For Frontotemporal Dementia Research Articles

Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia.

Neurophysiological biomarkers were assessed using a transcranial magnetic stimulation multiparadigm approach in 13 presymptomatic (n = 13 Granulin) and 14 symptomatic (n = 11 Granulin, n = 3 C9orf72) subjects with a pathogenic mutation for frontotemporal dementia (FTD). Intracortical facilitation and long-term potentiation-like plasticity were impaired in presymptomatic carriers, compared to healthy controls, more than 15 years before expected symptom onset. In symptomatic carriers, a decrease in short-interval intracortical inhibition, compared to presymptomatic carriers, was found. In conclusion, these biomarkers could provide the footprints of specific physiopathological processes in the development of this disease and possibly support the diagnosis of autosomal-dominant FTD. Ann Neurol 2016;80:472-476.

Cognitive-behavioral changes in amyotrophic lateral sclerosis: Screening prevalence and impact on patients and caregivers

Our objective was to evaluate the association between cognitive-behavioral deficits and patient quality of life (QoL), caregiver burden, and disease stage in a population of patients with amyotrophic lateral sclerosis (ALS). We administered the ALS Cognitive-Behavioral Screen™ to 86 patients with ALS. Multiple regression was used to evaluate the association between cognitive or behavioral deficits and disease stage, patient QoL, and caregiver burden while controlling for clinically important variables. Of 86 participants enrolled, 53 (62%) had some degree of cognitive impairment, 32 (37%) were behaviorally impaired and four met both cognitive and behavioral screening criteria for frontotemporal dementia (FTD). The severity of cognitive-behavioral deficits was not associated with patient QoL. More pronounced cognitive deficits (beta = –1.4, p = 0.04) and behavioral symptoms (–0.69, p < 0.001) predicted higher caregiver burden. Self-reported QoL was lower in patients with more depressive symptoms (beta = –0.32, p < 0.001) and more advanced disease (beta =0.10, p = 0.01). In conclusion, general QoL for patients with ALS is not associated with cognitive or behavioral deficits. More severe cognitive deficits and caregiver-reported behavioral symptoms predict higher caregiver burden. Routine cognitive-behavioral screening can identify patients who require full neuropsychological examination, inform patient counseling, and identify caregivers in need of early, targeted interventions.

Progranulin Mutations Affects Brain Oscillatory Activity in Fronto-Temporal Dementia.

Background: Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD). Progranulin (PGRN) has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non-carriers in patients with overt FTD.Materials and Methods: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE).Results: MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers.Conclusion: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations.

Traumatic brain injury causes frontotemporal dementia and TDP-43 proteolysis

Traumatic brain injury (TBI) is a major risk factor for dementia. Recently, TBI has also been suggested as a risk factor for frontotemporal dementia (FTD), and plasma immunoreactivity to the TAR-DNA binding protein 43 (TDP-43) has been observed in both patients with acute TBI and long-term survivors of this condition. We used a population-based study to estimate and compare the risk of FTD in individuals with and without TBI. Furthermore, we used a rat model of TBI to show that increased TDP-43 proteolysis following TBI produces FTD-like impairments, including abnormal limb-clasping, and impaired performances in the Morris water maze. We recruited 24,585 patients who received ambulatory or hospital care for TBI and 122,925 patients without TBI for this study. Each individual was investigated for 4years to evaluate FTD development, and data were analyzed by Cox proportional hazard regression. In the TBI rat model, behavior and TDP-43 inclusions were assessed following intracranial administration of a caspase-3 inhibitor or vehicle. FTD was more likely to occur in the TBI group than in the group without TBI (adjusted hazard ratio, 4.43; 95% confidence interval, 3.85–5.10; P<0.001). Rats developed behavioral impairments similar to those in patients with FTD after TBI. Further, the behavioral impairments were likely associated with TDP-43 short fragment mislocalization and accumulation. Our findings suggest that in humans, TBI is associated with a greater occurrence of FTD. Moreover, clinical FTD manifestations may be associated with TDP-43 proteolysis, since impaired behaviors in TBI rats were reminiscent of those in humans with FTD.

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene.

BackgroundHexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.ResultsWe examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).ConclusionsVariants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.

New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications

ObjectiveTo assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations.Methods178 consecutive neuropathologically...

