathology correlate with regions of lower Pin1 expression in normal human brain; Pin1 knockout mice suffer neurodegeneration; and Pin1 can ameliorate p-tau pathology by isomerizing p-tau, facilitating its trans-specific dephosphorylation and restoring its ability to bind to and restabilize microtubules and thence cytoskeletal integrity. Here, we report a novel localization of high levels of Pin1 with lipofuscin in aging neurons. This association could progressively drain available Pin1 and be deleterious to neuronal function during aging. We also show that Pin1 associates with lipofuscin when lipofuscin accumulations become marked and correlate with susceptibility to neurodegenerative disease. Our data are consistent with the possibility that neuronal Pin1 deficits may be a contributory factor in neurodegeneration associated with aging.

Neural correlates of semantic and behavioural deficits in frontotemporal dementia

Patients with frontotemporal dementia (FTD) can present with the clinical syndrome of semantic dementia due to a progressive loss of semantic knowledge or a neuropsychiatric syndrome characterised by aberrant social behaviours although frequently both co-exist. It has been assumed that the former is underpinned by damage to the temporal lobes and the latter, predominantly, by damage to the frontal lobes. Using the technique of voxel-based morphometry, we studied a group of FTD cases ( n = 18) with a range of cognitive and neuropsychiatric features to correlate loss of semantic knowledge (as measured by the sum of two semantic tests) and aberrant behaviour (as measured by the neuropsychiatric inventory, NPI) with regional loss of grey matter volume. Semantic breakdown correlated with extensive loss of grey matter volume throughout the left anterior temporal lobe and less significantly with right temporal pole and subcallosal gyrus. Aberrant behaviour correlated with loss of grey matter volume in the dorso-mesial frontal lobe—paracingulate region, Brodmann areas 6/8/9—more so on the right. The frontal paracingulate correlation suggests that damage to this region may significantly contribute to the genesis of the behavioural syndrome seen in FTD.

Neural basis for sentence comprehension deficits in frontotemporal dementia

Many patients with frontotemporal dementia (FTD) have impaired sentence comprehension. However, the pattern of comprehension difficulty appears to vary depending on the clinical subgroup. The purpose of this study was to elucidate the neural basis for these deficits in FTD. We studied patients with two different presentations: Three patients with Progressive Non-Fluent Ahasia (PNFA), and five non-aphasic patients with a dysexecutive and social impairment (EXEC). The FTD patient subgroups were compared to a cohort of 11 healthy seniors with intact sentence comprehension. We monitored regional cerebral activity with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) while subjects read sentences featuring both a grammatically complex object-relative center-embedded clause and a long linkage between the head noun phrase (NP) and the gap where the NP is interpreted in the center-embedded clause. Subjects decided whether the agent of the action is a male or a female. Healthy seniors activated both ventral portions of inferior frontal cortex (vIFC) and dorsal portions of IFC (dIFC) in the left hemisphere, often associated with grammatical and working memory components of these sentences, respectively. PNFA patients differed from healthy controls since they have reduced activation of left vIFC, while EXEC patients have less recruitment of left dIFC. We conclude that FTD subgroups have distinct patterns of sentence comprehension difficulty in part because of selective interruptions of a large-scale neural network for sentence processing.

Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias.

Synapse loss has been found to be the major correlate of cognitive decline in Alzheimer disease (AD), and prefrontal synapse loss has been found in patients with frontotemporal dementia (FTD). To see if our hypothesis that within each FTD case, regional synapse loss would correlate with lateralizing neuropsychologic and neurobehavioral deficits would be correct. We analyzed synaptophysin as a marker for synapse loss in snap-frozen brain samples, using an enzyme-linked immunosorbent assay technique. Quantitative results were obtained by comparing patient data with a standard curve made by analyzing serial dilutions of a recombinant synaptophysin protein fragment. A board-certified neuropsychologist and a board-certified neurologist, both unaware of the synaptophysin results, determined areas of primary neuropsychologic and neurobehavioral dysfunction. Relationships between areas of primary dysfunction and synapse loss were analyzed using the binomial test. Six cases of FTD, 28 cases of AD, and 16 nondemented control subjects. Five of 6 FTD cases had regional synaptophysins correlating with lateralizing frontal or temporal deficits. Three of 6 correlated in 2 or more regions. Although our results were higher than that expected based on a pure-chance mechanism (50% vs 34%), statistical significance was not attained. We found a trend for an association between synapse loss and lateralizing neuropsychologic and neurobehavioral deficits in FTD. Studies in larger numbers of FTD cases are planned with the goal of attaining statistically significant conclusions.