Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants.

Neuroimaging studies have described the brain alterations in primary progressive aphasia (PPA) variants (semantic, logopenic, nonfluent/agrammatic). However, few studies combined T1, FDG-PET, and diffusion MRI techniques to study atrophy, hypometabolism, and tract alterations across the three PPA main variants. We therefore explored a large early-stage cohort of semantic, logopenic and nonfluent/agrammatic variants (N = 86) and of 23 matched healthy controls with anatomical MRI (cortical thickness), FDG PET (metabolism) and diffusion MRI (white matter tracts analyses), aiming at identifying cortical and sub-cortical brain alterations, and confronting these alterations across imaging modalities and aphasia variants. In the semantic variant, there was cortical thinning and hypometabolism in anterior temporal cortices, with left-hemisphere predominance, extending toward posterior temporal regions, and affecting tracts projecting to the anterior temporal lobes (inferior longitudinal fasciculus, uncinate fasciculus) and tracts projecting to or running nearby posterior temporal cortices: (superior longitudinal fasciculus, inferior frontal-occipital fasciculus). In the logopenic variant metabolic alterations were more extensive than atrophy affecting mainly the left temporal-parietal junction and extending toward more anterior temporal cortices. Metabolic and tract data were coherent given the alterations of the left superior and inferior longitudinal fasciculus and the left inferior frontal-occipital fasciculus. In the nonfluent/agrammatic variant cortical thinning and hypometabolism were located in the left frontal cortex but Broca's area was only affected on metabolic measures. Metabolic and tract alterations were coherent as reflected by damage to the left uncinate fasciculus connecting with Broca's area. Our findings provide a full-blown statistically robust picture of brain alterations in early-stage variants of primary progressive aphasia which has implications for diagnosis, classification and future therapeutic strategies. They demonstrate that in logopenic and semantic variants patterns of brain damage display a non-negligible overlap in temporal regions whereas they are substantially distinct in the nonfluent/agrammatic variant (frontal regions). These results also indicate that frontal networks (combinatorial syntax/phonology) and temporal networks (lexical/semantic representations) constitute distinct anatomo-functional entities with differential vulnerability to degenerative processes in aphasia variants. Finally, the identification of the specific damage patterns could open an avenue for trans-cranial stimulation approaches by indicating the appropriate target-entry into the damaged language system.

Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias.

OBJECTIVE: To reveal the prevalence and localization of cerebral microbleeds (CMBs) in the 3 main variants of primary progressive aphasia (PPA) (logopenic, semantic, and nonfluent/agrammatic), to identify the relationship with underlying Alzheimer pathology, and to explore whether CMBs contribute to language breakdown. METHODS: We used a cross-sectional design in a multicenter cohort of 82 patients with PPA and 19 similarly aged healthy controls. MRI allowed for rating CMBs (2-dimensional gradient recalled echo T2*, susceptibility weighted imaging sequences) and white matter hyperintensities. CSF Alzheimer disease biomarker analyses available in 63 of the 82 patients provided the stratification of PPA into subgroups with patients who had or did not have probable underlying Alzheimer pathology. RESULTS: The prevalence of CMBs was higher in patients with PPA (28%) than in controls (16%). They were more prevalent in logopenic PPA (50%) than in semantic PPA (18%) and nonfluent/agrammatic PPA (17%). The localization of CMBs was mainly lobar (81%) with no difference between the PPA variants. CMBs were more frequent in PPA patients with positive than with negative CSF Alzheimer disease biomarkers (67% vs 20%). Patients with and without lobar CMBs had similar volumes of white matter hyperintensities. Language and general cognitive impairment in PPA was unrelated to CMB rates. CONCLUSIONS: CMB prevalence in PPA is higher than in healthy controls. CMBs were most prevalent in the logopenic variant, were related to underlying Alzheimer pathology, and did not affect the language/cognitive impairment. Our findings also suggest that CMB detection with MRI contributes to PPA variant diagnosis, especially of logopenic PPA, and provides an estimator of the underlying neuropathology.

Familiarity and recollection vs representational models of medial temporal lobe structures: A single-case study.