New behavioural variant FTD criteria and clinical practice

Since the first descriptions of circumscribed frontotemporal atrophies, and the first statement published by the Lund and Manchester groups, consensus clinical and pathological criteria for frontotemporal dementia (FTD) have been increasingly refined. The last international behavioural variant FTD criteria (FTDC) (Rascovsky et al., 2011) are the most sensitive, operational and reliable, for the clinical syndrome. Previously exclusion features, like early and severe amnestic syndrome or spatial disorientation, which turn out to be not so rare, are taken into account, as well as imaging, and biomarkers suggestive of other pathologies like Alzheimer's disease. So far, clinical features do not seem very helpful in predicting the underlying histopathology, although there are some clues, mainly related to neurological features (e.g. motor neuron disease, extra-pyramidal symptoms or language disorders), or associated disorders (e.g. Paget disease of bone) or genetics. BvFTD remains a difficult diagnosis at very early stage, which accounts for the delay of diagnosis, especially in late onset, where the frontotemporal atrophy may not be striking. At very young onset, psychiatric diseases must be ruled out. More systematic assessment of social cognition could be helpful. Further biomarkers are expected. Systematic use of recent criteria, for BvFTD and other neurodegenerative diseases especially AD, will contribute to make early and correct diagnoses in excluding or suggesting alternative diagnoses. Post-mortem assessment, with detailed recording of clinical information, is essential to progress.

Apolipoprotein Ε ε4 Frequency Is Increased among Chinese Patients with Frontotemporal Dementia and Alzheimer's Disease

The relationship between the apolipoprotein E (ApoE) ε4 genotype and an increased risk of developing Alzheimer's disease (AD) has been well established in Caucasians but is less established among other ethnicities. ApoE ε4 has also been associated with several other neurological disorders. Whether ApoΕ4 ε4 is a risk factor for frontotemporal dementia (FTD) remains controversial. This study examined 432 patients with AD, 62 with FTD, and 381 sex- and age-matched controls. The ApoE ε4 allele frequency was significantly increased among patients in the AD and FTD groups compared with controls. The frequency of the ApoΕ ε4 allele was 24.86% in late-onset AD (p < 0.01), 18.02% in early-onset AD (p < 0.01), 16.13% in FTD (p < 0.01), and 7.34% in controls. ApoΕ ε4 prevalence was similar in the FTD and AD groups. The present study suggests that the ApoE ε4 allele is a risk factor for both disorders.

Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia

We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex. Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found. This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

An International Needs Assessment of Caregivers for Frontotemporal Dementia

To guide development of public awareness and caregiver support resources for frontotemporal dementia (FTD) syndromes. We used an online survey to explore their needs. The survey was self-administered by self-identified, English-speaking caregivers for patients with FTD in several countries. Of 79 caregiver respondents, approximately half were caring for patients with behavioural variant FTD or semantic dementia. The most common initial symptoms were Changes in Thinking and Judgment. Half of the respondents identified "failure to recognize the early stage of illness as a dementia" as the most troublesome aspect. Accordingly, over 40% of respondents had difficulty obtaining an accurate diagnosis for the patient. Caregivers prioritized family counseling and the public educational message that dementia can affect young people. The largest international survey of FTD caregivers to-date showed that support is needed for all family members adapting to the shock of early-onset dementia, and this may be most readily provided online.

Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia

There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer’s disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.

Diagnostic Accuracy of Consensus Diagnostic Criteria for Frontotemporal Dementia in a Memory Clinic Population

Background/Aims: The goal of the present study was to evaluate the diagnostic accuracy of the core diagnostic criteria for frontotemporal dementia (FTD) [Neary D, et al: Neurology 1998;51:1546–1554] within a memory clinic population. Methods: The 5 core diagnostic criteria for FTD were operationalised in an informant-based written questionnaire. For a diagnosis of FTD the total clinical picture was weighted with findings on additional investigations and possible exclusion criteria, with follow-up of at least 1 year. Results: The operationalised core criteria for FTD had a sensitivity of 79% (95% CI = 57–92) and a specificity of 90% (95% CI = 85–94). Conclusion: The core diagnostic criteria for FTD applied in a caregiver questionnaire have good diagnostic accuracy among subjects without advanced dementia attending a memory clinic. This stresses the importance of the informant-based history in the differential diagnosis of dementia.

Prevalence of Neuropsychiatric Symptoms in Elderly Patients with Dementia in Mungialde County (Basque Country, Spain)

Background: Determination of the prevalence of neuropsychiatric symptoms in elderly patients with dementia inMungialde. Methods: 108 subjects with dementia, who participated in a door-to-door epidemiological study, were included. The 12-item Spanish version of the Neuropsychiatric Inventory was used to evaluate these symptoms. Results: The prevalence of at least 1 neuropsychiatric symptom was found to be 76.90% for all dementia types, 73.50% in patients with Alzheimer’s disease (AD), 80% for the Parkinson-Lewy body dementia complex (PLBD), 78.60% for vascular dementia (VD) and 100% for frontotemporal dementia (FTD). Apathy was found to be the most prevalent symptom for all dementia types and in patients with AD (53.70 and 54.30%, respectively). The next most prevalent symptoms were anxiety, depression and sleep disturbances (35.20, 32.40 and 30.60%) for all dementia types, and anxiety and depression (32.10 and 30.90%) in patients with AD. The most prevalent symptoms in patients with PLBD were apathy, appetite changes, sleep disturbances and agitation (50% each); in patients with VD they were apathy, depression and anxiety (42.90% each), and in patients with FTD they were apathy, anxiety and aberrant motor activity (100% each). Conclusions: Neuropsychiatric symptoms were found to be prevalent in patients with dementia, irrespective of dementia type.

