In-vivo signatures of neurodegeneration in isolated rapid eye movement sleep behaviour disorder.

BACKGROUND AND PURPOSE: Isolated rapid eye movement sleep behaviour disorder (iRBD) is a parasomnia, recently recognized as a risk factor for progression to Parkinson's disease, dementia with Lewy body and multiple system atrophy. Biomarker studies in iRBD are relevant due to lack of evidence in this condition. The identification of biomarkers able to predict progression to synucleinopathy diseases is critical for iRBD. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging might provide information about ongoing neurodegenerative processes. In the present study, we tested for presence of brain hypometabolism patterns as biomarkers of neurodegeneration in single iRBD individuals. METHODS: We recruited 37 subjects with polysomnography-confirmed iRBD, with neuropsychological assessment and available FDG-PET scan. Images were analysed with a validated statistical parametric mapping procedure, providing individual hypometabolism maps. RESULTS: According to the neuropsychological evaluation, 22 subjects with iRBD had normal cognition and 15 subjects showed impairments, particularly in visuoperceptive/visuospatial and memory domains. One-fifth of the cases were impaired on the Qualitative Scoring of Pentagon Test. In 32 iRBD cases, FDG-PET statistical parametric maps revealed significant cerebral hypometabolism, namely in the occipital lobes (n = 5), occipital and cerebellar regions (n = 13), occipitoparietal regions (n = 13) and a selective cerebellar hypometabolism (n = 1). Five cases had normal FDG-PET scans. CONCLUSIONS: These imaging findings indicate that brain neurodegenerative processes are present and already detectable in iRBD. The different hypometabolism patterns in the single individuals may reflect specific early pathophysiological events due to the underlying synucleinopathy, with a specific neural vulnerability for the occipital cortex that might pre-date a risk of progression towards dementia with Lewy body.

Italian consensus recommendations for a biomarker-based aetiological diagnosis in mild cognitive impairment patients.

BACKGROUND AND PURPOSE: Biomarkers support the aetiological diagnosis of neurocognitive disorders in vivo. Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker-based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts. METHODS: With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology - Società Italiana di Neurologia per le Demenze; neuroradiology - Associazione Italiana di Neuroradiologia; biochemistry - Società Italiana di Biochimica Clinica; psychogeriatrics - Associazione Italiana di Psicogeriatria; nuclear medicine - Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An N-1 majority defined consensus achievement. RESULTS: The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single-photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes-no-abstained): 3-1-1); 18 F-fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer's disease (round VII, 4-0-1); cerebrospinal fluid for suspected Alzheimer's disease (round IV, 4-1-0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4-1-0) or inconclusive (round VI, 5-0-0). CONCLUSIONS: These consensus recommendations can guide clinicians in the biomarker-based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence-to-decision procedures due to incomplete evidence.

Evaluation of an optimized [18 F]fluoro-deoxy-glucose positron emission tomography voxel-wise method to early support differential diagnosis in atypical Parkinsonian disorders.

BACKGROUND AND PURPOSE: Atypical Parkinsonian disorders (APD) frequently overlap in clinical presentations, making the differential diagnosis challenging in the early stages. The present study aimed to evaluate the accuracy of the [18 F]fluoro-deoxy-glucose positron emission tomography Statistical Parametric Mapping (SPM) optimized procedure in supporting the early and differential diagnosis of APD. METHODS: Seventy patients with possible APD were retrospectively included from a large clinical cohort. The included patients underwent [18 F]fluoro-deoxy-glucose positron emission tomography within 3 months of the first clinical assessment and a diagnostic follow-up. An optimized SPM voxel-wise procedure was used to produce t-maps of brain hypometabolism in single subjects, which were classified by experts blinded to any clinical information. We compared the accuracy of both the first clinical diagnosis and the SPM t-map classifications with the diagnosis at follow-up as the reference standard. RESULTS: At first diagnosis, 60% of patients were classified as possible APD (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy) and about 40% as APD with uncertain diagnosis, providing 52% sensitivity, 97% specificity and 86% accuracy with respect to the reference standard. SPM t-map classification showed 98% sensitivity, 99% specificity and 99% accuracy, and a significant agreement with the diagnosis at follow-up (P < 0.001). CONCLUSIONS: The SPM t-map classification at entry predicted the second diagnosis at follow-up. This indicates its significantly superior role for an early identification of APD subtypes, particularly in cases of uncertain diagnosis. The use of a metabolic biomarker at entry in the instrumental work-up of APD may shorten the diagnostic time, producing benefits for treatment options and support to the patients.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Simultaneous reconstruction of attenuation and activity in cardiac PET can remove CT misalignment artifacts.

