Is semantic dementia an outdated entity?

Does it still make clinical sense to talk about semantic dementia? For more than 10 years, some researchers and clinicians have highlighted the need for new diagnostic criteria, arguing for this entity either to be redefined or, more recently, to be divided into two partially distinct entities, each with its own supposed characteristics, namely the semantic variant primary progressive aphasia and the semantic behavioral variant frontotemporal dementia. Why such a shift? Is it no longer appropriate to talk about semantic dementia? Is it really useful to divide the concept of semantic dementia into verbal and socioemotional semantic subcomponents? Does this proposal have any clinical merit or does it solely reflect theoretical considerations? To shed light on these questions, the purpose of the present review was to explore theoretical considerations on the nature of the knowledge that is disturbed in this disease which might justify such terminological changes.

Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.

AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes. METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory. RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (ß = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (ß = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05). CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.

QSM-detected iron accumulation in the cerebellar gray matter is selectively associated with executive dysfunction in non-demented ALS patients.

Background: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients. Methods: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume. Results: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps ≤ 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps ≤ 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks. Discussion: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients.

A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.

Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA+ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCPR191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.

Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.

Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.

Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.

BACKGROUND: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients. METHODS: N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores. RESULTS: The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones. CONCLUSIONS: The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.

Multicenter Validation of the English Version of the Dépistage Cognitif de Québec: a Cognitive Screening Tool for Atypical Dementias.

BACKGROUND: Early detection of atypical dementia remains difficult partly because of the absence of specific cognitive screening tools. This creates undue delays in diagnosis and management. The Dépistage Cognitif de Québec (DCQ; dcqtest.org) was developed in French and later validated in participants with atypical syndromes. We report the validation of the English version. METHODS: This multicentre prospective validation study was conducted in 10 centers across Canada and the United States on 260 English-speaking participants aged over 50. We translated and modified the original French DCQ to add targeted stimuli to the Visusopatial Index and social cognition vignettes to the Behavioral Index. A backward translation was performed and equivalence between languages was assessed by administering both tests to 30 bilingual participants. RESULTS: Mean DCQ total score (out of 100) was 95.0 (SD = 3.6). Spearman's correlation coefficient showed a strong and significant correlation (r = 0.49, p < .001) with the Montreal Cognitive Assessment. Test-retest reliability was good (Spearman's coefficient = 0.72, p < .001) and interrater reliability, excellent (intraclass correlation = 0.97, p < .001). Normative data shown in percentiles were stratified by age and education for a population-based sample of 260 English-speaking controls aged between 50 and 87 years old. CONCLUSIONS: Similar to the French version, the English DCQ proved to be a valid cognitive screening test. The original version was very sensitive to detect atypical dementias such as primary progressive aphasias, Alzheimer's disease' variants and syndromes along the frontotemporolobar degeneration spectrum. This 20-min test can be administered à la carte and offers an alternative to detailed comprehensive neuropsychological evaluations.

Inappropriate trusting behaviour in dementia.

Background: Inappropriate trusting behaviour may have significant social, financial and other consequences for people living with dementia. However, its clinical associations and predictors have not been clarified. Here we addressed this issue in canonical syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods: In 34 patients with AD and 73 with FTD (27 behavioural variant (bv)FTD, 22 semantic variant primary progressive aphasia (svPPA), 24 nonfluent/agrammatic variant (nfv)PPA) we recorded inappropriate trusting and other abnormal socio-emotional behaviours using a semi-structured caregiver survey. Patients were comprehensively characterised using a general cognitive assessment and the Revised Self-Monitoring Scale (RSMS; an informant index of socioemotional awareness). Results: Inappropriate trusting was more frequent in svPPA (55%) and bvFTD (44%) than nfvPPA (17%) or AD (24%). After adjusting for age, sex, education and Mini-Mental State Examination (MMSE) score, inappropriate trusting was significantly more likely in svPPA (odds ratio 3.61; 95% confidence interval 1.41-8.75) and bvFTD (3.01, 1.23-6.65) than AD. Significant predictors of inappropriate trusting comprised apathy in svPPA, disinhibition and altered pain responsiveness in bvFTD, and lower MMSE and RSMS (self-presentation) scores in AD. Conclusion: Dementia syndromes vary in prevalence and predictors of abnormal trusting behaviour, with implications for clinical counselling and safeguarding.

Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.

Background: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates. Methods: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years. Results: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases. Conclusions: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.

Frontotemporal lobar degeneration changes neuronal beta-frequency dynamics during the mismatch negativity response.

