Search

Alzheimer's disease and dementia are neurodegenerative conditions characterized by memory loss and diminished capacity to perform daily tasks. These disorders pose a significant challenge in aging populations globally, underscoring the need to explore potential remedies. This systematic review aims to assess the efficacy of trigonelline, safranal, and chamomile in the treatment and prevention of Alzheimer's disease and dementia. A thorough search was conducted using PubMed and Google Scholar, encompassing human intervention studies, clinical trials, as well as in-vitro and in-vivo investigations when the former were not applicable. Out of the 107 studies identified, 27 (25.23%) conducted between 2005 and 2022 were included in the review. Results indicate that trigonelline may be an alternative for treating neurodegenerative conditions by regulating neuro-inflammation. Safranal, administered to rats, prevented memory and learning decline through molecular-level mechanisms, including the amelioration of apoptosis, oxidative stress, inflammation, cholinesterase activity, neutrophil infiltration, and preservation of mitochondrial integrity. Chamomile was seen to inhibit the activity of key enzymes associated with Alzheimer's disease, and also had a "neuroprotective effect against oxidative stress in neurological disorders and peripheral nerve degeneration". The results warrant need for confirmatory studies to validate the efficacy and safety of trigonelline, safranal and chamomile in the management of neurodegenerative diseases as established in the present data. [ABSTRACT FROM AUTHOR]

Young-onset dementia (YOD) symptoms often first present in the workplace, resulting in work performance challenges and eventually loss of employment. This study aims to investigate the experiences, work values, and support needs of employees with YOD and their relatives. Semi-structured interviews were conducted to explore the experiences, work values, and support needs of (former) employees with YOD and their relatives. Subsequently, separate focus group discussions were conducted for employees and relatives to review and prioritize interview findings. Inductive thematic analysis was applied to both datasets. A total of 15 interviews (six employees; nine relatives) and four focus group discussions (ten employees; six relatives) were conducted. Six themes emerged, with five revolving around the central theme: desire to work. The other themes represent essential contributing factors, including importance of receiving a YOD diagnosis; knowledge, awareness, and understanding regarding YOD; open communication, joint decision making, and collaboration; work adjustments, involvement, and support; phasing out work and future perspectives. The findings highlight a strong desire to work post-YOD diagnosis, serving as a foundation for developing workplace support tools and guidance. This has the potential to help individuals with YOD preserve their self-confidence and identity while working within their capabilities. [ABSTRACT FROM AUTHOR]

Background and Purpose: Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. The clinical distinction between FTD, Alzheimer's disease (AD), and other dementias is a clinical challenge. Brain perfusion SPECT may contribute to the diagnosis of FTD, but its value is unclear. Methods: We performed a systematic review to investigate the diagnostic accuracy of the brain SPECT in (1) distinguishing FTD from AD and other dementias and (2) differentiating FTD variants. Results: Overall, 391 studies were retrieved on the initial search and 35 studies composed the final selection, comprising a total number of 3142 participants of which 1029 had FTD. The sensitivity and the specificity for the differential diagnosis of FTD versus AD ranged from 56% to 88% and from 51% to 93%, respectively. SPECT is not superior to the clinical method of diagnosis, but the combination of SPECT with clinical data seems to improve the diagnostic accuracy. Conclusion: Brain perfusion SPECT has a limited value in the diagnostic framework of FTD. SPECT can be performed when FDG‐PET is not available. SPECT is recommended only for selected cases when the diagnosis is challenging using conventional methods. [ABSTRACT FROM AUTHOR]

Background: Studies on disease-related obstructions experienced in everyday life of younger people with dementia (YOD ≤ 65 years) and their families are encouraged. Aim: To explore how the family carers experience six predefined topics that influence the everyday life and needs of persons with YOD. Method: A quantitative and a qualitative study including family carers of persons with young-onset Alzheimer's dementia (AD) and frontotemporal dementia (FTD). Seventy-four informants responded to the Camberwell Assessment of Needs in the Elderly (CANE) and individual interviews were conducted with 13 informants. Results: Family carers of persons with YOD reported few unmet needs in the CANE assessment. Needs related to behavior and close relationships were reported significantly more frequent (p < 0.1) in persons with FTD than in persons with AD. From the qualitative data, six main themes were emphasized: daily activities turned upside down, involuntary loss of previous social network, losing close relationship, but maintaining a friendship with the spouse, unpredictable behavior adds burdens to a changing life, health and life risks, and economic insecurity for future life and caring costs. Conclusion: Whilst family carers quantitatively reported unmet needs, the individual interviews reported several major difficulties in everyday life. [ABSTRACT FROM AUTHOR]

