Analysis of power law models for the creep of nucleus pulposus tissue.

Tissue engineering approaches are now being investigated for altering the course of intervertebral disc degeneration (IDD). Because the disease changes the mechanical properties of the load bearing tissues of the disc, viscoelastic tissue behavior is a key measure for comparing the efficacy of treatments. To investigate the basic viscoelastic behavior of nucleus pulposus tissue, tissue from the rabbit disc was tested in torsional creep. Both the Andrade and Nutting creep models had a good fit to the data, however, the Andrade creep model gave a much better prediction of the longer term creep. This is the first application of Andrade creep to biological tissue and results indicate that this model may be particularly well suited for characterizing the viscoelastic behavior of very soft biological tissues.

TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course.

The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.

Cerebrovascular risk factors and triggers in transient global amnesia patients with and without jugular valve incompetence: results from a sample of 243 patients.

BACKGROUND/AIMS: Different etiologies for transient global amnesia (TGA) have been proposed, such as venous flow abnormalities, spreading depression and migraine-related mechanisms like focal ischemia. Jugular vein valve incompetence (JVI) is commonly described in TGA patients, but its contributing role in TGA pathogenesis is still unknown. We investigated the possible relationship between JVI and pathogenetic mechanisms in TGA. METHODS: 243 TGA patients underwent clinical and neurological assessment. Demographic characteristics, TGA-precipitating factors and vascular comorbidities were carefully recorded. In each patient, JVI was assessed by Doppler ultrasonography. RESULTS: TGA patients were grouped according to the presence (n = 171, 70.4%) or absence (n = 72, 29.6%) of JVI. TGA patients with JVI showed a higher presence of precipitating factors, namely a Valsalva-like maneuver (JVI-positive vs. JVI-negative, 35.8 vs. 17.1%, p = 0.004) and emotional stress (36.6 vs. 21.4%, p = 0.023), but had fewer vascular comorbidities, namely hypertension (37.2 vs. 51.4%, p = 0.047) and carotid arteriosclerosis (20.5 vs. 31.9%, p = 0.050). CONCLUSIONS: These findings support the argument for the existence of at least 2 different TGA-associated mechanisms defined by JVI. On the one hand, JVI associated with a Valsalva-like maneuver and emotional stress supported the venous blood congestion hypothesis, and on the other, the JVI-negative group may have another vascular basis, unrelated to venous congestion.

The FTLD-modified Clinical Dementia Rating scale is a reliable tool for defining disease severity in frontotemporal lobar degeneration: evidence from a brain SPECT study.

BACKGROUND: Frontotemporal Lobar Degeneration (FTLD) is a heterogeneous disorder characterized by impairment in executive functions, behavioural disturbance and language deficit. Reliable scales of global impairment are under evaluation. A consortium of Mayo Clinic and University of California FTLD Centers has recently developed the FTLD-modified Clinical Dementia Rating (CDR) scale to assess FTLD severity. OBJECTIVE: To evaluate whether FTLD-modified CDR scores correlate with the pattern and degree of brain SPECT hypoperfusion in patients with FTLD. METHODS: Ninety-nine patients with FTLD entered the study. Patients underwent a clinical evaluation and a wide standardized neuropsychological assessment, including mini-mental state examination (MMSE) and FTLD-modified CDR. A brain SPECT perfusion imaging study was carried out in each patient. A linear correlation analysis between frontotemporal dementia-modified CDR or neuropsychological tests scores and perfusion data was performed. RESULTS: There was a significant relationship between higher FTLD-modified CDR score and lower global regional cerebral blood flow in the frontal and temporal lobes, bilaterally. No significant correlation between MMSE and brain frontotemporal hypoperfusion was found. The correlation between brain hypoperfusion pattern and neuropsychological test scores tapping different cognitive domains fitted with previously published data. CONCLUSIONS: The recently introduced FTLD-modified CDR scale correlates with the degree of frontotemporal hypoperfusion in patients with FTLD. This study confirms and further supports the usefulness of FTLD-modified CDR in future clinical trials to monitor disease progression.

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.

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.

Is early-onset clinically different from late-onset frontotemporal dementia?

