MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study

The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer’s disease(AD)diagnosis.In this context,we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia(Mini-Mental State Examination score≥17 and Clinical Dementia Rating Scale score≤1.We identified 21 patients at Centro Hospitalar e Universitário de Coimbra,Portugal with GRN mutations belonging to fifteen different families.As our focus was bvFTD variants,FTD-related aphasic forms(3 patients)were excluded.The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging,age and education.All patients completed the Mini-Mental State Examination,Montreal Cognitive Assessment(MoCA)and a comprehensive NP assessment battery.Results were converted into z-scores.Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests(Kruskal-Wallis test analysis)and eta squared(ŋ2)was calculated as a measure of effect size.Group comparisons show that GRN patients have worse performances on verbal retrieval processes(P=0.039,ŋ2=0.110)and visuoconstructive abilities(P=0.039,ŋ2=0.190)than sporadic bvFTD forms.When compared to AD,GRN patients present a higher impairment in frontal(P=0.001,ŋ2=0.211)and parietal(P=0.041,ŋ2=0.129)measures and a better performance in memory tasks(P=0.020,ŋ2=0.120).Sporadic-bvFTD forms are worse than AD in frontal measures(P=0.032,ŋ2=0.200),being better in both memory(P=0.010,ŋ2=0.131)and visuospatial skills(P=0.023,ŋ2=0.231).Considering these results,we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits.This is particularly expressive in visuoconstructive abilities,which was the more discriminative feature between groups,followed by episodic verbal memory.This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra,Portugal(CE-029/2019)on June 24,2019.

Biomarkers for the diagnosis of Alzheimer's disease, dementia Lewy body, frontotemporal dementia and vascular dementia

Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body. Aim The aim of this systematic review is to create a concise overview of unique similarities within dementia used to locate and identify new biomarker methods in diagnosing dementia. Methods 123 300 articles published after 2010 were identified from PubMed, JSTOR, WorldCat Online Computer Library and PALNI (Private Academic Library Network of Indiana) using the following search items (in title or abstract):'Neurodegenerative Diseases' OR 'Biomarkers' OR 'Alzheimer's Disease' OR 'Frontal Temporal Lobe Dementia' OR 'Vascular Dementia, OR 'Dementia Lewy Body' OR 'Cerebral Spinal Fluid' OR 'Mental Cognitive Impairment'. 47 studies were included in the qualitative synthesis. Results Evidence suggested neuroimaging with amyloid positron emission tomography (PET) scanning and newly found PET tracers to be more effective in diagnosing Alzheimer's and amnesiac mental cognitive impairment than carbon-11 Pittsburgh compound-B radioisotope tracer. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia and neurodegenerative diseases. Conclusion Vast improvements in neuroimaging techniques have led to newly discovered biomarkers and diagnostics. Neuroimaging with amyloid PET scanning surpasses what had been considered the dominant method of neuroimaging and MRI. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia pathology. Continued research and studies must be conducted to improve current findings and streamline methods to further subcategorise neurodegenerative disorders and diagnosis.

Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia

Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.

The clinical effect of frontotemporal rhytidectomy combined with botulinum toxin type A injection facial rejuvenation treatment

Objective To investigate the effect of frontotemporal rhytidectomy combined with botulinum toxin A type injection on lifting upper facial skin,improving upper facial skin aging,removing peri-orbital,glabellar and forehead wrinkles a nd strengthening the effect of rhytidectomy.Methods 20 patients with upper facial wrinkle plastic surgery,female,were designed with incision marking line along forehead and temporal hairline for dissection.The forehead was stripped along the superficial layer of periosteum,and the temporal part was stripped against the superficial surface of superficial temporal fascia.Then the suspension was used to tight the skin,the redundant skin tissue was removed,the cosmetic incision was sutured,the drainage device was placed routinely after the operation,and the pressure dressing is applied for 72 hours.The stitches were removed 7 days after the operation,at the same time,the appropriate dose of botulinum toxin type A was injected into the glabella,the outer corner of both eyes and the forehead to remove wrinkles and to rejuvenate the upper facial skin.Results 20 patients were followed up for 1-12 months,the results were all satisfactory.The upper skin relaxation was obviously improved,the forehead,glabellar and periorbital wrinkles were significantly reduced,the skin was plump and lustrous,the scar was hidden,not obvious and without complications after the incision was healed,and the upper facial skin showed obvious rejuvenation ef fect.Conclusion Frontotemporal rhytidectomy combined with botulinum toxin type A injection facial rejuvenation treatment is safe,effective,and has less complications as well as quick recovery,which is a feasible and good treatment.