Background and Objectives: Frontotemporal dementia (FTD) is the second most common form of presenile dementia; however, its diagnosis has been poorly investigated. Previous attempts to diagnose FTD using quantitative electroencephalography (qEEG) have yielded inconsistent results in both spectral and functional connectivity analyses. This study aimed to introduce an accurate qEEG marker that could be used to diagnose FTD and other neurological abnormalities. Materials and Methods: We used open-access electroencephalography data from OpenNeuro to investigate the power ratio between the frontal and temporal lobes in the resting state of 23 patients with FTD and 29 healthy controls. Spectral data were extracted using a fast Fourier transform in the delta (0.5 ≤ 4 Hz), theta (4 ≤ 8 Hz), alpha (8–13 Hz), beta (>13–30 Hz), and gamma (>30–45 Hz) bands. Results: We found that the spectral power ratio between the frontal and temporal lobes is a promising qEEG marker of FTD. Frontal (F)-theta/temporal (T)-alpha, F-alpha/T-theta, F-theta/F-alpha, and T-beta/T-gamma showed a consistently high discrimination score for the diagnosis of FTD for different parameters and referencing methods. Conclusions: The study findings can serve as reference for future research focused on diagnosing FTD and other neurological anomalies. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system, which is crucial for memory, emotions, and learning. However, distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies. [ABSTRACT FROM AUTHOR]

The role of peptide probes’ conformational flexibility in extracting immunosignatures has not been sufficiently studied. Immunosignatures profile the antibody diversity and prove promising for early cancer detection and multi-disease diagnostics. A novel tool for modeling antibody repertoires, the concept of antibody reactivity graphs, proved instrumental in this respect. Serum samples from patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia of unknown etiology (DUE), and healthy controls were probed using a set of 130 7-mer peptides relevant to neurodegenerative diseases. Results show that linear peptides probed with IgM yielded higher graph density compared to IgG, indicating different levels of polyspecificities. Additionally, the impact of peptide topology and antibody isotype on feature selection was studied using recursive feature elimination. Findings reveal that IgM assays on linear peptides offer superior diagnostic differentiation of neurodegenerative diseases and define the degree of agreement between IgG and IgM immunosignatures with linear or cyclic peptides. [ABSTRACT FROM AUTHOR]

Informal caregivers of persons with early onset dementia (PWEOD) are usually the spouses of affected individuals. These caregivers face unique challenges related to the unexpected nature of disease onset at this early life stage along with the accompanying symptoms, which can be different from those in late onset dementia. The current study explores the meanings these caregivers make of their situations and actions in response to their experiences. Findings provide a basis for development of a conceptual framework illustrating the basic, psychosocial processes underlying their shared situation. Grounded theory methodology was used. Qualitative data were collected through semi-structured interviews with 15 participants. Data were analyzed using constant comparative techniques and situational analysis. A distinction was made across participants between identifying as spouse versus caregiver for their PWEOD. Each participant had made or was making an identity transition from viewing their role as becoming more caregiver-like toward an eventual, complete shift to that of caregiver in a stepwise fashion. Incremental shifts in identity reflected challenges to the notion held of what it means to be a spouse. Results support prior research highlighting the unique experiences of caregivers of PWEOD while providing a framework for understanding the unique situations of these care-givers. Findings also inform nursing interventions tailored for spouses of PWEOD. [Journal of Gerontological Nursing, 49(8), 27–34.] [ABSTRACT FROM AUTHOR]

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented orthochromatic leukodystrophy. We describe the clinicopathological and genetic findings of three patients with this disorder. All patients presented with dysarthria, with or without cognitive decline. The first and second patients were siblings who died of the disease at ages 42 and 54, respectively, while the third patient has been bedridden. Brain magnetic resonance imaging revealed T2 hyperintensities in the subcortical and periventricular white matter. Pathological diagnosis was established by brain autopsy in cases 1 and 2, and a stereotactic brain biopsy in case 3, followed by genetic analysis of colony stimulating factor-1 receptor gene. A heterozygous c.2345G > A (p.R782H) variant was identified in the autopsy-proven cases, and a c.1765G > A (p.G589R) variant in the biopsy-proven case. Postmortem examination revealed severe white matter degeneration involving the bilateral frontoparietal lobes, but sparing the subcortical U-fibers. All cases revealed widespread loss of myelinated axons in the white matter lesions; however, axonal spheroids and pigmented macrophages were abundant in cases 1 and 3 and much less in case 2. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia should be considered in patients with presenile dementia and diffuse white matter lesions. [ABSTRACT FROM AUTHOR]