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is the second most common neurodegenerative dementia in the young age after Alzheimer disease. Recent improvement in diagnostic assessment suggests that it is more common than previously, although with a great heterogeneity in clinical presentation. The different clinical patterns related to age of disease onset in behavioural variant FTD (bvFTD) have been fairly studied. Aim of the study was to evaluate whether age at disease onset modulate the heterogeneity of either cognitive impairment or behavioural disturbances in patients affected by bvFTD. METHODS: One hundred and thirty-four patients with bvFTD entered the study. Age at onset and demographic characteristics were carefully recorded. Each patient underwent a wide neuropsychological and behavioural standardized assessment, as well as a brain SPECT perfusion imaging study. RESULTS: Behavioural variant FTD were subdivided into four groups according to the age at onset. The four quartile groups did not differ for demographic characteristics and family history for dementia. Global cognitive impairment as well as analysis of the different cognitive domains and behavioural patterns were comparable. CONCLUSIONS: These findings provide evidence that the clinical heterogeneity of bvFTD is not explained by age at disease onset. Further studies are needed.

Preliminary evidence that VEGF genetic variability confers susceptibility to frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) recognizes a strong genetic background, with 30-50% of cases with a positive family history. Despite several efforts to identify monogenic causes of the disease, no clear-cut genetic risk factors for sporadic FTLD are yet known. Recently, increasing evidence points to a pivotal role of vascular endothelial growth factor (VEGF) in the neurodegenerative process, suggesting functions not confined to its originally described vascular effects. The aim of this study was to investigate the role of VEGF as a genetic determinant to FTLD susceptibility. We evaluated a cohort of 274 unrelated Italian patients, including 161 subjects with frontotemporal dementia (FTD), 56 with corticobasal degeneration syndrome, and 57 with progressive supranuclear palsy. Genotype and allele frequencies of four well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, -1154G/A, and -634G/C) were calculated in patients and in 216 age-matched healthy subjects. Genetic analysis revealed the presence of several significant changes in terms of allele, genotype, and haplotype frequency distributions between patients and controls. Marked differences were observed when the FTD patient subgroup was compared with healthy subjects. Overall, these data provide evidence for the first time that VEGF gene variability represents a susceptibility factor for sporadic FTLD, at least in an Italian population. Future confirmatory studies are mandatory.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is not significantly correlated to Transient Global Amnesia: preliminary results of an on-going study in Brescia Province, Italy.

Transient Global Amnesia (TGA) is a well defined pure amnesic clinical syndrome characterized by acute loss of memory in middle aged people. The aetiology of TGA is still unknown but clinical and neuroimaging studies support a hippocampi involvement, and some reports suggested a possible common genetic background in cases of familial TGA. A single nucleotide polymorphism (SNP) in the Brain-derived neurotrophic factor (BDNF) gene that causes a valine to methionine substitution at codon 66 (Val66Met) has been demonstrated to affect human memory and hippocampal function in the development and maintenance of adult neurons. Aim of this study was to evaluate the role of BDNF Val66Met polymorphism on TGA risk and all TGA clinical features. Ninety-eight TGA patients and 93 age-matched controls were enrolled in the study. Each patient underwent clinical and neurological examination, routine blood examination, EEG, Jugular vein valve (JVI) competence assessment, and neuroimaging study. TGA characteristics were carefully recorded. The distribution of BDNF genotype did not differ in TGA patients compared to controls (BDNF GG: 58.2% vs 55.9%, GA: 33.7% vs 36.6%, AA: 8.1% vs 7.5%, P=.91) as well as allele frequency (BDNF G, TGA vs CON: 75.0% vs 74.2, P=.47). No significant differences in age at onset, disease duration and recurrence or the presence of predisposing factors between TGA patients carrying BDNF AA, BDNF GA and BDNF GG genotype were found. This study, that firstly looked at genetic background in TGA, did not show a significant correlation between the BDNF Val66Met polymorphism and age of onset, risk factors, duration or recurrence of TGA.

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.

Transient global amnesia and brain lesions: new hints into clinical criteria.

BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is the abrupt onset of anterograde amnesia with repetitive queries. Different hypotheses have been considered for its aetiology, but it still remains obscure. In 1990, Hodges and Warlow proposed clinical criteria for TGA. Applying these criteria, clinical studies looked for an unifying theory, considering TGA almost a primary and benign disorder. However, spare descriptions of TGA in patients with brain structural lesions have been reported. The aim of this study was to evaluate the prevalence of brain structural lesions among TGA patients. METHODS: One hundred and thirty clinically defined TGA were consecutively recruited. Among them, 13 patients (10%) showed brain structural lesions (TGA-b). RESULTS: No significant difference in clinical features, duration of TGA episode, age of onset, gender between primary TGA (TGA-p) and TGA-b were found. Triggering factors were comparable, suggesting that TGA-b should be considered in the spectrum of TGA, being clinically indistinguishable. CONCLUSIONS: Transient global amnesia deserves a careful neuroimaging study and clinical follow-up considering the high prevalence of brain lesions among these patients and the impossibility to exclude TGA-b by clinical features. The follow-up of these patients and the evaluation of involved brain areas might help to further elucidate the pathogenetic mechanisms of the disease.