Application of Frontotemporal Expanded Flap with Bilateral Superficial temporal vessels in Repair of Large Area Scar Contracture in Face and Neck

Objective To summarize the clinical experience of frontotemporal expanded flap with bilateral superficial temporal vessels in repairing large area scar contracture in face and neck.Methods 14 patients with facial and Cervical scar contracture in our hospital were taken as the research object.With bilateral superficial temporal vessels as pedicles,a 400-600 ml skin dilator was inserted into the forehead and 50-100 ml skin dilator was inserted into the two temporal parts respectively.Within 3-4 months,the water injection volume reaches 2 times of the dilator volume.After maintaining for one month,skin flap transplantation was performed.The frontal flap was reserved for hairline reconstruction,and the flap was cut to cover the area after facial and Cervical scar release to reconstruct the jaw-neck angle.The pedicle division and pedicle trimming were performed 3-4 weeks after operation.Results All the 14 patients completed the operation successfully.The flap expansion time is 5-6 months.The expanded skin flap covers an area of 26 cm×9 cm-42 cm×16 cm,and all the skin flaps survived after operation.Among them,2 patients suffered from flap congestion after flap transplantation.Follow-up for 6-12 months showed that the color and texture of the skin flap were similar to those of facial skin,with natural transition and no obvious bloating.The angle between the lower jaw and the neck is about 90.The anterior flexion,posterior extension,lateral flexion and rotation of the neck are obviously improved compared with the anterior,and the posterior extension is close to normal.Conclusion Frontotemporal expanded flap with bilateral superficial temporal vessels is suitable for patients with large-area scar contracture in face and neck that cannot be repaired after expansion of adjacent local normal tissues.

Strategies for translating proteomics discoveries into drug discovery for dementia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

Agraphia in Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Degeneration

Frontotemporal lobe degeneration （FTLD） refers to a neurodegenerative dementia syndrome, which could be clinically classified into behavioral and language variant. Amyotrophic lateral sclerosis （ALS） is a progressive neurological disorder involving both upper motor neuron （UMN） and lower motor neuron （LMN）, eventually leading to muscle atrophy and weakness, bulbar palsy, and respiratory failure.

Cardiovascular risk factors and frontotemporal dementia: a case–control study

Cardiovascular risk factors(CRF)were widely described as related to dementia.There are very few studies regarding this association in FTD.The objective of the study was to compare the frequency of CRF in our population with FTD and controls.100 consecutive subjects with FTD diagnosis according to Lund-Manchester clinical criteria and 200 controls matched by age and sex were included between January 2003 to February 2007 at the Cognitive and Behavior Unit of Hospital Italiano de Buenos Aires.Clinical evaluation,laboratory tests,brain images(CT/MRI),neuropsychological and neuropsychiatric assessment were performed.Multiple regression analysis was performed to analyze the association in CRF between FTD patients vs.controls.The mean age in FTD was 69.7±0.9 vs.70.1±0.8 in controls(p 0.12).No difference in gender was observed between cases and controls.No differences were identified between patients and controls regarding hypertension(HTA)(65%vs.67,3%p 0.44);dyslipidemia(57%vs.54.7%p 0.74);obesity(39%vs.27.6%p 0.14)and hypothyroidism(26%vs.17.1%p 0.1).A significant difference was observed for Diabetes Mellitus(39%vs.22.6%p 0.001).In our population,Diabetes Mellitus was associated as an independent risk factor for FTD.To our knowledge this is the first report in which CRF were evaluated prospectively in FTD patients.More studies are needed to confirm this finding in larger populations.

Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotrophic lateral sclerosis(ALS) and frontotemporal dementia(FTD).ALS patients with C9ORF72 expansion show heterogeneous symptoms.Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients.Pathological and clinical features of C9ORF72 patients have been well mimicked via several models,including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins.The mechanisms implicated in C9ORF72 pathology include DNA damage,changes of RNA metabolism,alteration of phase separation,and impairment of nucleocytoplasmic transport,which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into nonC9ORF72 expansion-related ALS,FTD,and other neurodegenerative diseases.

Amyotrophic lateral sclerosis with frontotemporal dementia presented with prominent psychosis

Amyotrophic lateral sclerosis （ALS） is a neurodegenerative disease mainly involving motor neurons in spinal cord,brain stem,and motor cortex of brain,characterized by variable combinations of limb weakness,muscle atrophy,and pyramidal signs.TAR DNA-binding protein 43 （TDP-43） serves as the pathological protein for both ALS and a proportion of frontotemporal dementia （FTD）,where lies the foundation of a disease complex,ALS-FTD.Delusion and hallucination,core features of schizophrenia,are also regarded as common symptoms in the context of neurodegenerative dementia,including Alzheimer disease and dementia with Lewy body.Although rare in the course of FTD,these manifestations could be rather notable,causing a great challenge to differentiate FTD from schizophrenia.Emphasis of psychotic phenomenon also lies in its importance of predicting the progression to ALS-FTD and its underlying genetic mutation.Herein we report two cases of ALS-FTD presented with psychosis.

Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort

Background:The TANK-Binding Kinase 1(TBK1)gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort.Methods:A total of 270 cases with ALS,FTD,or their combination were recruited into this study.All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing.The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed.Results:A novel mutation(c.1959_1960insGT,p.E653fs)was identified in a sporadic case with semantic dementia,secondarily developing ALS.Another novel variant(c.2063_2064delTT,p.L688Rfs*14)was found in an ALS-FTD family.Totally,the TBK1 variants could only account for 0.7% of cases.Conclusions:This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort.Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.

Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may help advance our understanding of different neurodegenerative diseases.In this study,we investigated the diagnostic performance of plasma GFAP(pGFAP),plasma neurofilament light chain(pNfL)and their combination for frontotemporal dementia(FTD)and Alzheimer's disease(AD)and their clinical utility in predicting disease progression.Methods:pGFAP and pNfL concentrations were measured in 72 FTD,56 AD and 83 cognitively normal(CN)participants using the Single Molecule Array technology.Of the 211 participants,199 underwent cerebrospinal(CSF)analysis and 122 had magnetic resonance imaging.We compared cross-sectional biomarker levels between groups,studied their diagnostic performance and assessed correlation between CSF biomarkers,cognitive performance and cortical thickness.The prognostic performance was investigated,analyzing cognitive decline through group comparisons by tertile.Results:Unlike pNfL,which was increased similarly in both clinical groups,pGFAP was increased in FTD but lower than in AD(all P<0.01).Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD(area under the curve[AUC]:combination 0.78;pGFAP 0.7;pNfL 0.61,all P<0.05).In FTD,pGFAP correlated with cognition,CSF and plasma NfL,and cortical thickness(all P<0.05).The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD(1.40 points annually,hazard ratio[HR]3.82,P<0.005)and in AD(1.20 points annually,HR 2.26,P<0.005).Conclusions:pGFAP and pNfL levels differ in FTD and AD;and their combination is useful for distinguishing between the two diseases.pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes

Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia(FTD).Targets for intervention have been identified,therapies are being developed,and clinical trials are advancing.A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes.The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction,language impairments and behavioral disturbance.Behavioral variant FTD is characterized by an initial presentation of changes in personality,behavior and/or emotion,which are often difficult to objectively capture using traditional neuropsychological measures.The two principal language variants of FTD are Progressive Nonfluent Aphasia(PNFA)with predominant agrammatic/non-fluent impairments and Semantic Dementia(SD)with semantic impairments and visual agnosia.Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change,yet specific enough to isolate signal from noise,and acceptable to regulatory agencies.Given the anticipated potential for small effect sizes,measures must be able to identify small incremental changes over time.It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest.Selected outcome measures should be suitable for repeat administration,yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability.To facilitate widespread adoption as an endpoint,measures should be readily accessible.We provide several examples of potential global,composite,and individual cognitive measures,as well as behavioral measures promising for FTD trials.Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.

A transcranial magnetic stimulation study on Alzheimer's diseae and behavioral variant frontotemporal dementia

Objective To investigate the changes in cortical excitability and inhibitory circuits of patients with Alzheimer’s disease(AD)or behavioral variant frontotemporal dementia(bv FTD)using transcranial magnetic stimulation(TMS).Methods Forty-four patients with AD,30 patients with bv FTD and 44 healthy controls were enrolled in the study.The epidemiological data

Therapies for Tau-associated neurodegenerative disorders:targeting molecules,synapses,and cells

Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.

What can imaging tell us about cognitive impairment and dementia?

Dementia is a contemporary global health issue with far reaching consequences, not only for affected individuals and their families, but for national and global socio-economic conditions. The hallmark feature of dementia is that of irreversible cognitive decline, usually affecting memory, and impaired activities of daily living. Advances in healthcare worldwide have facilitated longer life spans, increasing the risks of developing cognitive decline and dementia in late life. Dementia remains a clinical diagnosis. The role of structural and molecular neuroimaging in patients with dementia is primarily supportive role rather than diagnostic, American and European guidelines recommending imaging to exclude treatable causes of dementia, such as tumor, hydrocephalus or intracranial haemorrhage, but also to distinguish between different dementia subtypes, the commonest of which is Alzheimer&#x02019;s disease. However, this depends on the availability of these imaging techniques at individual centres. Advanced magnetic resonance imaging (MRI) techniques, such as functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy, and molecular imaging techniques, such as 18F fluoro-deoxy glucose positron emission tomography (PET), amyloid PET, tau PET, are currently within the realm of dementia research but are available for clinical use. Increasingly the research focus is on earlier identification of at risk preclinical individuals, for example due to family history. Intervention at the preclinical stages before irreversible brain damage occurs is currently the best hope of reducing the impact of dementia.