Variations in regional SPECT hypoperfusion and clinical features in frontotemporal dementia

To characterize the presenting clinical features for frontotemporal dementia (FTD) and contrast them with the degree of frontal and temporal hypoperfusion on SPECT imaging. The authors evaluated 74 patients who eventually met Consensus Criteria for the FTD form of frontotemporal lobar degeneration (excluding primary progressive aphasia and semantic dementia) on 2-year follow-up. On first presentation, these patients had undergone both an FTD Inventory for 12 features based on core and supportive Consensus Criteria and SPECT imaging. The initial clinical diagnostic features were contrasted with variations in regional SPECT hypoperfusion. The patients with FTD had more hypoperfusion in the right frontal lobe than in other regions; the subgroup of 25 patients who met Consensus Criteria from the first presentation had the most right frontal hypoperfusion. Frontal lobe involvement was associated with significant apathy, whereas temporal lobe involvement was associated with hypomania-like behavior. Right frontal lobe hypoperfusion further predicted loss of insight, environmental dependency, and stereotyped behaviors. Other associations included left frontal hypoperfusion with a decline in personal hygiene and left temporal hypoperfusion with compulsions and mental rigidity. On first presentation, frontotemporal dementia (FTD) is disproportionately a right frontal disease evident on behavioral measures and on SPECT. Nonetheless, patients with FTD can initially present with further regional differences in clinical diagnostic features, such as apathy with bifrontal hypoperfusion and hypomania-like behaviors with anterior temporal involvement.

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia

To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.

Neuroquímica y neurofarmacología de la demencia frontotemporal

To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

Natural history of primary progressive aphasia

To characterize the natural history of primary progressive aphasia (PPA). Forty-nine patients (28 women) with newly diagnosed with PPA presenting to a memory disorders clinic between 1992 and 2001 were prospectively evaluated. Median age at onset was 62 years (range 49 to 73 years) and at first visit was 66 years (52 to 80 years). The median duration of follow-up was 4 years (1 to 11 years). Impairments in activities of daily living developed a median of 6 to 7 (2 to 12) years post onset. Seventy-five percent of patients eventually met clinical diagnostic criteria for frontotemporal dementia (FTD), 14% met diagnostic criteria for dementia with Lewy bodies, and 8% developed signs of corticobasal degeneration; 60% of the patients died after a median course of 7 years (3 to 17 years) at a median age of 71 years (56 to 81 years). Patients showing high Mini-Mental State Examination scores, moderate aphasia, and fluent language at first visit subsequently retained greater autonomy in daily life. Although activities of daily living are well maintained during the first years of the disease, patients with primary progressive aphasia (PPA) may lose autonomy 6 to 7 years after onset. The majority of patients with PPA in the current study developed frontotemporal dementia.

Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF

This investigation describes the discovery of novel possible cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD) using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS). Sixteen clinically diagnosed FTD patients and 12 non-demented controls were included in the study. CSF was collected and analyzed for protein expression by SELDI-TOF MS. The samples were analyzed on four different array surfaces using two different energy-absorbing molecules as matrices. In total each sample was subjected to eight different surface/matrix conditions. About 2000 protein peaks (mass/charge ratios) were detected. Forty-two peaks were differentially expressed in FTD ( P < 0.01). After exclusion of peaks with low signal-to-noise ratio and/or poor resolution and peaks representing differentially charged proteins, 10 peaks remained, five of which were increased and five decreased in FTD cases compared to controls. Using partial least square discriminant analysis (PLS-DA), the combination of these biomarkers discriminated FTD from non-demented controls with a sensitivity of 94%, a specificity of 83% and an accuracy of 89%. Five of the peaks were purified further and identified by tandem MS as a fragment of neurosecretory protein VGF, transthyretin, S-cysteinylated transthyretin, truncated cystatin C and a fragment of chromogranin B. With use of these potential biomarkers, FTD can be distinguished from control subjects with high accuracy in this pilot study.

Prevalence and patterns of cognitive impairment in sporadic ALS

To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Self awareness and personality change in dementia

Background: Loss of insight is a core diagnostic criterion for frontotemporal dementia (FTD), whereas failure to recognise cognitive deficits and unawareness of disease (anosognosia) are well established findings in Alzheimer’s...