Background: Creutzfeldt-Jakob disease (CJD) is a rare neuro degenerative disease that is mainly characterized by rapidly progressive dementia along with a varying combination of myoclonus, visual, cerebellar, pyramidal/extrapyramidal and akinetic mutism. Several movement disorders phenomenologies can occurs either at onset, as presenting symptom or during the course of illness. Present study aims to characterize the clinical, radiological features and the outcome of patients with CJD with movement disorders as the forthcoming manifestation. Methods: Chart review of patients with CJD with movement disorders. Demographic, clinical and radiological details of the patients were reviewed. Results: 25 patients (13 males) of sCJD with median age at presentation of 58 years and median duration of illness of 5 months were included in the study. According to revised CDC diagnostic criteria 1 patient was classified as definite sCJD, 20 as probable and 2 as possible CJD. Myoclonus, ataxia and parkinsonism were the most common movement disorder and chorea was the least common. Magnetic resonance imaging of brain was performed in all and basal ganglia abnormality and cortical ribboning was seen in more than two-third of cases. Electroencephalographic abnormality was noted in 21 patients with triphasic waves and periodic sharp waves seen in 7 and 6 patients respectively. Cerebrospinal fluid 14-3-3 assay was abnormal in 2 out of 4 patients. Atypical presentations were noted in the form of ataxic presentation, CBS like presentation and choreiform presentation. Conclusion: Myoclonus, ataxia and parkinsonism are the most frequent movement disorders phenomenology observed in patients with sCJD. [ABSTRACT FROM AUTHOR]

A 50-year-old male presented with a four-year history of gradually progressive rest tremor in the distal right lower limb and then spreading to the left lower limb in last 10-12 months. He developed right arm rest and action tremor two years later. Magnetic resonance imaging scans showed progressive frontotemporal and asymmetrical mesial temporal atrophy. Genetic testing revealed a heterozygous c.915+16C>T pathogenic variant in intron 9 of the MAPT gene. Presentation with rest tremor should not exclude frontotemporal dementia-parkinsonism due to a MAPT variant as a differential diagnosis though rest tremor is a rare presentation. [ABSTRACT FROM AUTHOR]

It is essential to find ways to engage adults living with dementia in meaningful and social activities, as well as elicit positive emotions and behaviors during the selected activities. Intergenerational programs (IGPs) involving young children have been shown to benefit the physical, emotional, and social health of older adults, including those living with dementia, and are often positively received by this population. This study examined how involvement in an IGP was associated with the way that individuals living with dementia engaged and the behaviors that they exhibited during the activities. Fourteen older adults living in a shared-site long-term care facility participated in an onsite IGP. Their interactions were recorded over a five-day period immediately prior to the children's arrival and throughout the duration of the program; adults' engagement and behaviors were coded using the Menorah Park Engagement Scale (MPES). Findings indicated that there were significant changes in engagement type and the behaviors exhibited by these adults during the IGPs. Constructive engagement significantly increased while non-engagement and other engagement were significantly reduced when the children were present. Greater displays of pleasure and helping behaviors were also exhibited during the IGPs. These findings have implications for recreational therapy practice in long-term care settings and support the use of IGPs with adults living with dementia as a nonpharmacological intervention to improve social engagement in this population. [ABSTRACT FROM AUTHOR]

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented orthochromatic leukodystrophy. We describe the clinicopathological and genetic findings of three patients with this disorder. All patients presented with dysarthria, with or without cognitive decline. The first and second patients were siblings who died of the disease at ages 42 and 54, respectively, while the third patient has been bedridden. Brain magnetic resonance imaging revealed T2 hyperintensities in the subcortical and periventricular white matter. Pathological diagnosis was established by brain autopsy in cases 1 and 2, and a stereotactic brain biopsy in case 3, followed by genetic analysis of colony stimulating factor-1 receptor gene. A heterozygous c.2345G > A (p.R782H) variant was identified in the autopsy-proven cases, and a c.1765G > A (p.G589R) variant in the biopsy-proven case. Postmortem examination revealed severe white matter degeneration involving the bilateral frontoparietal lobes, but sparing the subcortical U-fibers. All cases revealed widespread loss of myelinated axons in the white matter lesions; however, axonal spheroids and pigmented macrophages were abundant in cases 1 and 3 and much less in case 2. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia should be considered in patients with presenile dementia and diffuse white matter lesions.

