Progression of behavioural disturbances in frontotemporal dementia: a longitudinal observational study.

BACKGROUND AND PURPOSE: Behavioural disturbances are the core features of frontotemporal dementia (FTD); however, symptom progression is still not well characterized during the entire course of the disease. The aim of the present study was to investigate behavioural symptoms at baseline and during the disease course in a large cohort of patients with behavioural variant FTD (bvFTD), non-fluent/agrammatic variant primary progressive aphasia (nfvPPA) and semantic variant primary progressive aphasia (PPA). METHODS: We evaluated 403 patients with FTD, 167 of whom had at least 1-year follow-up evaluation (for a total of 764 assessments). Behavioural symptoms were assessed and rated through the Neuropsychiatric Inventory (NPI) and Frontal Behavioural Inventory (FBI). Disease severity was evaluated through the Frontotemporal Lobar Degeneration -Clinical Dementia Rating scale (FTLD-CDR). Linear mixed models were used to model behavioural measures (NPI, FBI and the five FBI-behavioural core criteria scores) as a function of disease severity (FTLD-CDR score) and clinical phenotype. RESULTS: At baseline, patients with bvFTD showed more behavioural disturbances compared with those with nfvPPA (P = 0.004). Negative symptoms (apathy and loss of empathy) showed a trend to an increase throughout the course of the disease in both bvFTD and PPA (P < 0.001 until intermediate stages). Positive symptoms (disinhibition, perseverations and hyperorality) increased until intermediate phases (P < 0.001) followed by a progressive reduction in later phases, whereas they were less common in nfvPPA throughout the disease course. CONCLUSION: We demonstrated that behavioural disturbances differed in FTD and with disease severity. Positive symptoms appeared to improve in the advanced stages, highlighting the importance of taking into account the disease severity as outcome measure in clinical trials.

Review: Molecular pathology of frontotemporal lobar degenerations.

Frontotemporal lobar degeneration (FTLD) is a group of disorders that principally affect the frontal and temporal lobes of the brain. In many parts of the world, FTLD is rapidly becoming a serious health burden on society and, as a result, the molecular mechanisms that underlie its onset and development have been the target of intense research efforts in recent years. Nonetheless, despite crucial pathological and genetic discoveries in this area much is still uncertain about how the many genes associated with this disease cause the observed neurodegeneration. Moreover, it has not been easy to define the molecular mechanisms that account for the clinical and pathological heterogeneity of the various FTLD subtypes, characterized by aggregates of Tau, TAR-DNA-Binding Protein-43 (TDP-43), and less often Fused in Sarcoma (FUS) protein. In this review, we will examine some of the emerging discoveries in this field: from the recent importance of autoimmunity to the presence of substantial variations in the composition and localization of TDP-43 and FUS brain aggregates in patients, and how they might affect the course of the disease. All together, these new results demonstrate how the observed clinical heterogeneity underlies considerable complexity at both the molecular and the disease pathway level. A better characterization of all this complexity will be essential for a more accurate stratification of patient cohorts for further studies and, eventually, for trials of therapy.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

BACKGROUND AND PURPOSE: Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. METHODS: We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. RESULTS: We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. CONCLUSIONS: Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment.

We report the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy. A 59-year-old man with a past history of diabetes was admitted to our department due to progressive gait difficulties and cognitive impairment. Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus. Brain T2-weighted MR imaging showed bilateral basal ganglia hypointensity with diffuse iron deposition. Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found. The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for two mutations, namely c.848G > A and c.2689_2690delCT. Treatment with FFP (500 mL i.v./once a week) and administration of iron chelator (Deferoxamine 1000 mg i.v/die for 5 days, followed by Deferiprone 500 mg/die per os) were undertaken. At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypointensity. This case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation.

Frontotemporal dementia (FTD) is one of the most important neurodegenerative conditions and Granulin (GRN) is one of the major genes associated to the disease. FTD-GRN patients are still orphan for any evidence-based target-therapy approach. Interestingly, it has been recently found that alkalizing agents rescued haploinsufficiency in cellular models expressing FTD-GRN mutations. We set up a pilot phase II clinical trial in five FTD patients with GRN Thr272s(g.1977_1980delCACT) mutation, to determine if amiodarone (200 mg/day) may (1) reverse progranulin deficiency and (2) delay disease progression. Each patient was scheduled for 7 study visits over 12 months period. We assessed GRN levels at baseline and after amiodarone administration during the treatment course. Somatic and neurologic examinations, along with cognitive and behavioral assessment were recorded as well. No significant effect on peripheral GRN levels was observed. In treated FTD, disease course did not differ when compared with a group of untreated FTD-GRN patients. This is the first trial targeting progranulin rescue in FTD-GRN patients using amiodarone. Despite the negative findings, it may be interesting to extend this attempt to a larger sample of subjects and to other alkalizing agents to restore granulin haploinsufficiency.

