Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.     

Frontotemporal lobar degeneration: clinical and pathological relationships

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.     

Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration

BACKGROUND: Differentiating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult, particularly in the earliest stages of the diseases. Patterns of atrophy on magnetic resonance imaging may help distinguish these diseases and aid diagnosis. OBJECTIVE: To assess the diagnostic utility of magnetic resonance imaging-derived amygdala and hippocampal volumes from patients with pathologically proved AD and FTLD. DESIGN: Cross-sectional volumetric magnetic resonance imaging study of the hippocampus and amygdala. SETTING: Specialist cognitive disorders clinic.Subjects Thirty-seven subjects, including 10 patients with pathologically proved AD, 17 patients with pathologically proved FTLD, and 10 age-matched control subjects. MAIN OUTCOME MEASURES: Hippocampal and amygdala volumes. RESULTS: Geometric mean amygdala and hippocampal volumes were, respectively, 15.0% (95% confidence interval [CI], 4.2%-24.5%) and 16.4% (95% CI, 5.9%-25.6%) lower in the AD than in the control group. In FTLD, the equivalent differences were 43.1% (95% CI, 31.9%-52.6%) in the amygdala and 36.1% (95% CI, 27.5%-43.7%) in the hippocampus. Volumes were significantly lower in the FTLD than in the AD group (P<.01 in both regions). Within the FTLD clinical subgroups, there was evidence of a difference in pattern of atrophy with greater asymmetry (left smaller than right) in semantic dementia compared with frontal variant FTLD (P<.001). On average, the left hippocampus was 14% smaller in semantic dementia than in frontal variant FTLD, whereas the right hippocampus was 37% larger. On average, the left amygdala was 39% smaller in semantic dementia than in frontal variant FTLD, whereas the right amygdala was only 1% smaller. CONCLUSIONS: Hippocampal atrophy is not specific to AD or FTLD. However, severe or asymmetrical amygdala atrophy should suggest FTLD. Atrophy patterns follow clinical syndromes rather than pathology.     

Rates of hemispheric and lobar atrophy in the language variants of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance.     

Cinguloparietal atrophy distinguishes Alzheimer disease from semantic dementia

BACKGROUND: Progressive brain atrophy is associated with Alzheimer disease (AD) and other dementias. Regional differences in brain atrophy may reflect clinical features of disease. OBJECTIVE: To identify regions of cerebral atrophy that are associated with AD vs other dementias. SETTING: University hospital dementia clinic. PARTICIPANTS: Eleven patients with AD and 11 with semantic dementia (SD), matched for age, sex, education, and degree of overall cognitive impairment and 15 normal controls. METHODS: Voxel-based morphometry was used to compare patterns of gray matter loss, measured on T1-weighted magnetic resonance images, between patients with AD or SD, a subtype of frontotemporal lobar degeneration, and controls. Statistically significant differences in regional gray matter concentration, after multiple-comparisons correction, between groups of subjects were identified. RESULTS: Patients with AD were more impaired than those with SD on tests of visuospatial function and on simple calculations. Consistent with these neuropsychological deficits, the most significant area of atrophy in the AD group was the left parietal cortex vs controls (z = 5.0; P =.04). Compared with SD, AD was associated with more atrophy in the left parietal lobe (z = 5.6; P =.04) and bilaterally in the posterior cingulate/precuneus (z = 5.1; P =.04). A discriminant function analysis demonstrated that the degree of atrophy of right posterior cingulate, left parietal lobe, right amygdala, and right anterior temporal lobe structures correctly classified 96% of the patients. CONCLUSION: Alzheimer disease is associated with a specific pattern of cortical atrophy compared with SD.     