Background: While it is less common, young onset dementia manifests at a significantly younger age (< 65). Many people with young onset dementia are parents; however, little is known about impact of the condition on children and young adults. A qualitative thematic analysis was conducted to synthesise the literature on the perspectives of children and young adults with a parent living with young onset dementia. Methods: Electronic databases were searched in order to identify all peer-reviewed literature in relation to the perspectives of children and young adults with a parent living with young onset dementia. A thematic analysis was conducted on the relevant literature. Results: The electronic database search resulted in 15 full texts articles. Four main themes with related subthemes emerged from the thematic analysis. The four main themes were: changing family dynamics; psychological and physical strain; stigma and coping strategies. Conclusion: The current synthesis outlines the perspectives of children and young adults with a parent living with young onset dementia. There is a significant lack of research in this area which adds to the stereotypical view of dementia as an older person's disease. This can lead to children and young adults being impacted by lack of awareness and stigma resulting in significant psychosocial problems. As the number of people living with dementia (including young onset) is set to increase, future research with children and young adults with a parent with young onset dementia is important in order to better support this cohort. [ABSTRACT FROM AUTHOR]

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Background: In the past years an increasing amount of research has been done on the experiences of adult children of a parent with early-onset dementia. However, little is still known about how the socio-cultural context influences the narratives of these children. Aim: This study aimed to provide insights into the far-reaching consequences of parental early-onset dementia for adult children in the Netherlands. It illustrates how the experiences of these adult children are shaped by the context they live in. Method: 16 in-depth interviews were conducted with adult children of a parent with early-onset dementia in the Netherlands. The interviews offered the children space to reflect on the impact the illness of their parent had on them and their lives. The data were analysed using thematic analysis. Findings: This article illustrates that the comparative processes of relating to others' experiences help the children to reflect on the impact that their parent's illness has on their own lives, which in turn aids them in contextualising and making meaning out of their changing lives and relationships. This contextualization and recovery of meaning is shaped by three processes. The first concerns the ways these adult children draw comparisons between their own lives and experiences and those of their peers of the same age group. The second process entails comparative understandings of having a parent with early-onset dementia versus having a parent with late-onset dementia. The third process explores how having a parent with early-onset dementia compares to having a parent with other diseases. The processes of contextualisation which the adult children engage in are shaped by what the children perceive to be normal and thus also by their socio-cultural contexts. Conclusions: This article reveals how meaning is created in a constant interplay between the primary experiences of having an ill parent and the socio-cultural context in which the experiences take place. It illustrates how this context provides for particular narratives, which in turn shape how the children are able to give meaning to their experiences. [ABSTRACT FROM AUTHOR]

Aim: To develop understanding of the lived experiences of children of people living with young onset dementia, defined as individuals both under and over the age of 18 years whose parent was diagnosed with dementia before the age of 65 years. Method: A critical appraisal and thematic synthesis of the available qualitative literature regarding the lived experience of individuals whose parent has a diagnosis of young onset dementia. A three-stage approach for conducing thematic synthesis was followed. Results: 15 articles were included in the review. Four analytical themes and 11 subthemes were found. The analytical themes were 'making sense of dementia', 'impact of dementia', 'coping' and 'support'. Conclusions: The experiences of those affected by parental young onset dementia vary widely. There is a lack of knowledge and understanding of young onset dementia by professionals and the public, and a scarcity of appropriate support. This has clinical implications for professionals working with families affected by young onset dementia, in particular with regards to service design and delivery. [ABSTRACT FROM AUTHOR]

Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer's disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p =