Prefrontal cortex rTMS enhances action naming in progressive non-fluent aphasia.

BACKGROUND AND PURPOSE: Progressive non-fluent aphasia (PNFA) is a neurodegenerative disorder that is characterized by non-fluent speech with naming impairment and grammatical errors. It has been recently demonstrated that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) improves action naming in healthy subjects and in subjects with Alzheimer's disease. PURPOSE: To investigate whether the modulation of DLPFC circuits by rTMS modifies naming performance in patients with PNFA. METHODS: Ten patients with a diagnosis of PNFA were enrolled. High-frequency rTMS was applied to the left and right DLPFC and the sham (i.e. placebo) condition during object and action naming. A subgroup of patients with semantic dementia was enrolled as a comparison group. RESULTS: A repeated-measure anova with stimulus site (sham, left and right rTMS) showed significant effects. Action-naming performances during stimulation of both the left and right DLPFC were better than during placebo stimulation. No facilitating effect of rTMS to the DLPFC on object naming was observed. In patients with a diagnosis of semantic dementia, no effect of stimulation was reported. CONCLUSIONS: Our study demonstrated that rTMS improved action naming in subjects with PNFA, possibly due to the modulation of DLPFC pathways and a facilitation effect on lexical retrieval processes. Future studies on the potential of a rehabilitative protocol using rTMS applied to the DLPFC in this orphan disorder are required.

Nature versus nurture in frontotemporal lobar degeneration: the interaction of genetic background and education on brain damage.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder with a strong genetic background. It has been reported that modifiable factors, i.e. education (E), might act as proxies for reserve capacity. OBJECTIVE: To evaluate the impact of genetic background (positive family history, FH) on reserve mechanisms, by measuring regional cerebral blood flow (rCBF) correlates in FTLD patients. METHODS: 145 FTLD patients were recruited and underwent clinical, neuropsychological, behavioral assessment, and SPECT study. The main effect of E and FH on rCBF was evaluated. To test the potential interaction between the E and rCBF in FTLD patients with or without positive FH, a difference of slope analysis in the two groups was calculated. All the analyses were controlled for disease severity (Clinical Dementia Rating Scale, FTD-CDR). RESULTS: A main effect of education (E+ < E-) in frontal regions was reported, and high genetic loading (FH+ < FH-) was associated with a greater bilateral temporoparietal hypoperfusion. Evaluating the relationship between E and rCBF, a greater hypoperfusion of cingulate region in FH+ as compared to FH- was observed. DISCUSSION: Reserve mechanisms are available also in presence of an unfavorable genetic status. However, these compensatory mechanisms are modulated by the interaction with genetic factors.

Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease.

It has been recently demonstrated that the 43-kDa transactive response (TAR)-DNA-binding protein (TARDBP) is the neuropathological hallmark of Frontotemporal Dementia (FTD) with ubiquitin-positive and tau-negative inclusions. Large series of FTD patients without motor neuron disease have been previously analysed, but no TARDBP mutation was identified. The aim of the present study was to evaluate whether TARDBP gene mutations may be associated with FTD. We report that a pathogenetic TARDBP mutation is causative of behavioural variant FTD (bvFTD). An aged woman in her seventies initially started to present apathy and depression associated with impairment in executive functions. The diagnosis of bvFTD (apathetic syndrome) was accomplished by three-year follow-up, and structural and functional neuroimaging. By five-years after onset, extensive electrophysiological investigations excluded subclinical motor neuron disease. In this patient, a single base substitution c.800A>G of TARDBP gene was identified. This mutation, already described as causative of ALS, predicted the amino acidic change arginine to serine at position 267 (N267S). In silico analysis demonstrated that this substitution generates a new phosphorylation site, and western blot analysis on lymphoblastoid cells reported a decrease of protein expression in N267S mutation carrier. Our study suggests that TARDBP mutations can be pathogenetic of bvFTD without motor neuron disease. TARDBP screening needs to be considered in FTD cases.

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.

Implications of metal exposure and liver function in Parkinsonian patients resident in the vicinities of ferroalloy plants.

