Presenile Dementia Research Articles

A Shotgun Proteomic Platform for a Global Mapping of Lymphoblastoid Cells to Gain Insight into Nasu-Hakola Disease.

Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.

Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging!

BackgroundFrontal variant frontotemporal dementia is a common cause of presenile dementia. A hexanucleotide expansion on chromosome 9 has recently been recognized as the most common genetic mutation cause of this illness. This sub-type tends to present psychiatrically with psychosis being a common presenting symptom before the onset of cognitive changes or brain atrophy. A few case series have been published describing the prominence of early psychotic symptoms, and lack of clear brain atrophy on clinical brain imaging imposing a challenge in reaching early accurate diagnosis. In this report, we present a case whereby the diagnosis of Schizophrenia syndrome was made and the patient was treated for years with multiple interventions for that syndrome before reaching the accurate diagnosis of Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9. This diagnosis was confirmed after genetic testing and findings on a hybrid Positron Emission Tomography/Magnetic Resonance Imaging scanning.Case summaryA 60-year-old female diagnosed with schizophrenia at age 50 after presenting with delusions and hallucinations, which proved to be refractor to several lines of pharmacological and non-pharmacological interventions including electroconvulsive therapy. Patient had a history of post-partum psychosis in her 20s. She was referred to cognitive neurology due to progressive decline in function. While clinical structural brain imaging data were not adequate to support an alternative neurological diagnosis, careful inquiry elicited a history of psychotic illness followed by progressive decline in a sister. Genetic testing confirmed hexanucleotide expansion on chromosome 9 mutation. The patient was offered a state-of-the-art FD-Glucose Positron Emission Tomography/Magnetic Resonance Imaging scan available at our centre. While volumetric Magnetic Resonance Imaging scan did not show volume loss in frontotemporal areas, the hybrid scan showed regionally specific deficit in FD-Glucose Positron Emission Tomography affecting medial superior frontal, insula, inferior temporal, thalamus, and anterior cingulate cortex consistent with behavioral variant frontotemporal dementia.ConclusionsThis case highlights the importance of considering Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9 when facing relatively late-onset, refractory schizophrenia-like syndrome. Careful history from all available sources to elicit family history of similar presentation is very important. Genetic testing and functional brain imaging can aid in confirming the diagnosis and potentially streamlining the management of these cases.

Before the light fades, who blows the whistle? : a narrative review on sports dementia

AimsTraumatic brain injury is a leading risk factor for degenerative conditions. Although in the past this was believed to affect mostly boxers, recent studies have expanded the at-risk population to include American football players, rugby players, hockey players and other athletes involved in contact sports. Hence, there has been growing interest in the media and the public at large on the short and long term impacts of head trauma in sportspersons. The aim of this study is provide an overview of the impact of traumatic brain injury in contact sports and the link to early onset dementia.MethodFor the purpose of this study we conducted a literature search using PubMed electronic base and Google scholar. The search was made in February 2021 and using the following keywords ‘early onset dementia’, ‘presenile dementia’, ‘traumatic brain injury’, ‘contact sports’, ‘sportsmen’, and ‘athletes’. The search words were used individually and in combination to gather relevant articles. Types of studies included were case reports, case series, cohorts, cross-sectional, editorial and newspaper articles.ResultMost of the published studies have shown significant associations between repeated head trauma and brain morphological changes evidenced by the presence of myelinated axons, astrocytosis, perivascular neuroinflammation and formation of phosphorylated Tau proteinopathy. These contribute significantly to alterations in axonal functioning and synaptic transmissions which sets the stage for neuronal degeneration. These changes affect both the macroscopic and microscopic structures with consequent neurochemical disturbances and functional deficits which, manifest primarily as executive dysfunction.ConclusionCurrent evidence supports an association between participation in contact sports and neurodegenerative disease, despite the protective aspects of sporting activities. Overall the studies reviewed have shown that brain injury remains a potent risk factor for the early onset dementia seen in sportspersons. Consequently, it is prudent for more proactive and precautionary measures to be put in place to reduce impacts of head injury and to better identify and manage brain injury in sports.

The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics.

