Translational Neurodegeneration - Latest Articles

Intranuclear inclusions in a Fragile X mosaic male

Dalyir Pretto — 2013-05-21T00:00:00Z

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55-200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45-54 CGG repeats) as well as in a subject with a full mutation with mosaicism.Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.

Quantitative evaluation of severity of behavioral and psychological symptoms of dementia in patients with vascular dementia

Wei-Dong Pan — 2013-04-22T00:00:00Z

To quantitatively evaluate severity of behavioral and psychological symptoms of dementia (BPSD) for vascular dementia (VD). Changes of 51 patients with VD in BPSD between the first and 24th week were assessed using the Neuropsychiatric Inventory (NPI) and the behavioral pathology in Alzheimer’s disease (BEHAVE-AD) rating scale, in detrended fluctuation analysis (DFA) represented by diurnal activity (DA), evening activity (EA), and nocturnal activity (NA), and the relationships were analyzed. The subscores of activity disturbances, diurnal rhythm disturbances, and anxieties and phobias in the BEHAVE-AD score, and that of agitation, irritability, and sleep disorder in the NPI score were significantly increased compared with the first week, as was for the changes for EA in the DFA value. A linear correlation was observed between the changes of activity disturbances plus anxieties and phobias, and those of DA, and between the development of diurnal rhythm and those of EA, the vehement and autism scores and those of DA, and the difference in sleep disorder scores and those of EA, respectively. Analysis of DA, NA, and EA may reflect the fluctuational degrees of VD-BPSD, can provide a useful assessment of VD-BPSD accompanied by clinical scores for VD.

Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review

Xiao-dong Pan — 2013-04-19T00:00:00Z

Frontotemporal lobar degeneration (FTLD) represents a group of clinically, neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype. FTLD is pathologically characterized by the frontal and temporal lobar atrophy. Frontotemporal dementia (FTD) clinically presents with abnormalities of behavior and personality and language impairments variants. The clinical spectrum of FTD encompasses distinct canonical syndromes: behavioural variant of FTD (bvFTD) and primary progressive aphasia. The later includes nonfluent/agrammatic variant PPA (nfvPPA or PNFA), semantic variant PPA (svPPA or SD) and logopenic variant PPA (lvPPA). In addition, there is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The FTLD spectrum disorders are based upon the predominant neuropathological proteins (containing inclusions of hyperphosphorylated tau or ubiquitin protein, e.g transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and fusedin-sarcoma protein in neurons and glial cells) into three main categories: (1) microtubule-associated protein tau (FTLD-Tau); (2) TAR DNA-binding protein-43 (FTLD-TDP); and (3) fused in sarcoma protein (FTLD-FUS). There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies, which are chromosome 9 open reading frame 72 (C9ORF72) gene, granulin (GRN) gene, microtubule associated protein tau gene (MAPT), the gene encoding valosin-containing protein (VCP) and the charged multivesicular body protein 2B (CHMP2B). In this review, recent advances on the different clinic variants, neuroimaging, genetics, pathological subtypes and clinicopathological associations of FTD will be discussed.

Social brain dysfunctions in patients with Parkinson¿s disease: a review of theory of mind studies

Rwei-Ling Yu — 2013-03-28T00:00:00Z

Human social interaction is essential in daily life and crucial for a promising life, especially in people who suffer from disease. Theory of Mind (ToM) is fundamental in social interaction and is described as the ability to impute the mental states of others in social situations. Studies have proposed that a complex neuroanatomical network that includes the frontal cortex mediates ToM. The primary neuropathology of Parkinson’s disease (PD) involves the frontal-striatal system; therefore, patients with PD are expected to exhibit deficits in ToM. In this review, we summarize the current research with a particular focus on the patterns of impaired ToM, potential mediators of ToM, and the impact of ToM deficits on clinical disability in PD. Further studies to investigate the progression of ToM and its relationship with dementia in subjects in PD are needed.

Annual acknowledgement of manuscript reviewers

Shengdi Chen — 2013-03-19T00:00:00Z

Contributing reviewersThe editors of Translational Neurodegeneration would like to thank all our reviewers who have contributed to the journal in Volume 1 (2012).

Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer¿s disease

Zhi-Kun Sun — 2013-02-28T00:00:00Z

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterized clinically by insidious onset of memory and cognition impairment, emergence of psychiatric symptoms and behavioral disorder, and impairment of activities of daily living (ADL). Traditional Chinese medicine (TCM) is practiced in the Chinese health care system for more than 2,000 years. In recent years, scientists have isolated many novel compounds from herbs, some of which improve dementia with fewer side effects than conventional drugs and are regarded as potential anti-AD drugs. In this review, we summarize the latest research progress on TCM showing their possible role of treatment of AD and other demented diseases and possible pharmacological actions.