BACKGROUND: Misalignment between positron emission tomography (PET) and computed tomography (CT) data is known to generate artifactual defects in cardiac PET images due to imprecise attenuation correction (AC). In this work, the use of a maximum likelihood attenuation and activity (MLAA) algorithm is proposed to avoid such artifacts in time-of-flight (TOF) PET. METHODS: MLAA was implemented and tested using a thorax/heart phantom and retrospectively on fourteen (13)N-ammonia PET/CT perfusion studies. Global and local misalignments between PET and CT data were generated by shifting matched CT images or using CT data representative of the end-inspiration phase. PET images were reconstructed with MLAA and a 3D-ordered-subsets-expectation-maximization (OSEM)-TOF algorithm. Images obtained with 3D-OSEM-TOF and matched CT were used as references. These images were compared (qualitatively and semi-quantitatively) with those reconstructed with 3D-OSEM-TOF and MLAA for which a misaligned CT was used, respectively, for AC and initialization. RESULTS: Phantom experiment proved the capability of MLAA to converge toward the correct emission and attenuation distributions using, as input, only PET emission data, but convergence was very slow. Initializing MLAA with phantom CT images markedly improved convergence speed. In patient studies, when shifted or end-inspiration CT images were used for AC, 3D-OSEM-TOF reconstructions showed artifacts of increasing severity, size, and frequency with increasing mismatch. Such artifacts were absent in the corresponding MLAA images. CONCLUSION: The proposed implementation of the MLAA algorithm is a feasible and robust technique to avoid AC mismatch artifacts in cardiac PET studies provided that a CT of the source is available, even if poorly aligned.

Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), ß-amyloid PET imaging tracer for Alzheimer's disease diagnosis.

[11C]PIB is the most used amyloid plaques-specific positron-emitting radiotracers. The radiosynthesis of this compound, carried out by methylation of its precursor with [11C]methyl triflate in 2-butanone, has been improved optimizing the initial concentration and the purification method. Two HPLC methods were compared: good radiochemical yields, specific activities, and chemical purity above 98% were achieved by using as eluant acetonitrile/citrate and formulation in 10% ethanol.

From primary progressive aphasia to corticobasal syndrome: two clinical and rCBF functional reports.

We describe two cases, both presenting with a 2-year history of isolated language disorders, one compatible with logopenic variant and the other with non-fluent variant of primary progressive aphasia (PPA). Afterwards, each developed a corticobasal syndrome (CBS) with alien limb phenomenon and a multi-domain cognitive impairment. Regional cerebral perfusion (rCBF) study using 99mTc-ECD single photon emission computed tomography (SPECT) revealed hypoperfusion patterns consistent with these aphasia types and with the presence of limb apraxia. We report two cases of PPA variants associated with CBS and we suggest that SPECT rCBF correlates can be useful in making a differential diagnosis within the PPA spectrum.

In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson's disease.

