Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49•5 years (SD 10•0; onset) and 58•5 years (11•3; death) in the MAPT group, 58•2 years (9•8; onset) and 65•3 years (10•9; death) in the C9orf72 group, and 61•3 years (8•8; onset) and 68•8 years (9•7; death) in the GRN group. Mean disease duration was 6•4 years (SD 4•9) in the C9orf72 group, 7•1 years (3•9) in the GRN group, and 9•3 years (6•4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0•45 between individual and parental age at onset, r=0•63 between individual and mean family age at onset, r=0•58 between individual and parental age at death, and r=0•69 between individual and mean family age at death) than in either the C9orf72 group (r=0•32 individual and parental age at onset, r=0•36 individual and mean family age at onset, r=0•38 individual and parental age at death, and r=0•40 individual and mean family age at death) or the GRN group (r=0•22 individual and parental age at onset, r=0•18 individual and mean family age at onset, r=0•22 individual and parental age at death, and r=0•32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even mor...

Physical as well as cognitive training interventions improve specific cognitive functions but effects barely generalize on global cognition. Combined physical and cognitive training may overcome this shortcoming as physical training may facilitate the neuroplastic potential which, in turn, may be guided by cognitive training. This study aimed at investigating the benefits of combined training on global cognition while assessing the effect of training dosage and exploring the role of several potential effect modifiers. In this multi-center study, 322 older adults with or without neurocognitive disorders (NCDs) were allocated to a computerized, game-based, combined physical and cognitive training group (n = 237) or a passive control group (n = 85). Training group participants were allocated to different training dosages ranging from 24 to 110 potential sessions. In a pre-post-test design, global cognition was assessed by averaging standardized performance in working memory, episodic memory and executive function tests. The intervention group increased in global cognition compared to the control group, p = 0.002, Cohen’s d = 0.31. Exploratory analysis revealed a trend for less benefits in participants with more severe NCD, p = 0.08 (cognitively healthy: d = 0.54; mild cognitive impairment: d = 0.19; dementia: d = 0.04). In participants without dementia, we found a dose-response effect of the potential number and of the completed number of training sessions on global cognition, p = 0.008 and p = 0.04, respectively. The results indicate that combined physical and cognitive training improves global cognition in a dose-responsive manner but these benefits may be less pronounced in older adults with more severe NCD. The long-lasting impact of combined training on the incidence and trajectory of NCDs in relation to its severity should be assessed in future long-term trials.

Background The novel coronavirus disease (COVID‐19) was first detected in Mainland China in December 2019, and soon it spread throughout the world, with multiple physical and psychological consequences across the affected populations. Aims The aim of the current study was to analyze the impact of COVID‐19 pandemic on older adults with mild cognitive impairment (MCI)/dementia and their caregivers as well. Materials and Methods Two hundred and four caregivers took part in the study, completing a self‐reported questionnaire about the person with MCI/dementia and their own, since the lockdown period which started in February and ended in May of 2020 in Greece. Results Results indicated a significant overall decline of the people with MCI/dementia. Further, the domains in which people with MCI/dementia were mostly affected were: communication, mood, movement and compliance with the new measures. Caregivers also reported a great increase in their psychological and physical burden during this period, where the available support sources were limited. Discussion The pandemic threatens to disrupt the basic routines that promote mental and physical health of both people with MCI/dementia and t heir caregivers. Conclusion Further measures to protect and provide support to people who suffer and their families are needed.

Neurodegeneration in Alzheimer’s disease (AD) is closely associated with accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro which was impaired by the p.Asp395Gly mutation. Additionafsupplly, intracerebral microinjection of pathologic tau led to increased tau aggregates in p.Asp395Gly VCP knock-in mice compared to injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal dominant genetic mutation associated with neurofibrillary degeneration in part due to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) of abnormal hyperphosphorylated tau protein are the pathological hallmarks of the disease, accompanied by other pathological processes such as microglia activation. Functional and molecular nuclear medicine imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques provides valuable information about the underlying pathological processes, many years before the appearance of clinical symptoms. Nuclear neuroimaging in AD has made great progress in the past two decades and has extended beyond the traditional role of brain perfusion and glucose metabolism evaluation. Intense efforts in radiopharmaceuticals research have led to the development of various probes able to detect Aβ deposits, tau protein accumulation, microglia activation and neuroinflammation. As a result, SPECT and PET have proposed to serve as biomarkers in recently revised diagnostic clinical criteria for the early diagnosis of AD and the prediction of progression to AD in mild cognitive impairment (MCI) subjects.