Backgbround: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. Methods: To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. In this review, we summarized the characteristics of each FTD gene. We also reassessed their pathogenicity and revised some mutations from pathogenic to uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Results: Thirty-two rare variants in genes of MAPT, GRN, C9orf72, CHCHD10, VCP, and TBK1 were identified in Chinese FTD populations, including 25 pathogenic mutations and seven variants of uncertain significance (VUS). Among them, the frequency of rare variants in the CHCHD10 gene was the highest. Surprisingly, twelve variants reported as pathogenic mutations were revised as VUS by ACMG. The correlations between genes and clinical manifestations were MAPT and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), GRN and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), C9orf72/CHCHD10/TBK1 and amyotrophic lateral sclerosis (ALS)-FTD spectrum, and VCP corresponds inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Conclusions: It is necessary to strictly interpret the contributions of genes to diseases by ACMG. MAPT is the most common pathogenic gene for FTD in China. [ABSTRACT FROM AUTHOR]

It is now known that the inherited prion disease is caused by over 60 different mutations in the Prion protein (PRNP) gene. Four missense mutations at codons 102, 178, 200 and 210, account for over 95% of these cases. In this study we describe, a large Indian family with familial Creutzfeldt Jakob Disease (fCJD). One affected member presented with a presenile dementia, a protracted clinical course and characateristic MRI features. Genetic analysis revealed a D178N mutation in the 2 affected individuals and 7 unaffected members. The neuropathological examination of the brain of one of the affected member was conspicuous by spongiform degeneration, neuronal loss and gliosis. This is a detailed report of a genetically and neuropathologically proven fCJD from India.

The article presents a case of a 34-year-old businessman who was rushed to a clinic due to left-sided focal seizures with secondary generalisation and stiffness of his lower limbs without walking difficulties to discuss an unusual cause of early-onset dementia. Other topics include superficial siderosis (SS) as a rare cause of cortico-subcortical dementia, and the recurrent bleeding of multiple cavernomas as the cause of SS.

The article discusses the results of a study on the role that microbial infection can play in Alzheimer's disease. Topics mentioned include the association of the build up of amyloid plaques in the brain that can trigger Alzhemier's disease, the increase in the expression of the receptor for advanced glycation endproducts due to pneumococcal meningitis, and the protection provided by amyloid-beta plaques during infection.

“Young-onset dementia” (YOD) includes clinical presentations of dementia with the onset before age of 65. There are several important clinical differences between much more frequent late onset dementia (LOD) and YOD syndromes. First, YOD has much wider range of different aetiologies comparing to LOD. Among all possible aetiologies, treatable/potentially reversible causes are much more common in YOD then in LOD. There is also significantly higher prevalence of inherited dementias in younger age-groups. Furthermore, atypical cognitive (non-amnestic) presentations of common degenerative dementias (e. g. Alzheimer’s disease) are more frequent in YOD. Therefore, routine cognitive evaluation using standard screening tests (e.g. MMSE) may be insufficient. YOD is more often accompanied by neurological and systemic features (dementia plus syndromes) and the identification of these features can aid the diagnosis. Based on these specificities of YOD, diagnostic approach is always challenging. Therefore, a thorough neurocognitive assessment and a structured and rational diagnostic approach is mandatory to ensure early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Teaching Point: Nasu-Hakola disease (NHD) is characterized by multiple bone cysts in the appendicular skeleton and progressive presenile dementia.

Aim: Investigating the incidence rate of early‐onset dementia is challenging. We explored the incidence rate of early‐onset dementia in Japan using annual performance reports from the Medical Centers for Dementia. Methods: Medical Centers for Dementia are specialized health services for dementia established as part of Japan's national health program. There are 440 such centers nationwide as of 2018. Using the annual performance reports of these centers, we calculated the number of newly diagnosed cases of early‐onset dementia or late‐onset dementia from April 1, 2018 to March 31, 2019, and the composition ratio by diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The annual incidence rate of early‐onset dementia was estimated using the number of cases as the numerator and the national population aged 18–64 years as the denominator. Results: In total, 1733 of cases were diagnosed with early‐onset dementia, of which 52.1% were diagnosed as major neurocognitive disorder due to Alzheimer's disease, 8.9% major frontotemporal neurocognitive disorder, 8.8% major vascular neurocognitive disorder, 7.1% substance/medication‐induced major neurocognitive disorder, 6.5% major neurocognitive disorder with Lewy bodies and 3.9% major neurocognitive disorder due to another medical condition. The annual incidence rate of early‐onset dementia was estimated to be 2.47/100 000 person‐years. Conclusions: This study provides the first nationwide estimate of the incidence rate of early‐onset dementia in Japan and suggests that Medical Centers for Dementia are important resources for the epidemiological monitoring of early‐onset dementia nationwide. Geriatr Gerontol Int 2020; 20: 1050–1055.. [ABSTRACT FROM AUTHOR]