Frontotemporal dementia (FTD) is a common cause of presenile dementia and is characterized by behavioural and/or language changes and progressive cognitive deficits. Genetics is an important component in the aetiology of FTD, with positive family history of dementia reported for 40% of cases. This review synthesizes current knowledge of the known major FTD genes, including C9orf72 (chromosome 9 open reading frame 72), MAPT (microtubule-associated protein tau) and GRN (granulin), and their impact on neuronal and glial pathology. Further, evidence for white matter dysfunction in the aetiology of FTD and the clinical, neuroimaging and genetic overlap between FTD and leukodystrophy/leukoencephalopathy are discussed. The review highlights the role of common variants and mutations in genes such as CSF1R (colony-stimulating factor 1 receptor), CYP27A1 (cytochrome P450 family 27 subfamily A member 1), TREM2 (triggering receptor expressed on myeloid cells 2) and TMEM106B (transmembrane protein 106B) that play an integral role in microglia and oligodendrocyte function. Finally, pharmacological and non-pharmacological approaches for enhancing remyelination are discussed in terms of future treatments of FTD.

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia.MethodsTo investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.ResultsWhile mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity.ConclusionOur findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Ik2/TBK1 and Hook/Dynein, an adaptor complex for early endosome transport, are genetic modifiers of FTD-associated mutant CHMP2B toxicity in Drosophila

Mutations in CHMP2B, encoding a protein in the endosomal sorting complexes required for transport (ESCRT) machinery, causes frontotemporal dementia linked to chromosome 3 (FTD3). FTD, the second most common form of pre-senile dementia, can also be caused by genetic mutations in other genes, including TANK-binding kinase 1 (TBK1). How FTD-causing disease genes interact is largely unknown. We found that partial loss function of Ik2, the fly homologue of TBK1 also known as I-kappaB kinase ε (IKKε), enhanced the toxicity of mutant CHMP2B in the fly eye and that Ik2 overexpression suppressed the effect of mutant CHMP2B in neurons. Partial loss of function of Spn-F, a downstream phosphorylation target of Ik2, greatly enhanced the mutant CHMP2B phenotype. An interactome analysis to understand cellular processes regulated by Spn-F identified a network of interacting proteins including Spn-F, Ik2, dynein light chain, and Hook, an adaptor protein in early endosome transport. Partial loss of function of dynein light chain or Hook also enhanced mutant CHMP2B toxicity. These findings identify several evolutionarily conserved genes, including ik2/TBK1, cut up (encoding dynein light chain) and hook, as genetic modifiers of FTD3-associated mutant CHMP2B toxicity and implicate early endosome transport as a potential contributing pathway in FTD.

Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

BackgroundTriggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. Homozygous TREM2 mutations cause early onset progressive presenile dementia while heterozygous, point mutations triple the risk of Alzheimer’s disease (AD). Although human genetic findings support the notion that loss of TREM2 function exacerbates neurodegeneration, it is not clear whether activation of TREM2 in a disease state would result in therapeutic benefits. To determine the viability of TREM2 activation as a therapeutic strategy, we sought to characterize an agonistic Trem2 antibody (AL002a) and test its efficacy and mechanism of action in an aggressive mouse model of amyloid deposition.MethodsTo determine whether agonism of Trem2 results in therapeutic benefits, we designed both intracranial and systemic administration studies. 5XFAD mice in the intracranial administration study were assigned to one of two injection groups: AL002a, a Trem2-agonizing antibody, or MOPC, an isotype-matched control antibody. Mice were then subject to a single bilateral intracranial injection into the frontal cortex and hippocampus and euthanized 72 h later. The tissue from the left hemisphere was histologically examined for amyloid-beta and microglia activation, whereas the tissue from the right hemisphere was used for biochemical analyses. Similarly, mice in the systemic administration study were randomized to one of the aforementioned injection groups and the assigned antibody was administered intraperitoneally once a week for 14 weeks. Mice underwent behavioral assessment between the 12- and 14-week timepoints and were euthanized 24 h after their final injection. The tissue from the left hemisphere was used for histological analyses whereas the tissue from the right hemisphere was used for biochemical analyses.ResultsHere, we show that chronic activation of Trem2, in the 5XFAD mouse model of amyloid deposition, leads to reversal of the amyloid-associated gene expression signature, recruitment of microglia to plaques, decreased amyloid deposition, and improvement in spatial learning and novel object recognition memory.ConclusionsThese findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders.