The consequences of frontotemporal lobar degeneration include changes in prefrontal cortical neurophysiology, with abnormalities of neural dynamics reported in the beta frequency range (14-30 Hz) that correlate with functional severity. We examined beta dynamics in two clinical syndromes associated with frontotemporal lobar degeneration: the behavioral variant of frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP). Whilst these two syndromes are partially convergent in cognitive effects, they differ in disease mechanisms such as molecular pathologies and prefrontal atrophy. Whether bvFTD and PSP also differ in neurophysiology remains to be fully investigated. We compared magnetoencephalography from 20 controls, 23 people with bvFTD and 21 people with PSP (Richardson's syndrome) during an auditory roving oddball paradigm. We measured changes in low and high total beta power responses (14-22 and 22-30 Hz respectively) over frontotemporal cortex in the period of the mismatch negativity response (100-250 ms post-stimulus). In controls, we found increased 14-22 Hz beta power following unexpected sensory events (i.e. increased deviant versus standard response), from right prefrontal cortex. Relative to controls, PSP reversed the mismatch response in this time-frequency window, reflecting reduced responses to the deviant stimuli (relative to standard stimuli). Abnormal beta at baseline in PSP could account for the reduced task-modulation of beta. Across bvFTD and PSP groups, the beta response to deviant stimuli (relative to standard stimuli) correlated with clinical severity, but not with atrophy of the prefrontal source region. These findings confirm the proposed importance of higher-order cortical regions, and their beta-power generators, in sensory change detection and context-updating during oddball paradigms. The physiological effects are proposed to result from changes in synaptic density, cortical neurotransmitters and subcortical connections, rather than merely atrophy. Beta-power changes may assist clinical stratification and provide intermediate outcomes for experimental medicine studies of novel therapeutic strategies.

The role of parvalbumin interneuron dysfunction across neurodegenerative dementias.

Parvalbumin-positive (PV+) basket neurons are fast-spiking, non-adapting inhibitory interneurons whose oscillatory activity is essential for regulating cortical excitation/inhibition balance. Their dysfunction results in cortical hyperexcitability and gamma rhythm disruption, which have recently gained substantial traction as contributing factors as well as potential therapeutic targets for the treatment of Alzheimer's Disease (AD). Recent evidence indicates that PV+ cells are also impaired in Frontotemporal Dementia (FTD) and Dementia with Lewy bodies (DLB). However, no attempt has been made to integrate these findings into a coherent pathophysiological framework addressing the contribution of PV+ interneuron dysfunction to the generation of cortical hyperexcitability and gamma rhythm disruption in FTD and DLB. To fill this gap, we epitomized the most recent evidence on PV+ interneuron impairment in AD, FTD, and DLB, focusing on its contribution to the generation of cortical hyperexcitability and gamma oscillatory disruption and their interplay with misfolded protein accumulation, neuronal death, and clinical symptoms' onset. Our work deepens the current understanding concerning the role of PV+ interneuron dysfunction across neurodegenerative dementias, highlighting commonalities and differences among AD, FTD, and DLB, thus paving the way for identifying novel biomarkers and potential therapeutic targets for the treatment of these diseases.

Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.

BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates. METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi). RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031). CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.

Simulating the Growth of TATA-Box Binding Protein-Associated Factor 15 Inclusions in Neuron Soma.

To the best of the author's knowledge, this paper presents the first attempt to develop a mathematical model of the formation and growth of inclusions containing misfolded TATA-box binding protein associated factor 15 (TAF15). It has recently been shown that TAF15 inclusions are involved in approximately 10% of cases of frontotemporal lobar degeneration (FTLD). FTLD is the second most common neurodegenerative disease after Alzheimer's disease (AD). It is characterized by a progressive loss of personality, behavioral changes, and a decline in language skills due to the degeneration of the frontal and anterior temporal lobes. The model simulates TAF15 monomer production, nucleation and autocatalytic growth of free TAF15 aggregates, and their deposition into TAF15 inclusions. The accuracy of the numerical solution of the model equations is validated by comparing it with analytical solutions available for limiting cases. Physiologically relevant parameter values were used to predict TAF15 inclusion growth. It is shown that the growth of TAF15 inclusions is influenced by two opposing mechanisms: the rate at which free TAF15 aggregates are deposited into inclusions and the rate of autocatalytic production of free TAF15 aggregates from monomers. A low deposition rate slows inclusion growth, while a high deposition rate hinders the autocatalytic production of new aggregates, thus also slowing inclusion growth. Consequently, the rate of inclusion growth is maximized at an intermediate deposition rate of free TAF15 aggregates into TAF15 inclusions.

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362). CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.

Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

Cognitive deficits in ALS patients with SOD1 mutations.

OBJECTIVE: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene. METHODS: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls. RESULTS: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS. CONCLUSION: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.

TDP-43 nuclear condensation and neurodegenerative proteinopathies.

RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.

Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers.

INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. HIGHLIGHTS: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Multimodal nonlinear correlates of behavioural symptoms in frontotemporal dementia.

Studies exploring the brain correlates of behavioral symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioral symptoms. We analyzed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behavior Scale, and Neurobehavioral Rating Scale. We used a data-driven approach to identify the principal components underlying behavioral variability, then related the identified components to brain variability using a newly developed method fusing maps of grey matter volume and FDG metabolism. A component representing apathy, executive dysfunction, and emotional withdrawal was associated with atrophy in bilateral anterior insula and putamen, and with hypometabolism in the right prefrontal cortex. Another component representing the disinhibition versus depression/mutism continuum was associated with atrophy in the right striatum and ventromedial prefrontal cortex for disinhibition, and hypometabolism in the left fronto-opercular region and sensorimotor cortices for depression/mutism. A component representing psychosis was associated with hypometabolism in the prefrontal cortex and hypermetabolism in auditory and visual cortices. Behavioral symptoms in FTD are associated with atrophy and altered metabolism of specific brain regions, especially located in the frontal lobes, in a hierarchical way: apathy and disinhibition are mostly associated with grey matter atrophy, whereas psychotic symptoms are mostly associated with hyper-/hypo-metabolism.

Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.

Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 µT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.