Confrontation naming and morphometric analyses of structural MRI in frontotemporal dementia

We studied the neural basis for confrontation naming difficulty in 29 patients with frontotemporal dementia (FTD) by correlating naming with voxel-based morphometric analyses of gray matter volume in structural MRI. We found that naming is significantly impaired in FTD, including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA), and nonaphasic patients (NON-APH) with a disorder of social and executive functioning. Significant cortical atrophy was found in the left anterior temporal cortex in all three FTD subgroups relative to healthy seniors. We also found significant cortical atrophy in unique anatomic distributions in each FTD subgroup. This included: lateral, ventral, and parahippocampal regions of the left temporal lobe in SD; inferior, orbital, dorsolateral, and premotor regions of the left frontal lobe in PNFA, and bilateral frontal regions in NON-APH. Direct correlations between confrontation naming and gray matter volume revealed distinct patterns in each FTD subgroup. SD patients showed a significant correlation in the left lateral temporal cortex, PNFA patients in several left frontal regions, and NON-APH patients in the right dorsolateral prefrontal cortex. These findings suggest that confrontation naming is supported by a large-scale neural network, and that naming is compromised in FTD due to interruption of the network in several different ways.     

Patterns of brain atrophy in frontotemporal dementia and semantic dementia.

OBJECTIVE: To identify and compare the patterns of cerebral atrophy associated with two clinical variants of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (FTD) and semantic dementia (SemD). METHODS: Twenty patients with FTLD were classified as having FTD (N = 8) or SemD (N = 12) based on current clinical criteria. Both groups showed a similar spectrum of behavioral abnormalities, as indicated by the neuropsychiatric inventory. T1-weighted MRI was obtained for each patient and 20 control subjects. The regions of focal gray matter tissue loss associated with both FTD and SemD, as well as those differing between the two groups were examined using voxel-based morphometry. RESULTS: Regions of significant atrophy seen in both groups were located in the ventromedial frontal cortex, the posterior orbital frontal regions bilaterally, the insula bilaterally, and the left anterior cingulate cortex. The FTD, but not the SemD, group showed atrophy in the right dorsolateral frontal cortex and the left premotor cortex. The SemD, but not the FTD, group showed tissue loss in the anterior temporal cortex and the amygdala/anterior hippocampal region bilaterally. CONCLUSIONS: Although FTD and SemD are associated with different overall patterns of brain atrophy, regions of gray matter tissue loss in the orbital frontal, insular, and anterior cingulate regions are present in both groups. The authors suggest that pathology in the areas of atrophy associated with both FTD and SemD may underlie some the behavioral symptoms seen in the two disorders.     

Primary Progressive Aphasia and Alzheimer’s Disease: Brief History, Recent Evidence

Primary progressive aphasia (PPA) has been recognized as a syndrome distinct from the usual pattern of language deterioration in Alzheimer??s disease and typically more related to the pathology of frontotemporal dementia (FTD). In recent years, however, the syndromes of primary progressive aphasia have become more complex, divided into the three subtypes of progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic/phonological progressive aphasia (LPA). These syndromes have not only made the linguistic analysis more complex, but the associated pathologies have also become more variable. In particular, PNFA is usually, but not always, associated with FTD pathology and often evidence of a tau mutation, but rarely AD; SD is usually associated with FTD of the ubiquitin staining or progranulin (TAR-DNA) mutation type, but, again, occasionally AD; LPA is typically associated with AD pathology. Patterns of atrophy on magnetic resonance imaging (MRI) generally conform to these subtypes, with PNFA associated with left frontal and insular atophy, SD associated with bilateral temporal atrophy, and LPA associated with L superior-posterior temporal and parietal atrophy. These patterns can also be seen on positron emission (PET) scanning with fluorodeoxyglucose. The newer amyloid binding ligand PET technologies are less useful for detecting regional atrophy patterns but more useful for indication of the underlying pathology. We can thus speak of syndromes of PPA or underlying pathological bases of PPA.     