Using diffusion tensor imaging to detect cortical changes in fronto-temporal dementia subtypes

Fronto-temporal dementia (FTD) is a common type of presenile dementia, characterized by a heterogeneous clinical presentation that includes three main subtypes: behavioural-variant FTD, non-fluent/agrammatic variant primary progressive aphasia and semantic variant PPA. To better understand the FTD subtypes and develop more specific treatments, correct diagnosis is essential. This study aimed to test the discrimination power of a novel set of cortical Diffusion Tensor Imaging measures (DTI), on FTD subtypes. A total of 96 subjects with FTD and 84 healthy subjects (HS) were included in the study. A “selection cohort” was used to determine the set of features (measurements) and to use them to select the “best” machine learning classifier from a range of seven main models. The selected classifier was trained on a “training cohort” and tested on a third cohort (“test cohort”). The classifier was used to assess the classification power for binary (HS vs. FTD), and multiclass (HS and FTD subtypes) classification problems. In the binary classification, one of the new DTI features obtained the highest accuracy (85%) as a single feature, and when it was combined with other DTI features and two other common clinical measures (grey matter fraction and MMSE), obtained an accuracy of 88%. The new DTI features can distinguish between HS and FTD subgroups with an accuracy of 76%. These results suggest that DTI measures could support differential diagnosis in a clinical setting, potentially improve efficacy of new innovative drug treatments through effective patient selection, stratification and measurement of outcomes.

Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most prevalent form of pre-senile dementia after Alzheimer’s disease. Amyotrophic lateral sclerosis (ALS) can overlap genetically, pathologically and clinically with FTD indicating the two conditions are ends of a spectrum and may share common pathological mechanisms. FTD–ALS causing mutations are known to be involved in endosomal trafficking and RNA regulation. Using an unbiased genome-wide genetic screen to identify mutations affecting an FTD–ALS-related phenotype in Drosophila caused by CHMP2BIntron5 expression, we have uncovered repressors of retrovirus (RV) activity as modifiers of CHMP2BIntron5 toxicity. We report that neuronal expression of CHMP2BIntron5 causes an increase in the activity of the endogenous Drosophila RV, gypsy, in the nervous system. Genetically blocking Drosophila gypsy activation and pharmacologically inhibiting viral reverse transcriptase activity prevents degenerative phenotypes observed in fly and rat neurons. These findings directly link endosomal dysfunction to RV de-repression in an FTD–ALS model without TDP-43 pathology. These observations may contribute an understanding to previous discoveries of RV activation in ALS affected patients.

Comparison Study of Various Nano Technology Formulation of Curcumin in Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive deterioration affecting day to day living and behavioural activities. It is commonest cause of senile and pre-senile dementia. In Alzheimer’s disease, a peptide referred as amyloid beta aggregates (oligomers), and accumulates in the brain to form deposits called as amyloid plaques. According to the world health organization (WHO), 5% of men and 6% of women of above 60 years are victims with Alzheimer’s type dementia globally. In India prevalence of dementia is 33.6%, of which AD contributes approximately 54% and vascular dementia constitutes approximately 39%. Patients with the prolonged use of some Non-steroidal anti-inflammatory (NSAID) drugs such as ibuprofen have lower risk of developing the symptoms of AD; however the chronic use of NSAID can produce a toxic effect on the kidney, liver and GI tract. Recent studies have demonstrated that a curcumin delivery system based on nanoscience and nanotechnology increases the therapeutic potential of this compound. Specifically, several nano-sized carriers such as phospholipid vesicles (liposomes), micelles, solid lipid nanoparticles, polymeric nanoparticles, emulsions, proteins and other molecular complexes have been developed for the efficient delivery of curcumin. Nano particles have demonstrated the enhanced Bioavailability of curcumin including circulation time in the blood. Various nano technology drug delivery system of curcumin showed increased Bio accessibility during treatment of Alzheimer’s disease.

A Review on Biological Activity of Heterocyclic Nucleus Carbazole

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive deterioration affecting day to day living and behavioural activities. It is commonest cause of senile and pre-senile dementia. In Alzheimer’s disease, a peptide referred as amyloid beta aggregates (oligomers), and accumulates in the brain to form deposits called as amyloid plaques. According to the world health organization (WHO), 5% of men and 6% of women of above 60 years are victims with Alzheimer’s type dementia globally. In India prevalence of dementia is 33.6%, of which AD contributes approximately 54% and vascular dementia constitutes approximately 39%. Patients with the prolonged use of some Non-steroidal anti-inflammatory (NSAID) drugs such as ibuprofen have lower risk of developing the symptoms of AD; however the chronic use of NSAID can produce a toxic effect on the kidney, liver and GI tract. Recent studies have demonstrated that a curcumin delivery system based on nanoscience and nanotechnology increases the therapeutic potential of this compound. Specifically, several nano-sized carriers such as phospholipid vesicles (liposomes), micelles, solid lipid nanoparticles, polymeric nanoparticles, emulsions, proteins and other molecular complexes have been developed for the efficient delivery of curcumin. Nano particles have demonstrated the enhanced Bioavailability of curcumin including circulation time in the blood. Various nano technology drug delivery system of curcumin showed increased Bio accessibility during treatment of Alzheimer’s disease.