BACKGROUND: Reactive microgliosis, hallmark of neuroinflammation, may contribute to neuronal degeneration, as shown in several neurodegenerative diseases. We in vivo evaluated microglia activation in early dementia with Lewy bodies, still not reported, and compared with early Parkinson's disease, to assess possible differential pathological patterns. METHODS: We measured the [(11)C]-PK11195 binding potentials with Positron Emission Tomography, using a simplified reference tissue model, as marker of microglia activation, and cerebral spinal fluid protein carbonylation levels, as marker of oxidative stress. Six dementia with Lewy bodies and 6 Parkinson's disease patients within a year from the onset, and eleven healthy controls were included. Clinical diagnosis was confirmed at a 4-year follow-up. RESULTS: In dementia with Lewy bodies as well as in Parkinson's disease, we found significant (p < 0.001) [(11)C]-PK11195 binding potential increases in the substantia nigra and putamen. Patients with Lewy bodies dementia had extensive additional microglia activation in several associative cortices. This was evident also at a single subject level. Significant increase of Cerebral Spinal Fluid protein carbonylation was shown in both patients' groups. CONCLUSIONS: [(11)C]-PK11195 Positron Emission Tomography imaging revealed neuroinflammation in dementia with Lewy bodies and Parkinson's disease, mirroring, even at a single subject level, the common and the different topographical distribution of neuropathological changes, yet in the earliest stages of the disease process. Focusing on those events that characterize parkinsonisms and Parkinson's disease may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: Despite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions. PATIENTS AND METHODS: Investigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure. RESULTS: The comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex. CONCLUSION: Deep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.

Education and occupation provide reserve in both ApoE ε4 carrier and noncarrier patients with probable Alzheimer's disease.

According to the reserve hypothesis, a high educational/occupational attainment can modulate Alzheimer's disease (AD) clinical expression. The impact of the Apolipoprotein E (ApoE) ε4 allele on the reserve mechanism in AD has not been assessed. Aim of this European multicenter study was to evaluate the metabolic correlates of reserve and ApoE genotype in early probable AD. 51 AD subjects, 27 ε4 carriers, and 24 noncarriers, underwent FDG-PET brain imaging. We used the general linear model as implemented in SPM2 to test for the linear correlation of a reserve index, accounting for both educational and occupational level, with brain glucose metabolism, controlling for demographic variables (age and gender) and for cognitive performance. We found an inverse correlation between a reserve index, accounting for educational/occupational level, and metabolism in the posterior cingulate cortex and precuneus in both ε4 carriers and noncarriers, and no significant difference between the groups. We show that education and occupation act as proxies for reserve in ε4 carriers, compensating for an unfavorable genetic background; we also show that the degree of compensation does not differ significantly by ApoE ε4 status.

Generalization of the effects of phonological training for anomia using structural equation modelling: a multiple single-case study.

Structural Equation Modelling analysis of three longitudinal er-fMRI sessions was used to test the impact of phonological training and of the generalization process on the pattern of brain connectivity during overt picture naming in two chronic anomic patients. Phonological training yielded a positive effect on the trained material. Six months after the training, a generalization of the positive impact on the untrained items was also observed. Connectivity analysis showed that training and generalization effects shared paralleled cortical patterns of functional integration. These findings may represent the neurophysiological correlate of the training-induced cognitive strategies for the compensation of anomia.

Disorganization of anatomical connectivity in obsessive compulsive disorder: a multi-parameter diffusion tensor imaging study in a subpopulation of patients.

Obsessive-compulsive disorder (OCD) is thought to involve large-scale brain systems but the anatomical connectivity via association fibers has not been specifically investigated yet. We evaluated organization and directionality of the major fiber bundles in a subpopulation of OCD, including washers and checkers who presented decision making deficits, by measuring MRI parameters related to water self-diffusion (Fractional Anisotropy, FA) and fiber directionality (Principal Diffusion Direction, PDD) in 15 OCD and 16 control subjects. OCD patients showed significantly lower FA and altered PDD along the corpus callosum, cingulum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus bilaterally. The track-based analysis of the inferior fronto-occipital fasciculus confirmed a significant bilateral FA reduction. Lower FA values in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus and corpus callosum correlated with symptom severity and neuropsychological performance. This multi-parameter MRI study revealed specific white matter abnormalities in OCD suggesting tract disorganization as main feature, reflected by local changes in fiber directionality. This altered anatomical connectivity might play a specific role in OCD pathophysiology.