Topographical patterns of lobar atrophy in frontotemporal dementia and Alzheimer's disease

BACKGROUND/AIMS: Fronto-temporal dementia (FTD) designates a group of relatively common neurodegenerative disorders. The aim of this study was to characterize the patterns of brain atrophy in FTD compared to Alzheimer's disease (AD). METHODS: A novel semiautomatic volumetric MRI analysis method was applied to measure regional brain volumes in FTD (n = 15; behavioural variant n = 9, language variant n = 6) in contrast with AD patients (n = 15) and age-matched controls (NC) (n = 15). FTD and AD patients were matched on demographic measures and Mini Mental State Examination scores. RESULTS: Significant atrophy was present in the frontal and anterior temporal lobes of subjects with FTD compared to AD (p = 0.02; effect size = 1.11) and compared to NC (p < 0.001; effect size = 1.86). Severe atrophy of the left anterior temporal region distinguished the language variant. AD patients, by contrast, did not differ from NC for frontal lobe volume but had smaller anterior temporal lobes (p = 0.03). Both dementia groups had medial temporal lobe atrophy of similar magnitude. A logistic regression model including 4 regional measures correctly classified 100% of subjects. CONCLUSION: FTD can be reliably differentiated from AD by virtue of a topographical pattern of atrophy involving the frontal lobes and anterior temporal regions. Medial temporal lobe volumes do not distinguish FTD from AD.     

Epidemiology of frontotemporal lobar degeneration

A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick's disease. The aim of this study was to review the epidemiologic studies of FTLD in western countries and to compare them with those in Japan. A community-based study of early-onset dementia in London revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund-Manchester criteria in contrast to 34% of cases with Alzheimer's disease (AD) in a sample of 185 cases. The Cambridge Group has recently examined the prevalence of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD (29%) had a positive family history. Of our consecutive 330 outpatients with dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215 (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified. There was no family history in all subtypes of FTLD. Epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy is supposed to be mainly based on the role of heredity.     

Progressive nonfluent aphasia: A rare clinical subtype of FTLD‐TDP in Japan

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD‐tau) and FTLD with TDP‐43 accumulation (FTLD‐TDP) both cause PNFA. We reviewed clinical records of 29 FTLD‐TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81‐year‐old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP‐43‐immunoreactive neuronal cytoplasmic inclusions and round or irregular‐shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD‐TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.     

Longitudinal white matter changes in frontotemporal dementia subtypes

Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffusion and T₁‐weighted images were collected from behavioral‐variant FTD (bvFTD: 12), progressive non‐fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measurements using tract‐based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel‐based morphometry. At baseline, bvFTD showed severe cross‐sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12‐month. In PNFA, cross‐sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circumscribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffusivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with disease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression. Hum Brain Mapp 35:3547–3557, 2014. © 2013 Wiley Periodicals, Inc .     

Does Alzheimer's disease affect hippocampal asymmetry? Evidence from a cross-sectional and longitudinal volumetric MRI study

OBJECTIVE: To determine whether Alzheimer's disease (AD) is associated with preferential atrophy of either the left or right hippocampus. METHODS: We examined right-left asymmetry in hippocampal volume and atrophy rates in 32 subjects with probable AD and 50 age-matched controls. Hippocampi were measured on two serial volumetric MRI scans using a technique that minimizes laterality bias. RESULTS: We found a non-significant trend for right > left (R > L) asymmetry in controls at both time points (R > L: 1.7%; CI: -0.3-3.7%; p = 0.1). AD subjects showed a similar non-significant trend for R > L asymmetry at baseline (R > L: 1.8%; CI: -1.9-5.5%; p = 0.32), but not at repeat (p = 0.739). Change in R/L ratio between visits in AD patients was significant (p = 0.02). The AD group had significantly higher variance in these ratios than the controls at baseline (p = 0.02), but not repeat (p = 0.06). AD patients had higher atrophy rates than controls (p < 0.001). Mean (CI) annualized atrophy rates for left and right hippocampi were 1.2% (0.5-1.8%) and 1.1% (0.5-1.8%) for the controls, and 4.6% (3.3-6.0%) and 6.3% (4.9-7.8%) for AD subjects. There was no significant asymmetry in atrophy rates in controls (p = 0.9), but borderline significantly higher atrophy rates in the right hippocampus of the AD group (p = 0.05) compared to the left. Presence of an APOEepsilon4 allele had no significant effect on the size, asymmetry or atrophy rates in AD (p > 0.20). CONCLUSIONS: We report minor R > L asymmetry in hippocampal volumes in controls and present some evidence to suggest that there is a change in the natural R > L asymmetry during the progression of AD.     