Short communication: genetic variations of SLC2A9 in relation to Parkinson¿s disease

Jianjun Gao — 2013-02-19T00:00:00Z

Background: Epidemiological studies showed that higher plasma urate was associated with lower risk for Parkinson’s disease (PD) and slower disease progression. Recent genome-wide association studies (GWAS) consistently showed that several single nucleotide polymorphisms (SNPs) in the solute carrier family 2 member 9 gene (SLC2A9 ) were associated with plasma urate concentration and the risk of gout. Methods: We conducted a case–control study to examine twelve tag SNPs of the SLC2A9 gene in relation to PD among 788 cases and 911 controls of European ancestry. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models, adjusting for age, sex, smoking and caffeine consumption. Results: These SNPs were all in linkage disequilibrium (R2 > 0.7). None of them were associated with PD risk. Among women, however, there was a suggestion that the presence of the minor allele of one SNP (rs7442295) was related to a small increase in PD risk [OR (95% CI) = 1.48 (1.01-2.16)]. Conclusion: This study provides little support for genetic variations of SLC2A9 and PD risk.

Can we clinically diagnose dementia with Lewy bodies yet?

Yue Huang — 2013-02-11T00:00:00Z

Dementia with Lewy Bodies (DLB) was initially identified and confirmed primarily by pathology, but is soon to be incorporated into the Diagnostic and Statistical Manual criteria as a clinical disease entity. Despite these advances over more than 20 years, current data suggest that the sensitivity of accurate clinical diagnosis of DLB is still very low, although there is mounting evidence that supportive features may increase diagnostic accuracy. Although DLB remains easy to identify pathologically with different cellular pathologies differentiating it from other dementia syndromes, pathological identification using only Lewy body pathology has been shown to be inaccurate due to overlap with patients without dementia symptoms. A number of studies now suggest that a combination of cellular pathologies, which include α-synuclein and β-amyloid deposition as well as dopamine denervation, assist with differentiating this dementia syndrome from others. The clinical and pathological overlap with the tauopathy of Alzheimer’s disease still remains to be clarified. To determine more robust and independent clinicopathological correlates from Alzheimer’s disease, longitudinal prospective studies, using specific clinical batteries on dementia patients reaching the proposed criteria for DLB, with post-mortem assessment of the multiple pathologies associated with dementia, are required. Identifying genetic causes for DLB is another approach to investigate the pathogenesis of DLB. However this approach has been hindered to date by difficulties with identifying DLB clinically. The use of novel techniques is likely to advance knowledge on the pathogenesis of DLB and assist with redefining clinical and pathologic diagnostic criteria. To achieve the goal of more accurate clinical diagnosis of DLB, breakthroughs are necessary on the pathogenesis of DLB.

Translational research in Huntington¿s disease: opening up for disease modifying treatment

Jean-Marc Burgunder — 2013-01-25T00:00:00Z

Research on the molecular mechanisms involved in Huntington’s disease, a monogenic disorder with a complex phenotype including motor, behaviour, and cognitive impairments, is advancing at a rapid path. Knowledge on several of the multimodal pathways has now lead to the establishment of rational strategies to prepare trials of several compounds in affected people. Furthermore, improved understanding of the phenotype and on ways of assessing it, as well as the process of developing biomarkers, allows setting the frame for such studies. In this brief review, the present status of some of these aspects is examined.

Changes in Timing and kinematics of goal directed eye-hand movements in early-stage Parkinson¿s disease

Danya Muilwijk — 2013-01-09T00:00:00Z

ObjectiveMany daily activities involve intrinsic or extrinsic goal-directed eye and hand movements. An extensive visuomotor coordination network including nigro-striatal pathways is required for efficient timing and positioning of eyes and hands. The aim of this study was to investigate how Parkinson’s disease (PD) affects eye-hand coordination in tasks with different cognitive complexity. Methods: We used a touch screen, an eye-tracking device and a motion capturing system to quantify changes in eye-hand coordination in early-stage PD patients (H&Y < 2.5) and age-matched controls. Timing and kinematics of eye and hand were quantified in four eye-hand coordination tasks (pro-tapping, dual planning, anti-tapping and spatial memory task). Results: In the pro-tapping task, saccade initiation towards extrinsic goals was not impaired. However, in the dual planning and anti-tapping task initiation of saccades towards intrinsic goals was faster in PD patients. Hand movements were differently affected: initiation of the hand movement was only delayed in the pro-tapping and dual planning task. Overall, hand movements in PD patients were slower executed compared to controls.InterpretationWhereas initiation of saccades in an extrinsic goal-directed task (pro-tapping task) is not affected, early stage PD patients have difficulty in suppressing reflexive saccades towards extrinsic goals in tasks where the endpoint is an intrinsic goal (e.g. dual planning and anti-tapping task). This is specific for eye movements, as hand movements have delayed responses in the pro-tapping and dual planning task. This suggests that reported impairment of the dorsolateral prefrontal cortex in early-stage PD patients affects only inhibition of eye movements. We conclude that timing and kinematics of eye and hand movements in visuomotor tasks are affected in PD patients. This result may have clinical significance by providing a behavioral marker for the early diagnosis of PD.