The cytoxicity of Alzheimer’s disease has been linked to the self-assembly of the 40/42 amino acid of the amyloid-β (Aβ) peptide into oligomers. To understand the assembly process, it is important to characterize the very first steps of aggregation at an atomic level of detail. Here, we focus on the N-terminal fragment 1–28, known to form fibrils in vitro. Circular dichroism and NMR experiments indicate that the monomer of Aβ(1–28) is α-helical in a membranelike environment and random coil in aqueous solution. Using the activation-relaxation technique coupled with the OPEP coarse grained force field, we determine the structures of the monomer and of the dimer of Aβ(1–28). In agreement with experiments, we find that the monomer is predominantly random coil in character, but displays a non-negligible β-strand probability in the N-terminal region. Dimerization impacts the structure of each chain and leads to an ensemble of intertwined conformations with little β-strand content in the region Leu17-Ala21. All these structural characteristics are inconsistent with the amyloid fibril structure and indicate that the dimer has to undergo significant rearrangement en route to fibril formation. [ABSTRACT FROM AUTHOR]

One year later, Perusini better defined his own position in a paper about plaques and tangles in brain aging and senile dementia: "[although their] number, diffusion and size may be different [...], no clear-cut distinction can be made between normal aging and senile dementia, including the atypical forms [described] by Alzheimer", thus anticipating the concept of a continuum from normal to pathological brain aging and also classifying Alzheimer's disease as a presenile form of senile dementia. There is no doubt that after his return to Italy in 1911, Perusini faced indifference and opposition from academics even though he did not have academic aspirations. When Perusini was in Munich studying senile psychoses under Alzheimer and Kraepelin, the author of I Psychiatrie i , he was asked by Alzheimer to review the cases, perhaps to settle a nosographic dispute. [Extracted from the article]

Background: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD).Objective: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer's disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD.Methods: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test.Results: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe.Conclusion: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB. [ABSTRACT FROM AUTHOR]

It is now known that the inherited prion disease is caused by over 60 different mutations in the Prion protein (PRNP) gene. Four missense mutations at codons 102, 178, 200 and 210, account for over 95% of these cases. In this study we describe, a large Indian family with familial Creutzfeldt Jakob Disease (fCJD). One affected member presented with a presenile dementia, a protracted clinical course and characateristic MRI features. Genetic analysis revealed a D178N mutation in the 2 affected individuals and 7 unaffected members. The neuropathological examination of the brain of one of the affected member was conspicuous by spongiform degeneration, neuronal loss and gliosis. This is a detailed report of a genetically and neuropathologically proven fCJD from India. [ABSTRACT FROM AUTHOR]

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive presenile dementia and bone cysts, caused by variants in either TYROBP or TREM2. Despite the well-researched role of TREM2 and TYROBP/DAP12 in immunity, immunological phenotypes have never been reported in NHD patients. We initially diagnosed an Italian patient, using whole exome sequencing, with classical NHD clinical sequelae who additionally showed a decrease in NK cells and autoimmunity features underlined by the presence of autoantibodies. Based on this finding, we retrospectively explored the immunophenotype in another two NHD patients, in whom a low NK cell count and positive autoantibody serology were recorded. Accordingly, Trem2 −/− mice show abnormal levels of circulating proinflammatory cytokines and the dysfunction of immune cells, whereas knockout mice for Tyrobp , encoding the adapter for TREM2, exhibit increased levels of autoantibodies and defective NK cell activity. Our findings tend to redefine NHD as a multisystem "immunological" disease, considering that osteoclasts are derived from the fusion of mononuclear myeloid precursors, whereas neurological anomalies in NHD are directly caused by microglia dysfunction. [ABSTRACT FROM AUTHOR]

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy. [ABSTRACT FROM AUTHOR]