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.

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.

Behavioral and psychological symptoms in dementia with Lewy-bodies (DLB): frequency and relationship with disease severity and motor impairment.

Clinical criteria for DLB have been more and more accurate over time, and they had focused on psychotic symptoms for their high frequency. Recent literature suggests that behavioral and psychological symptoms of dementia (BPSD) are frequently associated with DLB, beyond the presence of psychosis. Notwithstanding, the occurrence of BPSD in DLB is under-investigated, and no data are available yet in the different stages. Aim of the present study was to evaluate BPSD pattern in the different stages of DLB, and characterize the relationship with both cognitive deficits and Parkinsonian signs. Ninety-two DLB patients were enrolled and were divided into mild (n=63, 68.5%) and moderate-severe (n=29, 31.5%) subgroups according to the severity of cognitive impairment. Considering the absence/presence of symptoms, anxiety was the most common BPSD (67.4%), followed by depression (61.9%), apathy (57.6%), agitation and sleep disorder (55.4%). Psychosis was present in half of the patients. These symptoms worsened over disease course and represented a core-feature of the disease. No association between BPSD severity and the degree of motor disability was found. These observations suggest that a careful and systematic evaluation of BPSD is mandatory for carefully characterizing disease-related features and for developing new therapeutic approaches. Knowledge of the specific weight of BPSD in DLB would contribute to improve the allocation of health resources for dementia and to a better management of the disease.

Cognitive and behavioral assessment in the early stages of neurodegenerative extrapyramidal syndromes.

Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration Syndrome (CBDS) are the most common neurodegenerative extrapyramidal syndromes. Beyond motor symptoms, cognitive dysfunctions and behavioral disturbances are reported. Neuropsychological and neuropsychiatry features in the early stages, however, are under-investigated, and few comparison studies are available yet. The aim of the present study was to evaluate the cognitive and behavioral profile in the early stages of neurodegenerative extrapyramidal syndromes. Thirty-nine PD, 27 DLB, 16 CBDS, and 24 PSP were recruited. Groups were matched for global cognitive and motor impairment. The overall sample showed a common neuropsychological core characterized by visuospatial deficits. Although in the early stage of the disease, a high presence of behavioral disturbances was detected, depression and anxiety were the most common disorders, followed by apathy and sleep disturbances. The observation of overlapping clinical entities points the attention on the need of adjunctive diagnostic markers for early differential diagnosis.

Recurrency in transient global amnesia: a retrospective study.

Transient global amnesia (TGA) is a well-defined clinical syndrome of unknown etiology, which often occurs once in life. Several mechanisms have been proposed but only trigger events have been clearly associated with the attack such as physical exertion, emotional stress, sexual intercourse or immersion in cold water. According to our knowledge, this is the first study, which associates trigger events and TGA recurrency. The aim of this retrospective study was to evaluate the risk factors which contribute to TGA recurrency. TGA patients consecutively admitted, performed clinical and neurological evaluation, electroencephalogram and structural brain imaging scan. TGA-trigger events were evaluated and comorbidities were carefully recorded. The risk factor sum was calculated as the sum of the considered triggers. Eighty-five TGA patients were grouped according to the presence of single TGA (n = 73) or two episodes of TGA (n = 12). The 14.11% of patients experienced two episodes. A logistic regression analysis showed that the more increased number of TGA the more number of trigger events (P < 0.11; chi2 = 6.38; beta = -3.29). These observations claim that TGA may be considered a complex epiphenomenon, and the sum of the trigger factors can be responsible for recurring of this almost unique-in-life event.

Primitive reflex evaluation in the clinical assessment of extrapyramidal syndromes.

The aim of the present study was to evaluate the role of primitive reflexes (PRs) as additional alert sign in routine clinical practice in patients with extrapyramidal syndrome. We considered glabellar, snout, palmomental and grasp reflexes in patients with mild stage of Lewy body dementia (LBD), corticobasal degeneration, progressive supranuclear palsy or Parkinson disease (PD). We also enrolled mild Alzheimer disease (AD) patients, and healthy subjects, as controls. LBD patients showed the highest prevalence of PRs compared with the other groups. The odds ratio of the risk of LBD in PRs > or = 2 was 27.9 (95% CI 2.9-269.0) compared with control group, 14.6 (95% CI 2.7-79.6) compared with mild AD, and 19.7 (95% CI 3.7-104.3) compared with PD. These data suggest that the occurrence of combination of PRs might be an useful additional warning sign of possible diffuse Lewy body pathology more than other causes of extrapyramidal syndrome.