Serum Progranulin Levels in Patients with Frontotemporal Lobar Degeneration and Alzheimer's Disease: Detection of GRN Mutations in a Spanish Cohort

Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers, and 18 control individuals. We detected 5 patients with PGRN levels below 94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean = 145.5 ng/mL, SD = 28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean = 50.5 ng/mL, SD = 21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139R (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels.     

Shape analysis of the neostriatum in subtypes of frontotemporal lobar degeneration: Neuroanatomically significant regional morphologic change

Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD) and may differ across subtypes of FTLD. We manually segmented the neostriatum (caudate nucleus and putamen) in FTLD subtypes: behavioral variant frontotemporal dementia, FTD, n = 12; semantic dementia, SD, n = 13; and progressive non-fluent aphasia, PNFA, n = 9); in comparison with controls (n = 27). Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intracranial volume was calculated via a stereological point counting technique and was used for normalizing the shape analysis. Segmented binaries were analyzed using the Spherical Harmonic (SPHARM) Shape Analysis tools (University of North Carolina) to perform comparisons between FTLD subtypes and controls for global shape difference, local significance maps and mean magnitude maps of shape displacement. Shape analysis revealed that there was significant shape difference between FTLD subtypes and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. These differences were not significant for SD compared to controls; lesser for PNFA compared to controls; whilst FTD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with a differential between FTLD subtypes, compared to controls.     

Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration

To better define the anatomic distinctions between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we retrospectively applied voxel-based morphometry to the earliest magnetic resonance imaging scans of autopsy-proven AD (N = 11), FTLD (N = 18), and controls (N = 40). Compared with controls, AD patients showed gray matter reductions in posterior temporoparietal and occipital cortex; FTLD patients showed atrophy in medial prefrontal and medial temporal cortex, insula, hippocampus, and amygdala; and patients with both disorders showed atrophy in dorsolateral and orbital prefrontal cortex and lateral temporal cortex (P(FWE-corr) < .05). Compared with FTLD, AD patients had decreased gray matter in posterior parietal and occipital cortex, whereas FTLD patients had selective atrophy in anterior cingulate, frontal insula, subcallosal gyrus, and striatum (P < .001, uncorrected). These findings suggest that AD and FTLD are anatomically distinct, with degeneration of a posterior parietal network in AD and degeneration of a paralimbic fronto-insular-striatal network in FTLD.     

Rates of global and regional cerebral atrophy in AD and frontotemporal dementia.

OBJECTIVE: Serial registered MRI provides a reproducible technique for detecting progressive cerebral atrophy in vivo and was used to determine if there were differences between the rates of cerebral atrophy in AD and frontotemporal dementia (FTD). METHODS: Eighty-four patients with dementia (54 AD and 30 FTD) and 27 age-matched control subjects each had at least two volumetric MR scans. Serial scans were positionally matched (registered), and brain volume loss was determined by calculation of the brain boundary shift integral. RESULTS: There was a difference between the rates of whole-brain atrophy in patients (mean annual volume loss 2.7% of total brain volume) and in control subjects (mean annual volume loss 0.5%). AD and FTD were associated with different rates of atrophy (mean annual losses 2.4 and 3.2%). The range of atrophy rates in the FTD group (0.3 to 8.0%) greatly exceeded that in the AD group (0.5 to 4.7%). Frontal-variant FTD was associated with a wider range of atrophy rates than temporal-variant FTD. Analysis of regional brain atrophy rates revealed that there was widespread symmetrically distributed cerebral volume loss in AD, whereas in frontal FTD there was greater atrophy anteriorly and in temporal FTD the atrophy rate was greatest in the left anterior cerebral cortex. CONCLUSIONS: Both AD and FTD patients had increased rates of brain atrophy. Whereas the patients with AD were associated with a relatively restricted spread of atrophy rates, the greater spread of rates observed in the patients with FTD may reflect the heterogeneity of disease in FTD, with differences observed between frontal and temporal FTD. Increased rates of whole-brain atrophy did not discriminate AD from FTD, but analysis of regional atrophy rates revealed marked differences between patient groups.     