Although it is known that medial temporal lobe (MTL) structures support declarative memory, the fact these structures have different architectonics and circuitry suggests they may also play different functional roles. Selective lesions of MTL structures offer an opportunity to understand these roles. We report, in this study, on JMG, a patient who presents highly unusual lesions that completely affected all MTL structures except for the right hippocampus and parts of neighbouring medial parahippocampal cortex. We first demonstrate that JMG shows preserved recall for visual material on 5 experimental tasks. This finding suggests that his right hippocampus is functional, even though it appears largely disconnected from most of its MTL afferents. In contrast, JMG performed very poorly, as compared to control subjects, on 7 tasks of visual recognition memory for single items. Although he sometimes performed above chance, neither familiarity nor recollection appeared fully preserved. These results indicate that extrahippocampal structures, damaged bilaterally in JMG, perform critical operations for item recognition; and that the hippocampus cannot take over that role, including recollection, when these structures are largely damaged. Finally, in a set of 3 recognition memory tasks with scenes as stimuli, JMG performed at the level of control participants and obtained normal indices of familiarity and recollection. Overall, our findings suggest that the right hippocampus and remnants of parahippocampal cortex can support recognition memory for scenes in the absence of preserved item-recognition memory. The patterns of dissociations, which we report in the present study, provide support for a representational account of the functional organization of MTL structures.

Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year-old man.

BACKGROUND: Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. CASE PRESENTATION: We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. CONCLUSIONS: This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.

Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease.

There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.

Proper name anomia with preserved lexical and semantic knowledge after left anterior temporal lesion: a two-way convergence defect.

This article describes the case of a patient who, following herpes simplex encephalitis (HSE), retained the ability to access rich conceptual semantic information for familiar people whom he was no longer able to name. Moreover, this patient presented the very rare combination of name production and name comprehension deficits for different categories of proper names (persons and acronyms). Indeed, besides his difficulty to retrieve proper names, SL presented a severe deficit in understanding and identifying them. However, he was still able to recognize proper names on familiarity decision, demonstrating that name forms themselves were intact. We interpret SL's deficit as a rare form of two-way lexico-semantic disconnection, in which intact lexical knowledge is disconnected from semantic knowledge and face units. We suggest that this disconnection reflects the role of the left anterior temporal lobe in binding together different types of knowledge and supports the classical convergence-zones framework (e.g., Damasio, 1989) rather than the amodal semantic hub theory (e.g., Patterson, Nestor, & Rogers, 2007).

Neuropsychological outcome after carbon monoxide exposure following a storm: a case-control study.

BACKGROUND: The cognitive consequences of carbon monoxide (CO) poisoning are well described. However, most studies have been carried out without an ad-hoc group of control subjects. The main aim of this study was to evaluate cognitive and psychiatric outcome after CO exposure during the storm Klaus in the South West of France (January 2009) in a homogeneous group of patients compared to a group of 1:1 paired controls. METHODS: Patients and controls were asked to fill out questionnaires about quality of life and cognitive complaints. They then underwent a cognitive assessment derived from the Carbon Monoxide Neuropsychological Screening Battery. Psychiatric assessment was performed using subtests of the Mini International Neuropsychiatric Interview. RESULTS: 38 patients and 38 paired controls were included (mean age 38.8 years) and evaluated 51 days after the poisoning. No difference was found between groups on the cognitive complaint questionnaire but patients had a lower quality of life than controls. Patients showed significantly lower cognitive performance than controls on processing speed, mental flexibility, inhibition and working and verbal episodic memories. Patients were more depressed than controls, and suffered more from post-traumatic stress disorder. CONCLUSIONS: We report the first study investigating cognitive and psychiatric outcome in consecutive patients after CO poisoning during a natural disaster, using a group comparison method. CO poisoning during storms needs to be dealt with adequately and clinicians should be aware of its possible consequences.

A case of logopenic primary progressive aphasia with C9ORF72 expansion and cortical florbetapir binding.

We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimer's disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.

Cortical florbetapir-PET amyloid load in prodromal Alzheimer's disease patients.

BACKGROUND: Florbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria. METHODS: We recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito-frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed. RESULTS: Twenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests. CONCLUSIONS: These findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical ß-amyloid load.

MR, (18)F-FDG, and (18)F-AV45 PET correlate with AD PSEN1 original phenotype.

We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease.

C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing.

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers.

We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AßPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AßPP, and 13 AßPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.

Amyloid imaging with AV45 ((18)F-florbetapir) in a cognitively normal AßPP duplication carrier.

We report the case of a 62-year-old asymptomatic carrier of AßPP gene duplication. He was investigated by MRI and the amyloid ligand (18)F-AV45, and compared to Alzheimer's disease patients (n = 11) and healthy controls (n = 11). The neuropsychological examination was normal. Cortical thickness and AV45 retention were comparable to Alzheimer's disease patients. AßPP duplication was diagnosed because cerebral amyloid angiopathy and Alzheimer's disease pathology were found on the neuropathological examination of his youngest brother, who died at 42 from intracerebral hemorrhage. This is the first description of a pre-symptomatic AßPP duplication carrier over 60, despite widespread cerebral amyloid angiopathy, "Alzheimer's like" atrophy, and amyloid deposition.

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-ß peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aß metabolism or signalling, and for which animal or cellular models have already been developed.