Revisiting brain reserve hypothesis in frontotemporal dementia: evidence from a brain perfusion study.

BACKGROUND: Literature data on Alzheimer's disease suggest that years of schooling and occupational level are associated with a reserve mechanism. No data on patients with behavioral variant frontotemporal dementia (bvFTD) are available yet. OBJECTIVE: To evaluate the impact of education, occupation, and midlife leisure activities on brain reserve in bvFTD. METHODS: Fifty-four bvFTD patients entered the study and underwent neuropsychological and behavioral assessment, including the FTD-modified Clinical Dementia Rating for FTD (FTD-modified CDR), and SPECT imaging. We tested for the linear correlation of educational and occupational level, and midlife leisure activities with regional cerebral blood flow (rCBF), controlling for demographic variables (age and gender) and for cognitive performance (FTD-modified CDR) (statistical parametric mapping). RESULTS: A significant relationship between higher educational and occupational attainments and lower rCBF in medial frontal cortex and dorsolateral frontal cortex, bilaterally, was found (p < 0.005). When midlife leisure activities were considered, no correlation was found. The correlation between a reserve index, accounting for both educational and occupational level, and rCBF showed the same pattern of hypoperfusion. CONCLUSIONS: This study suggests that education and occupation act as proxies for reserve capacity in bvFTD. These lifestyle attainments may counteract the onset of this genetic-based disease in at-risk individuals.

Survival in frontotemporal lobar degeneration and related disorders: latent class predictors and brain functional correlates.

BACKGROUND: Establishing survival rate in frontotemporal lobar degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. Using the latent profile analysis (LPA) approach, we have previously suggested that FTLD patients can be grouped into specific phenotypes- "pseudomanic behavior" (LC1), "cognitive" (LC2), and "pseudodepressed behavior" (LC3)-on the basis of neuropsychological, functional, and behavioral data. OBJECTIVE: The aim of this study was to evaluate the rate of survival in FTLD, to identify predictors of survival, and to determine the likely usefulness of LPA in defining prognosis. METHODS: A total of 252 FTLD patients entered the study. A clinical evaluation and standardized assessment were carried out, as well as a brain imaging study. LPA on neuropsychological, functional, and behavioral data was performed. Each patient was followed up over a 5-year period, and institutionalization or death was considered. RESULTS: The survival rate was associated neither with demographic characteristics, co-morbidities, family history for dementia, nor clinical diagnosis. The presence of the three LC phenotypes was confirmed by LPA. A different survival rate was predicted by LCs, the worse prognosis being found in LC1 (hazard ratio [HR] = 15.7, 95% confidence interval [CI] = 7.2-34.9, p < 0.001, reference LC3). LC2 had a worse prognosis compared to LC3 (HR = 2.07, 95% CI = 0.98-4.37, p = 0.06). Greater hypoperfusion in the orbitomesial frontal cortex was specifically associated with LC1 compared with the other LCs. CONCLUSIONS: A data-driven approach regarding neuropsychological and behavioral assessment might be useful in clinical practice for defining a FTLD prognosis and hopefully will lead to the possibility of identifying patient groups for the evaluation of treatment response in future trials.

Supercalifragilisticexpialidocious: how the brain learns words never heard before.

Vocabulary acquisition is such a major aspect of language learning in children, but also in adults when learning a foreign language, that a dedicated vocabulary learning device may exist within the language organ. To identify the relevant brain systems, we performed regional cerebral blood flow measurements in normal subjects while they were learning a list of neologisms or a list of word-nonword pairs. Structures implicated in phonological short-term memory (Broca's area, left temporo-parietal junction) were steadily activated during nonwords learning, while the left temporal lobe neocortical and paralimbic structures (parahippocampal region), associated with long-term memory, contributed to learning in a time-dependent manner, with maximal activation at the beginning of the process. The neural system specifically activated when learning new vocabulary was strongly lateralized to the left hemisphere. This evidence refines current models of memory function and supports theories which emphasise the importance of phonological competence in hemispheric dominance for language.

Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence.

BACKGROUND: Previous reports have shown that higher education is associated with more severe brain pathology in patients with Alzheimer disease (AD), suggesting that these individuals have a functional reserve provided by education, which masks the clinical expression of a higher degree of neurodegeneration. It is unknown if a similar reserve mechanism exists in patients with amnestic mild cognitive impairment (aMCI). The aim of this study was to assess the impact of education and occupation on brain glucose metabolism (rCMRglc) measured with FDG-PET in aMCI and in a very large sample of subjects with probable AD (pAD). METHODS: A total of 242 patients with pAD, 72 with aMCI, and 144 healthy controls participated in the study. At follow-up, 21 subjects with aMCI progressed to AD. A regression analysis was conducted (SPM2), with education and occupation as independent variables, and rCMRglc as dependent variable, adjusting for demographic data, global cognitive status, and neuropsychological scores. RESULTS: The analysis showed a significant association between higher education/occupation and lower rCMRglc in posterior temporoparietal cortex and precuneus in pAD and aMCI converters, and no correlation in aMCI nonconverters and healthy controls. This means that, when submitted to FDG-PET for diagnostic evaluation, pAD and aMCI converters with higher education/occupation had, for comparable cognitive impairment, a more severe rCMRglc reduction than the ones with lower education/occupation. CONCLUSIONS: This study suggests that education and occupation may be proxies for brain functional reserve, reducing the severity and delaying the clinical expression of Alzheimer disease (AD) pathology. The results in aMCI converters suggest that functional reserve is already at play in the predementia phase of AD.

Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy.

OBJECTIVE: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. METHODS: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. RESULTS: Tau form ratio was significantly reduced in patients with PSP (0.504 +/- 0.284) when compared to age-matched controls (0.989 +/- 0.343), and to patients with other neurodegenerative conditions (range = 0.899-1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. CONCLUSIONS: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness.

Brain magnetic resonance imaging structural changes in a pedigree of asymptomatic progranulin mutation carriers.

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p < 0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p < 0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.

The logopenic/phonological variant of primary progressive aphasia.

OBJECTIVE: Primary progressive aphasia (PPA) is characterized by isolated decline in language functions. Semantic dementia and progressive nonfluent aphasia are accepted PPA variants. A "logopenic" variant (LPA) has also been proposed, but its cognitive and anatomic profile is less defined. The aim of this study was to establish the cognitive and anatomic features of LPA. METHODS: Six previously unreported LPA cases underwent extensive neuropsychological evaluation and an experimental study of phonological loop functions, including auditory and visual span tasks with digits, letters, and words. For each patient, a voxel-wise, automated analysis of MRI or SPECT data were conducted using SPM2. RESULTS: In LPA, speech rate was slow, with long word-finding pauses. Grammar and articulation were preserved, although phonological paraphasias could be present. Repetition and comprehension were impaired for sentences but preserved for single words, and naming was moderately affected. Investigation of phonological loop functions showed that patients were severely impaired in digit, letter, and word span tasks. Performance did not improve with pointing, was influenced by word length, and did not show the normal phonological similarity effect. Atrophy or decreased blood flow was consistently found in the posterior portion of the left superior and middle temporal gyri and inferior parietal lobule. CONCLUSIONS: Logopenic progressive aphasia (LPA) is a distinctive variant of primary progressive aphasia. Cognitive and neuroimaging data indicate that a deficit in phonological loop functions may be the core mechanism underlying the LPA clinical syndrome. Recent studies suggest that Alzheimer disease may be the most common pathology underlying the LPA clinical syndrome.