Despite the known validity of clinical diagnostic criteria, significant overlap of clinical symptoms between Frontotemporal dementia (FTD) subtypes exists in several cases, resulting in great uncertainty of the diagnostic boundaries. We evaluated the perfusion between FTD subtypes using brain perfusion (99m)Tc-HMPAO SPECT with Brodmann areas (BA) mapping. NeuroGam software was applied on single photon emission computed tomographic (SPECT) studies for the semi-quantitative evaluation of perfusion in BA and the comparison with the software's normal database. We studied 91 consecutive FTD patients: 21 with behavioural variants (bvFTD), 39 with language variants (lvFTD) [12 with progressive non-fluent aphasia (PNFA), 27 with semantic dementia (SD)], and 31 patients with progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). Stepwise logistic regression analyses showed that the BA 28L and 32R could independently differentiate bvFTD from lvFTD, while the BA 8R and 25R could discriminate bvFTD from SD and PNFA, respectively. Additionally, BA 7R and 32R were found to discriminate bvFTD from CBD/PSP. The only BA that could differentiate SD from PNFA was 6L. BA 6R and 20L were found to independently differentiate CBD/PSP from lvFTD. Moreover, BA 20L and 22R could discriminate CBD/PSP from PNFA, while BA 6R, 20L and 45R were found to independently discriminate CBD/PSP from SD. Brain perfusion SPECT with BA mapping can be a useful additional tool in differentiating FTD variants by improving the definition of brain areas that are specifically implicated, resulting in a more accurate differential diagnosis in atypical or uncertain forms of FTD.

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychological characteristics of more than 300 patients diagnosed with FTLD in the United States (US), Greece and Turkey. We find that patients with the frontal variant of FTLD (FTD) are diagnosed at an earlier age and report earlier symptom onset in the US, than in Greece or Turkey. Furthermore, neuropsychological measures indicate that at diagnosis, FTD patients in the US are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally-appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage. Keywords diagnosis; frontotemporal dementia; neuropsychological measures progressive supranuclear palsy; cross-cultural Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease affecting the frontal and anterior temporal lobes. Once considered rare, recent work suggests that frontotemporal lobar degeneration (FTLD) is a common cause for dementia, particularly in patients under the age of 70 years. FTLD's prevalence is similar to that of AD with 15 cases per 100,000 between 45-to 64-years 1, 2 . Other studies suggest that FTLD accounts for up to 20% of all patients with degenerative dementias 3, 4 . FTLD is often further subdivided into Address for correspondence: Indre V. Viskontas, PhD, Memory & Aging Center, Department of Neurology, University of California, San Francisco, 350 Parnassus Ave., Ste. 706, San Francisco, CA 94143, iviskontas@memory.ucsf.edu, Ph: (415) Fax: (415) 476-4800. * These authors contributed equally. NIH Public Access Author ManuscriptAlzheimer Dis Assoc Disord. Author manuscript; available in PMC 2010 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript three subtypes, based upon differences in regional atrophy and symptom patterns. These three subtypes are: 1) progressive non-fluent aphasia (PNFA), in which patients primarily show deficits in verbal expression, and predominantly left-frontal atrophy 2) frontal-variant frontotemporal dementia (FTD), in which first symptoms are generally behavioral disturbances and atrophy is symmetrical and predominately frontal and 3) semantic dementia (SD) or temporal-variant frontotemporal dementia, in which patients gradually lose access to semantic concepts (ie, meanings of words) resulting from temporal atrophy.To date, the bulk of the studies on the prevalence and de...

Self-monitoring is a crucial component of human empathy and necessary for the formation and repair of social relations. Several studies have brought to light possible neuronal substrates associated with self-monitoring, but the information that they have provided is inconclusive. The authors, therefore, studied a large group of patients with dementia to assess what brain structures are necessary for the self-monitoring function.Methods: Seventy-seven patients with dementia of various types were screened using voxel-based morphometry to assess possible volume reduction in the brain structures of patients with self-monitoring problems, and the decrease of socioemotional expressiveness and modification of self-presentation was estimated using the Revised Self-Monitoring Scale. Regression analysis was employed to investigate the correlation between gray matter loss and deficient self-monitoring. Results:The socioemotional expressiveness scores were associated with decreased gray matter volume in the right olfactory cortex, inferior frontal gyrus, superior temporal pole, parahippocampal gyrus, insula, and medial temporal gyrus bilaterally. Self-presentation scores were associated with bilateral gray matter volume reduction in the olfactory cortex, insula, rectus gyrus and inferior frontal gyrus, right superior temporal pole, and parahippocampal gyrus, as well as the left medial temporal gyrus and anterior superior frontal gyrus.Conclusions: These results suggest that patients with dementia present decreased ability of self-monitoring, probably due to impaired insula and orbitofrontal cortex and their disconnection from structures of the salience network.