Aluminium Induced DNA-damage and Oxidative Stress in Cultures of the Marine Sponge Hymeniacidon perlevis

Aluminium is the most abundant element in the earth crust, and has no known biological function. However, it is an established neurotoxicant in its trivalent oxidation state, with exposure resulting in neurodegenerative diseases like Parkinson’s disease and presenile dementia. Although, the potential genotoxic and carcinogenic effects of aluminium are established in mammalian and other model system, there is however very limited information on aluminium genotoxicity in aquatic invertebrates. Mechanism of aluminium toxicity is also largely unclear. With a concentration range between 0.001– 0.05mg/L in near neutral pH water, and up to 0.5-1mg/L in an acidic water , aluminium poses a potential threat to the marine ecosystem, however it is poorly studied. This study, therefore presents for the first time, aluminium-induced DNA damage using the comet assay and reactive oxygen Species (ROS) formation using 2’, 7’-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay as biomarkers of genotoxicity and oxidative stress in the inter-tidal marine sponge Hymeniacidon perlevis, respectively. H. perlevis is widely distributed in the British Isles, Mediterranean and the Arctic sea and has been reported as a model for environmental biomonitoring in aquatic ecosystem and as a suitable alternative to bivalves. In this study, cryopreserved single sponge cells of H. perlevis were cultured as viable aggregates and were thereafter treated with 0.1, 0.2, 0.3 and 0.4mg/L aluminium chloride (AlCl3) for 12 hours. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our results showed that non-cytotoxic concentrations of AlCl3 caused a statistically significant concentration-dependent increase in the level of DNA-strand break and reactive oxygen species formation single sponge cells of H. perlevis. There was also a statistically significant positive linear correlation between aluminium-induced DNA strand break and ROS formation suggesting the involvement of ROS in the causative mechanism of the aluminium induced DNA-strand breaks observed.

Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. GPNMB is widely expressed in various tissues, where it is involved in cell differentiation, migration, inflammation/anti-inflammation, tissue regeneration, and neuroprotection. GPNMB is identified in microglia of adult rat brains, neurons and astrocytes of GPNMB transgenic (Tg) mouse brains, and motor neurons of amyotrophic lateral sclerosis (ALS) patients. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Pathologically, the brains of NHD patients exhibit leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes and the basal ganglia. At present, molecular mechanisms responsible for development of leukoencephaolpathy in NHD brains remain totally unknown. Recent evidence indicates that disease-associated microglia (DAM) that cluster around amyloid plaques express high levels of GPNMB in Alzheimer's disease (AD) brains. Because microglia act as a key regulator of leukoencephalopathy in NHD brains, it is proposed that GPNMB expressed on microglia might play a protective role in progression of leukoencephalopathy possibly via active phagocytosis of myelin debris. In the present study using immunohistochemistry, we have attempted to clarify the expression of GPNMB in NHD brains, compared with AD brains. We found that microglia accumulating in the white matter express an intense GPNMB immunoreactivity in both NHD and AD brains, suggesting that the accumulation of GPNMB-immunoreactive microglia is a general phenomenon in neurodegenerative brains.

PIH52 DEMENTIA-RELATED PSYCHOSIS: REAL-WORLD PATIENT CHARACTERISTICS AND HEALTHCARE UTILIZATION FROM A LARGE US ADMINISTRATIVE CLAIMS DATABASE

To examine the characteristics and healthcare resource utilization of patients with dementia in the 12 months before diagnosis of dementia-related psychosis (DRP) within a large US health insurer database. Commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years with evidence of DRP were identified between 01-Jan-2009 and 31-Mar-2017. The first observed indicator of psychosis (≥2 claims-diagnosis or pharmacy fill) co-occurring or following evidence of dementia (≥2 claims-diagnosis or pharmacy fill) was the index date. Continuous enrollment was required from 12 months prior to dementia until index date and 12 months post-index. Patient characteristics were examined in the year prior to the index date. Of 13,006 patients identified, 32.4% had ≥1 diagnosis of “Alzheimer’s Disease,” 28.1% of presenile dementia, senile dementia, or dementia associated with other conditions, and 27.5% of unspecified dementia. Mean age was 80.2 (SD=6.9) years, 67% were female, and 86.3% had MAPD coverage. Mean Charlson Comorbidity Index score was 1.9 (1.9); 76.4% of patients were diagnosed with hypertension, 57.6% with disorders of lipid metabolism, 55.2% with diseases of the urinary system, and 55.3% with diseases of the heart. All-cause utilization was frequent in the year before psychosis occurred: 92.8% of patients had ≥1 office visit (mean # of visits=16.6 [17.2]), 78.1% had ≥1 outpatient visit (8.5 [12.5]) and 58.5% had ≥1 emergency room visit (1.6 [2.9]). Inpatient admissions occurred among 34.6% of patients (0.6 [1.0]) and lasted an average of 12.0 (41.5) days. Mean all-cause total costs were $20,737 ($29,383), with $5,780 ($8,836) spent on pharmacy. The largest portion of medical costs ($14,958 [$27,049]) was from inpatient stays ($7,660 [$22,128]). Patients with DRP were elderly and primarily Medicare beneficiaries. On average, they had low Charlson scores but used health care services more than twice a month in the year before psychosis occurred.