Depressive symptoms in neurodegenerative diseases

Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer's disease and related conditions like Parkinson's disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have aparticular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment.

Associated mortality risk of atypical antipsychotic medication in individuals with dementia

BACKGROUND Antipsychotic medications such as risperidone,olanzapine and aripiprazole are used to treat psychological and behavioural symptoms among dementia patients.Current evidence indicate prescription rates for antipsychotics vary and wider consensus to evaluate clinical epidemiological outcomes is limited.AIM To investigate the potential impact of atypical antipsychotics on the mortality of patients with dementia.METHODS A retrospective clinical cohort study was developed to review United Kingdom Clinical Record Interactive Search system based data between January 1,2013 to December 31,2017.A descriptive statistical method was used to analyse the data.Mini Mental State Examination(MMSE)scores were used to assess the severity and stage of disease progression.A cox proportional hazards model was developed to evaluate the relationship between survival following diagnosis and other variables.RESULTS A total of 1692 patients were identified using natural language processing of which,587 were prescribed olanzapine,quetiapine or risperidone(common group)whilst 893(control group)were not prescribed any antipsychotics.Patients prescribed olanzapine showed an increased risk of death[hazard ratio(HR)=1.32;95%confidence interval(CI):1.08-1.60;P<0.01],as did those with risperidone(HR=1.35;95%CI:1.18-1.54;P<0.001).Patients prescribed quetiapine showed no significant association(HR=1.09;95%CI:0.90-1.34;P=0.38).Factors associated with a lower risk of death were:High MMSE score at diagnosis(HR=0.72;95%CI:0.62-0.83;P<0.001),identifying as female(HR=0.73;95%CI:0.64-0.82;P<0.001),and being of a White-British ethnic group(HR=0.82;95%CI:0.72-0.94;P<0.01).CONCLUSION A significant mortality risk was identified among those prescribed olanzapine and risperidone which contradicts previous findings although the study designs used were different.Comprehensive research should be conducted to better assess clinical epidemiological outcomes associated with diagnosis and therapies to improve clinical management of these patients.

Prevalence of cerebrospinal fluid Alzheimer disease-like pattern in atypical dementias

BACKGROUND: Differential diagnosis between Frontotemporal Dementia (FTD), Corticobasal Syndrome (CBS), Progressive Supranuclear Palsy Syndrome (PSP), FTD with motor neuron disease (FTD-MND) is often challenging, because of the occurrence of atypical cases. Autopsy series have identified Alzheimer Disease (AD) pathology in a consistent percentage of patients with atypical dementias. It has been demonstrated that Cerebrospinal Fluid (CSF) Tau/Aβ42 dosage is a reliable marker for AD. OBJECTIVE: To evaluate the presence and percentage of CSF AD-like patterns (high CSF tau/Aβ42 ratio) in patients with atypical dementias in order to identify an ongoing AD neurodegenerative process. METHODS: One hundred seventy two consecutive patients fulfilling current clinical criteria for behavioural variant FTD (bvFTD, n = 73), agrammatic variant of Primary Progressive Aphasia (avPPA, n = 19), semantic variant of PPA (svPPA, n = 12), FTD-MND (n = 5), CBS (n = 42), PSP (n = 21) were recruited and underwent CSF analysis. CSF AD-like and non AD (nAD-like) patterns were identified. RESULTS: CSF AD-like pattern was reported in 6 out of 73 cases (8.2%) in the bvFTD group, in 3 out of 19 (15.8%) in the avPPA group, and in 7 out of 42 (16.7%) in the CBS group. One out of 12 (8.3%) of svPPA had CSF AD-like pattern. None of patients FTD-MND and PSP had CSF AD-like pattern. No differences in demographic characteristics were detected between subgroups in each phenotype. CONCLUSIONS: Our findings convey that the CSF tau/ Aβ42 ratio could be found in a proportion of cases with clinical bvFTD, avPPA and CBD. Detecting anon-going AD pathological process in atypical dementias has several implications for defining distinctive therapeutic approaches, guiding genetic screening and helping in patients’ selection in future clinical trials.