Memantine in behavioral variant frontotemporal dementia: negative results.

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

Visual recognition memory: a double anatomo-functional dissociation.

There is an ongoing debate regarding the respective role of anterior subhippocampal structures and the hippocampus in recognition memory. Here, we report a double anatomo-functional dissociation observed in two brain-damaged patients, FRG and JMG. They both suffered from complete destruction of left MTL structures. In the right hemisphere however, FRG sustained extensive lesions to the hippocampus sparing anterior subhippocampal structures, while JMG suffered from the reversed pattern of lesion, i.e., extensive damage to anterior subhippocampal structures but preserved hippocampus. FRG was severely amnesic and failed all recall tasks involving visual material, but exhibited normal performance at a large battery of visual recognition memory tasks. JMG was not amnesic and showed the opposite pattern of performance. These results strongly support the view that right anterior subhippocampal structures are a critical relay for visual recognition memory in the human.

Brain perfusion SPECT with an automated quantitative tool can identify prodromal Alzheimer's disease among patients with mild cognitive impairment.

OBJECTIVE: To improve diagnosis of early Alzheimer's disease (AD), i.e., prodromal AD, by an automated quantitative tool combining brain perfusion single-photon emission computed tomography (SPECT) images and memory tests scores in order to be applied in clinical practice. PATIENTS AND METHODS: In this prospective, longitudinal, multi-centric study, a baseline (99m)Tc-ECD perfusion SPECT was performed in 83 patients with memory complaint and mild cognitive impairment (MCI). After a 3-year follow-up, 11 patients progressed to Alzheimer's disease (MCI-AD group), and 72 patients remained stable (MCI-S group), including 1 patient who developed mild vascular cognitive impairment. After comparison between the MCI-S and MCI-AD groups with a voxel-based approach, region masks were extracted from the statistically significant clusters and used alone or in combination with Free and Cued Selective Reminding Test (FCSRT) scores for the subject's categorization using linear discriminant analysis. Results were validated using the leave-one-out cross-validation method. RESULTS: Right parietal and hippocampal perfusion was significantly (p<0.05, corrected) decreased in the MCI-AD group as compared to the MCI-S group. The patients' classification in the MCI group using the mean activity in right and left parietal cortex and hippocampus yielded a sensitivity, specificity, and accuracy of 82%, 90%, and 89%, respectively. Combination of SPECT results and FCSRT free recall scores increased specificity to 93%. CONCLUSION: The combination of an automated quantitative tool for brain perfusion SPECT images and memory test scores was able to distinguish, in a group of amnestic MCI, patients at an early stage of AD from patients with stable MCI.

Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve.

Brain atrophy measured by magnetic resonance structural imaging has been proposed as a surrogate marker for the early diagnosis of Alzheimer's disease. Studies on large samples are still required to determine its practical interest at the individual level, especially with regards to the capacity of anatomical magnetic resonance imaging to disentangle the confounding role of the cognitive reserve in the early diagnosis of Alzheimer's disease. One hundred and thirty healthy controls, 122 subjects with mild cognitive impairment of the amnestic type and 130 Alzheimer's disease patients were included from the ADNI database and followed up for 24 months. After 24 months, 72 amnestic mild cognitive impairment had converted to Alzheimer's disease (referred to as progressive mild cognitive impairment, as opposed to stable mild cognitive impairment). For each subject, cortical thickness was measured on the baseline magnetic resonance imaging volume. The resulting cortical thickness map was parcellated into 22 regions and a normalized thickness index was computed using the subset of regions (right medial temporal, left lateral temporal, right posterior cingulate) that optimally distinguished stable mild cognitive impairment from progressive mild cognitive impairment. We tested the ability of baseline normalized thickness index to predict evolution from amnestic mild cognitive impairment to Alzheimer's disease and compared it to the predictive values of the main cognitive scores at baseline. In addition, we studied the relationship between the normalized thickness index, the education level and the timeline of conversion to Alzheimer's disease. Normalized thickness index at baseline differed significantly among all the four diagnosis groups (P < 0.001) and correctly distinguished Alzheimer's disease patients from healthy controls with an 85% cross-validated accuracy. Normalized thickness index also correctly predicted evolution to Alzheimer's disease for 76% of amnestic mild cognitive impairment subjects after cross-validation, thus showing an advantage over cognitive scores (range 63-72%). Moreover, progressive mild cognitive impairment subjects, who converted later than 1 year after baseline, showed a significantly higher education level than those who converted earlier than 1 year after baseline. Using a normalized thickness index-based criterion may help with early diagnosis of Alzheimer's disease at the individual level, especially for highly educated subjects, up to 24 months before clinical criteria for Alzheimer's disease diagnosis are met.

Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia.

The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.

Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.