Parting with the Concept of Alzheimer’s Disease in Senium

Our understanding of the mental deterioration associated with old-age have undergone a number of changes over the past two centuries and have spurred major scientific debates. In the 19th century, this disorder was still considered to be an inevitable feature of aging. The dawn of the 20th century offered a histological explanation for presenile dementia, and Alois Alzheimer was credited as the discoverer of a new disease that bears his name. During the last quarter of the twentieth century, the findings of Alois Alzheimer were massively applied also to late-onset dementia, thus virtually excluding natural intellectual impairment as an explanation. In contradiction to Alzheimer´s original concept, amyloid plaques and neurofibrillary tangles are now considered the cause of psychic depreciation at all ages, and their presence is interpreted as a disease. We wish to dispute these common views and suggest that continuing with this approach may be increasingly counterproductive. Instead, we offer an unbiased view without any preconceived ideas, which respects a long list of natural biological failures that inevitably accompany every human life, i.e., microinjuries, microinfarcts, leukoaraiosis as a consequence of partly failing cerebral blood flow, microbleeds, glycemic fluctuations in diabetics, alcohol and toxic influences, decreasing anisotropy, increasing mean diffusivity on MRIs, and many others.

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

Familial Creutzfeldt-Jakob Disease in an Indian Kindred.

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.

Chapter 20 - Vascular cognitive impairment: A preventable component of dementia

For many decades during the 20th century, the common belief was that the slow strangulation of the brains' blood supply from hardening of the brain arteries led to chronic brain ischemia and neuronal death. Not surprisingly, to counter this, vasodilators rapidly became one of the most commonly used and profitable medications worldwide; however, no clinical benefits were ever proven. In the 1970s and early 1980s cerebral blood flow studies strongly disproved the idea of brain failure due to chronic ischemia. It was also shown that infarcts and not chronic ischemia caused dementia, leading to the concept of multiinfarct dementia. In addition to infarcts, it was then realized that other vascular lesions can also cause cognitive decline. Gradually, as "atherosclerotic dementia" lost ground, Alzheimer's disease (AD) that once had been considered a presenile dementia and rare, became almost synonymous with dementia. Subsequent memory-based definitions and evaluations of dementia led to a bias in favor of diagnosing AD, overshadowing vascular contributions. The widespread use of brain imaging in the 1980s and 1990s contributed to the resurgence of evidence of cerebrovascular diseases. Moreover, it was shown that most cognitive impairment of the elderly results from mixed pathologies, emphasizing the need for a change in the traditional categorical diagnosis of dementia, e.g., AD vs vascular dementia. The alternative diagnostic method was named the vascular cognitive impairment approach, meaning identifying any impairment caused by or associated with vascular factors. The importance of this approach is that vascular lesions are currently the most important treatable and preventable components of dementia, even before any symptoms manifest, i.e., at the brain at risk stage. This chapter provides a summary of the vascular cognitive impairment approach to diagnosis, treatment, and prevention of cognitive decline.

Recent Advances in the Quest for Treatment and Management of Alzheimer and Other Dementia

Alzheimer’s disease (AD) is a neurodegenerative disease distinguished by progressive cognitive deterioration along with declining activities of daily living and behavioral changes. It is the commonest type of pre-senile and senile dementia. Many new therapeutic strategies have been developed in the last few years. We aimed at reviewing the evidence supporting these new therapeutic targets, including anti-amyloid and anti-Tau strategies. This review is focused on important future direction in investigation of potential therapeutic targets for AD drug discovery. Medical advances have improved treatment of many diseases but still there is a need to establish new tools for early diagnosis of AD. A thorough comprehensive understanding of the unexplored mechanism can ameliorate the diagnostic and therapeutic management of AD. There have been several disease-modifying therapeutic strategies for AD in the last few years and are presently at various phases of investigation. Few of them have shown promising results, but their safety and efficacy need to be further explored.

History of Pick's disease

History of Pick's disease