Time-dependent data collected in studies of Alzheimer’s disease usually has missing and irregularly sampled data points. For this reason time series methods which assume regular sampling cannot be applied directly to the data without a pre-processing step. In this paper we use a random forest to learn the relationship between pairs of data points at different time separations. The input vector is a summary of the time series history and it includes both demographic and non-time varying variables such as genetic data. To test the method we use data from the TADPOLE grand challenge, an initiative which aims to predict the evolution of subjects at risk of Alzheimer’s disease using demographic, physical and cognitive input data. The task is to predict diagnosis, ADAS-13 score and normalised ventricles volume. While the competition proceeds, forecasting methods may be compared using a leaderboard dataset selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with standard metrics for measuring accuracy. For diagnosis, we find an mAUC of 0.82, and a classification accuracy of 0.73 compared with a benchmark SVM predictor which gives mAUC = 0.62 and BCA = 0.52. The results show that the method is effective and comparable with other methods. [ABSTRACT FROM AUTHOR]

Co-occurrence of different prion strains into the same host has been recognized as a natural phenomenon for several sporadic Creutzfeldt-Jakob disease (sCJD) patients and natural scrapie cases. The final outcome of prion coinfection is not easily predictable. In addition to the usual factors that influence prion conversion, the replication of one strain may entail positive or negative consequences to the other. The main aim of this study was to gain insights into the prion coinfection and interference concepts and their potential therapeutic implications. Here, different mouse models were challenged with several combinations of prion strains coupled on the basis of the lengths of their incubation periods and the existence/absence of a species barrier in the tested animal model. We found that nontransmissible strains can interfere the replication of fully transmissible strains when there is a species transmission barrier involved, as happened with the combination of a mouse (22L) and a human (sCJD) strain. However, this phenomenon seems to be strain dependent, since no interference was observed when the human strain coinoculated was vCJD. For the other combinations tested in this study, the results suggest that both strains replicate independently without effect on the replication of one over the other. It is common that the strain with more favorable conditions (e.g., a higher speed of disease development or the absence of a species barrier) ends being the only one detectable at the terminal stage of the disease. However, this does not exclude the replication of the least favored strain, leading to situations of the coexistence of prion strains. [ABSTRACT FROM AUTHOR]

Two of the most predominant features of the Alzheimer's disease (AD) brain are deposition of β-amyloid (Aβ) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of Aβ. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain's immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase-inhibitory peptide has gained much importance since it can inhibit acetylcholinesterase (AChE) and increase the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission in pharmacological treatment of Alzheimer's disease (AD). Natural peptides have received considerable attention as biologically important substances as a source of AChE inhibitors. These natural peptides have high potential pharmaceutical and medicinal values due to their bioactivities as neuroprotective and neurodegenerative treatment activities. These peptides have attracted great interest in the pharmaceutical industries, in order to design potential peptides for use in the prophylactic and therapy purposes. Some natural peptides and their derivatives have high commercial values and have succeeded in reaching the pharmaceutical market. A large number of peptides are already in preclinical and clinical pipelines for treatment of various diseases. This review highlights the recent researches on the various natural peptides and future prospects for AD management. [ABSTRACT FROM AUTHOR]

Abnormal interaction of amyloid-β peptide (Aβ) and metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal chelators to reverse metal-triggered Aβ aggregation has become one of the potential therapies for AD. In our work, the effect of metal chelator, NBD-BPEA, on Zn 2+ - or Cu 2+ -mediated Aβ 40 aggregation and neurotoxicity has been systematically studied. NBD-BPEA exhibits the capability to inhibit the metal-mediated Aβ 40 aggregation and disassemble performed Aβ 40 aggregates. It also prevents the formation of the β-sheet structure and promotes the reversion of the β-sheet to the normal random coil conformation. Moreover, it can alleviate Zn 2+ - or Cu 2+ -Aβ 40 -induced neurotoxicity, suppress the intracellular ROS and protect against cell apoptosis. These preliminary findings indicate that NBD-BPEA has promising perspective of application in the treatment of AD, and therefore deserve further investigation as potential anti-AD agents. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is still a major problem nowadays. Under the circumstance of many chemical drugs have poor effects on AD, traditional Chinese medicine has become a hot spot for us due to its multi-target and multi-path advantages. To explore the potential therapeutic targets of Kaixinsan (KXS) protects against AD in APP/PS1 transgenic mice model. All mice were divided into three groups: control group, model group and KXS group. Orally given KXS from two month old, and the control and model groups were given the same dose of distilled water. We collected all mice's serum samples at the 12th month age to determine the lipid markers of AD by compare with the model and control groups in full-scan analysis based on high-throughput serum lipidomics technology. Then we found the lipid molecules called back by KXS from the KXS protects against AD. Compared with the control group, the metabolic profile of the model mice was obviously disordered, and we identified 16 lipid-related biomarkers associated with AD. After KXS treatment, the metabolic profiles of these disorders tended to recover compared with the model group. And we identified eight key lipid molecules, of which four had statistical significance. We found that the main perturbation pathways related to AD were linoleic acid metabolism, arachidonic acid metabolism and sphingolipid metabolism. All these metabolic pathways showed different degrees of rotation after KXS administration. Through the pathways analysis, we found 4 lipids molecules with significant differences, which could be used as new targets for the treatment of AD. [ABSTRACT FROM AUTHOR]