Konsortium zur Erforschung der frontotemporalen Lob?rdegeneration

Frontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group was restricted to Pick's disease or Pick's complex. Several updates of the clinical classification systems were performed and discussed. Currently we summarize the following diseases under the FTLD spectrum: frontotemporal dementia (FTD) as a behavioural variant, primary non-fluent aphasia (PNFA) and semantic dementia as language variants, amyotrophic lateral sclerosis with FTD (ALS-FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).From the pathophysiological aspect major progress was made. Neuropathologically FTLDs are now defined based on the molecular composition of these protein accumulations. A major distinction of tau-associated (FTLD-tau) and TDP43-associated (FTLD-TDP43) and to a lesser extend FUS-associated (FTLD-FUS) has been made. Additional risk genes were described. However from the therapeutic perspective even symptomatic therapy is under discussion. A major aim of our consortium is to develop parameters allowing an early diagnosis and follow-up, thus providing effective and objective parameters for therapeutic strategies.     

Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration

Objective To correlate clinical diagnosis and genetic features with different pathological substrates in patients with frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD). Methods 32 cases with pathological proven FTLD or CBD were selected. Patients were classified clinically as frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), CBD or FLTD with motor neuron disease (FLTDMND). Coding exons 1 and 9–13 of MAPT and exons 0–12 of the PGRN gene were screened by direct sequencing. Regarding the neuropathological findings, cases were classified as tau-positive, ubiquitinpositive tau-negative (FTLD-U), neuronal intermediate filaments inclusions disease (NIFID), dementia lacking distinctive histology (DLDH) or CBD. Results 17 patients were clinically diagnosed with FTD. Ten showed tau pathology, 3 FTLD-U, 1 NIFID and 3 DLDH. All patients clinically classified as FTLD-MND (6 patients) or SD (3 patients) were FTLD-U. Tau-positive pathology was the substrate of the three patients with PNFA. All three patients classified clinically as CBD presented neuropathologic features of CBD. The three individuals with familial history of early onset FTD and tau-positive pathology carried the P301L mutation in the MAPT gene. One out of 3 cases with FTLD-U and intranuclear inclusions carried a mutation in the PGRN gene. Conclusions We found that pathology underlying sporadic FTD is heterogeneous and not predictable. MAPT mutations and clinical diagnosis of PNFA and CBD were associated with tau-positive pathology. The presence of signs of lower MND and SD correlated with FTLD-U.A genetic study of MAPT is only recommended when familial history of early onset DFT is present. * Other members of the Catalan collaborative Study Group for FTLD are listed in the Appendix.     

Volumetric study of lobar atrophy in Pick complex and Alzheimer's disease

BACKGROUND: Lobar atrophy is an important neuroimaging feature of Pick complex (PiC). However, differences in patterns of focal brain atrophy between PiC and Alzheimer's disease (AD), and among PiC subgroups, have not been studied quantitatively. OBJECTIVE: To compare volumetric measures among primary progressive aphasia (PPA), frontotemporal dementia (FTD) and AD; to assess association between brain atrophy and cognition. PATIENTS: Seventeen patients with PPA, 11 with FTD and 24 with probable AD were studied. METHODS: We measured total and regional volume quantitatively using MRI and computerized volumetry. Contributing factors were controlled statistically or by adopting brain volume ratios. We investigated the classifying power of volumetry and correlated regional brain volume with cognitive and language test scores. RESULTS: The ratio for fronto-temporo-central region was smaller on the left in PPA and on the right in FTD. AD and some PPA patients had smaller parietal lobes. The frontal ratios correctly classified 93% of PPA and FTD patients, but only 50% of the entire PiC and AD patients. Language-dependent examinations correlated with the left fronto-temporal volume. CONCLUSIONS: Brain atrophy differs in PPA, FTD and AD, but there is some morphological overlap between PiC and AD in parietal volumes. Focal brain atrophy is most consistently associated with language impairments.