Valcamonica is an Italian valley where ferro-manganese industries have been active for a century and where an increased prevalence of parkinsonism was observed. A group of 93 patients (65 from Valcamonica, 28 from the reference area of Brescia city) and 76 controls (52 from Valcamonica, 24 from Brescia) were screened for serum Cu, Zn, Fe, Mn in blood (MnB) and urine (MnU), transferrin, peroxides, alanine (ALT) and aspartate (AST) transaminases and direct bilirubin. Test results were compared among groups according to the residential area and related to the disease severity. Valcamonica patients had a serum-increase of Cu, as well as of AST/ALT ratio, and a serum-decrease of Zn and Fe compared with other subgroups of cases and controls. Cases and controls from Valcamonica had higher MnB and MnU levels compared to cases and controls from Brescia. After controlling for the duration of illness, the Unified Parkinson's Disease Rating Scale III domain correlated with serum Cu and AST/ALT ratio. Our results suggest the possibility that, in this area, a lifetime exposure to neurotoxicants and to Mn in particular, when accompanied to a subclinical liver dysfunction, may pose an increased risk for neurodegenerative disorders via metal metabolism (Cu, Zn, Fe) abnormalities.

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.

Serum leptin levels are higher in females affected by frontotemporal lobar degeneration than Alzheimer's disease.

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.

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.

Tau haplotype influences cerebral perfusion pattern in frontotemporal lobar degeneration and related disorders.

OBJECTIVE: The modulating factors on phenotypic expression of frontotemporal lobar degeneration (FTLD) remain still unknown. The aim of this study was to determine whether tau genetic variability modulates the brain functional and the clinical phenotypic expression of FTLD. MATERIALS AND METHODS: Clinical and neurological evaluations, a standardized neuropsychological assessments as well as a brain single photon emission tomography perfusion imaging studies were performed in 48 FTLD patients. Cerebral perfusion patterns were analysed according to H1 or H2 tau haplotypes by statistical parametric mapping and principal component analysis. RESULTS: Two different patterns of cerebral dysfunction characterized the haplotypes, as hypoperfusion of frontal medial and cingulated cortex in H2-carriers and a prevalent involvement of posterior parietal regions in H1-carriers. Further, a significant increase of cerebrospinal fluid total tau and phospho tau levels was found in H2-carriers. CONCLUSIONS: These findings support a role of tau haplotype in modulating disease phenotype by influencing the hypoperfusion pattern and cerebrospinal fluid tau levels in FTLD.

The contribution of TMS to frontotemporal dementia variants.

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

Antinuclear antibodies in Frontotemporal Dementia: the tip's of autoimmunity iceberg?

Recent studies suggest a role of the autoimmune system dysregulation in Frontotemporal dementia (FTD). In the present study, we performed a broad immunological screening in a large sample of sporadic FTD patients. We reported a significant increase of antinuclear autoantibodies (ANA) positivity in 100 FTD patients as compared to 100 healthy controls (HC) (60% vs. 13%, p < .001). In FTD, ANA-positive and ANA-negative patients did not differ for any clinical feature. These data extend and further confirm autoimmune dysregulation in FTD. However, it still remains to be clarified whether these antibodies have a potential pathogenic role or represent simply an epiphenomenon.

Publisher Correction: Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Dementia, delusions and seizures: storage disease or genetic AD?

We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended.

Source-Based Morphometry Multivariate Approach to Analyze [123I]FP-CIT SPECT Imaging.

PURPOSE: [123I]FP-CIT (DaTSCAN®) single-photon emission computed tomography (SPECT) imaging is widely used to study neurodegenerative parkinsonism, by measuring presynaptic dopamine transporter (DAT) in striatal regions. Beyond DAT, [123I]FP-CIT may be considered for other monoaminergic systems, in particular the serotonin transporter (SERT). Independent component analysis (ICA) implemented in source-based morphometry (SBM) could represent an alternative method to explore monoaminergic pathways, studying the relationship among voxels and grouping them into "neurotransmission" networks. PROCEDURES: One hundred forty-three subjects [84 with Parkinson's disease (PD) and 59 control individuals (CG)] underwent DATSCAN® imaging. The [123I]FP-CIT binding was evaluated by multivariate SBM approach, as well as by a whole-brain voxel-wise univariate (statistical parametric mapping, SPM) approach. RESULTS: As compared to the univariate whole-brain approach (SPM) (only demonstrating striatal [123I]FP-CIT binding reduction in PD group), SBM identified six sources of non-artefactual origin, including basal ganglia and cortical regions as well as brainstem. Among them, three sources (basal ganglia and cortical regions) presented loading scores (as index of [123I]FP-CIT binding) significantly different between PD and CG. Notably, even if not significantly different between PD and CG, the remaining three non-artefactual sources were characterized by a predominant frontal, brainstem, and occipito-temporal involvement. CONCLUSION: The concept of source blind separation by the application of ICA (as implemented in SBM) represents a feasible approach to be considered in [123I]FP-CIT (DaTSCAN®) SPECT imaging. Taking advantage of this multivariate analysis, specific patterns of variance can be identified (involving either striatal than extrastriatal regions) that could be useful in differentiating neurodegenerative parkinsonisms.