In many epidemiological and clinical studies, observations on individuals are recorded longitudinally on a Likert-type scale. In the process of recording, or due to some other causes, a proportion of outcomes and time-dependent covariates may be missing in one or more follow-up visits (non monotone missing). Even when the number of patients with intermittent missing data is small, exclusion of those patients from the study seems unsatisfactory. This apart, often due to misreporting, miscategorization of response can occur that results in potentially invalid inference when no correction is made. We propose a joint mixed model that corrects the likelihood function to account for missing response and/or covariates and adjusts the likelihood to tackle miscategorization of response. Under this extreme complex but useful setup, we seek to estimate the parameters of the proposed model that accounts for baseline and/or time dependent covariates. Monte Carlo expectation–maximization (MCEM) is a convenient approach for estimating the parameters in the model. A simulation study was carried out to assess the approach. We also analyzed Alzheimer’s Disease Neuroimaging Initiative (ADNI) data where some responses and covariates are missing and some responses are possibly miscategorized. Our investigation reveals that apolipo-protein plays a significant role in Alzheimer’s disease progression. This was not visible in earlier analyses of ADNI data. [ABSTRACT FROM AUTHOR]

Background and purpose: Frontotemporal dementia (FTD) is the second most common presenile dementia characterized by behavioral changes and language impairment. The diagnosis of FTD relies heavily on neuroimaging, and sometimes on genetic screening. However, the genetic components in Chinese FTD patients remain largely unknown. Only a few FTD cases with established mutations have been reported in China. This study reported the detailed clinical and neuroimaging features in a Chinese behavioral variant FTD family. The role of MAPT gene mutation in Chinese dementia patients was also reviewed. Methods: By detailed inquiry of all affected individuals in the family, this study summarized the main clinical features of the disease. Four candidate genes (MAPT, PSEN1, PSEN2, and APP) were screened by direct sequencing. Structural magnetic resonance imaging (MRI), functional imaging of cerebral blood flow with arterial spin-labeled MRI (ASL-MRI), and cerebral metabolism with fluorodeoxyglucose positron emission tomography (FDG-PET) were collected in the proband and healthy mutation carriers. Results: By direct sequencing of candidate genes (MAPT, PSEN1, PSEN2, and APP), this study identified the P301L mutation in the MAPT gene in the proband and three unaffected family members. The phenotype of the affected cases was consistent within the pedigree. In this genetically proven behavioral variant FTD (bvFTD) patient, the maps of hypoperfusion on ASL-MRI look fairly similar to the hypometabolism on FDG-PET. The clinical feature for this bvFTD was in line with the hypoperfusion or hypometabolism pattern on functional neuroimagings. The phenotype of P301L in east Asia seems similar to western countries. Conclusion: For the inherited FTD patients, ASL-MRI and genetic identification were strongly recommended for the final diagnosis. In case of being underestimated, the role of MAPT gene mutation in Chinese FTD patients warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Mutations in the GRN (granulin precursor) are a frequent cause of frontotemporal dementia (FTD) and other atypical parkinsonian disorders. However, the frequency of GRN mutations in Asian patients with atypical parkinsonian disorders is still uncertain.Methods: We screened GRN mutations by sequencing cDNA from 98 patients with FTD or atypical parkinsonian disorders. The functional properties of the identified mutation were evaluated by overexpression in human embryonic kidney (HEK)-293 cells.Results: We identified a new missense (GRN p.T487I) mutation in a female patient with undefined atypical parkinsonism. The overexpression experiment further demonstrated that p.T487I mutation reduced the progranulin protein level and stability in HEK-293 cells.Conclusion: GRN p.T487I mutation, which decreases the stability of progranulin protein, could be a new causative mutation in patients with atypical parkinsonian disorders. [ABSTRACT FROM AUTHOR]