Parkinson’s disease (PD) is a complex disorder characterized by a wide spectrum of symptoms. Depression and anxiety are common manifestations in PD and may be determinants of health-related quality of life (HRQoL). The objective of this study is to determine the association of depression and anxiety with the dimensions of HRQoL in subjects with PD enrolled in an association of patients. Ninety-five community-based patients with PD diagnosis at different disease stages were studied. HRQoL was assessed using the Parkinson’s Disease Questionnaire (PDQ-39); depression and anxiety were assessed using the Beck Depression Inventory (BDI-II) and the State-Trait Anxiety Inventory (STAI), respectively. Our results showed that depression and anxiety were negatively associated with HRQoL measured by PDSI. Higher motor dysfunction measured by Hoehn and Yahr (H&Y) staging was also associated with worse HRQoL. Depression was the most influential variable in the model. All PDQ-39 dimensions except social support and bodily discomfort were associated with depression. Anxiety was associated with the emotional well-being and bodily discomfort dimensions. These results suggest that physicians should pay attention to the presence of psychiatric symptoms and treat them appropriately.
Here we describe the larger series of clinical cases (n = 14) with HD-like phenotype and IAs published to date. MRI and FDG-PET neuroimaging findings compatible with HD can be found in some patients with IA. Larger and more detailed series are needed to assess the pathogenic role of IAs in HTT gene.
Intermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported.
We reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the “intermediate range”. We gathered the type of symptoms in all cases and the main neuroimaging findings when available.
We found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET.
The clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD.
Patients with Parkinson’s Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests
Background: Visuospatial skills are impaired in Parkinson's disease (PD). Other related skills exist, such as spatial orientation have been poorly studied. The egocentric (based on internal cues) and allocentric frameworks (based on external cues) are used in daily spatial orientation. Depending on PD onset, the allocentric framework may have a higher level of impairment in tremor-dominant and the egocentric one in akinetic-rigid.
Objective: To evaluate spatial orientation and visuospatial functions in PD patients and controls, and to assess whether their performance is related to disease duration and the PD subtype (tremor-dominant and akinetic-rigid).
Methods: We evaluated egocentric and allocentric spatial orientation (Egocentric and Allocentric Spatial Memory Tasks) and visuospatial abilities, span and working memory in 59 PD patients and 51 healthy controls.
Results: Visuospatial skills, visuospatial span, and egocentric and allocentric orientation are affected in PD. Visuospatial skills and allocentric orientation undergo deterioration during the first 5 years of the disease progression, while egocentric orientation and visuospatial span do so at later stages (9-11 years). The akinetic-rigid subtype presents worse results in all the spatial abilities that were measured when compared to controls, and worse scores in visuospatial working memory, visuospatial abilities and allocentric orientation when compared to the tremor-dominant group. The tremor-dominant group performed worse than controls in egocentric and allocentric orientation.
Conclusion: PD patients show deficits in their visuospatial abilities and in their egocentric and allocentric spatial orientation compared to controls, specifically in akinetic-rigid PD. Only spatial orientation are affected in tremor-dominant PD patients. Allocentric orientation is affected earlier in the progression of the disease.
Reference: Fernandez-Baizan C, Paula Fernandez Garcia M, Diaz-Caceres E, Menendez-Gonzalez M, Arias JL, Mendez M. Patients with Parkinson's Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests. J Parkinsons Dis. 2020;10(4):1807-1816. doi: 10.3233/JPD-202122
Frontotemporal dementia (FTD) is a clinical, genetic and pathological heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 frontotemporal dementia (FTD) patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p<0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (HR=4.12) and the PNFA group showed the highest onset-age (p=0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p=0.02) and survival (HR= 1.73) and rs5848 GRN with a significant shorter survival in CC homozygous patients (HR= 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 non carriers (p=0.022). Although validation of our findings is necessary, our results suggest that TP53,GRN and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials (full text).
A role for ATXN1, ATXN2 and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease
We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2 and HTT genes in several neurodegenerative diseases. The study included 1,126 Alzheimer disease (AD), 440 frontotemporal dementia (FTD) and 610 Parkinson's disease (PD) patients. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. Additionally, in the FTD cohort we determined the number of HTT CAG-repeats. The frequency of HTT IAs was higher in FTD patients (6.9%) vs controls (2.9%) and in the C9orf72 expansion non carriers (7.2%) vs. controls (2.9%), although the difference was non-significant after correction for multiple testing. Compared to controls, progressive non-fluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs ( 13.6% vs 2.9% controls). For the ATXN2 gene, we observed an IAs increased frequency in AD cases (AD 4.1% vs controls 1.8%) and in the behavioural FTD (bvFTD) group (4.8% vs 1.8%). For the ATXN1 gene we found a significant increase of IAs in PNFA patients (18.6%) vs controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.
The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight
Background The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.
Objectives To perform the largest PD genome‐wide association study restricted to a single country.
Methods We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population‐specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease‐associated loci, heritability estimates, genetic correlations, and burden analyses.
Results We identified a novel population‐specific genome‐wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome‐wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA‐DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non‐Spanish origin. Seventeen PD‐related genes showed functional consequence by two‐sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.
Conclusions Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine‐mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.
Amyloid β (Aβ) in brain parenchyma is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ is transported from the brain to the plasma via complex transport mechanisms at the blood-brain barrier (BBB). About 90–95% of plasma Aβ may be bound to albumin. Replacement of serum albumin in plasma has been proposed as a promising therapy for AD. However, the efficacy of this approach may be compromised by altered BBB Aβ receptors in AD, as well as multiple pools of Aβ from other organs in exchange with plasma Aβ, competing for albumin binding sites. The flow of interstitial fluid (ISF) into cerebrospinal fluid (CSF) is another major route of Aβ clearance. Though the concentration of albumin in CSF is much lower than in plasma, the mixing of CSF with ISF is not impeded by a highly selective barrier and, hence, Aβ in the two pools is in more direct exchange. Furthermore, unlike in plasma, Aβ in CSF is not in direct exchange with multiple organ sources of Aβ. Here we consider albumin replacement in CSF as an alternative method for therapeutic brain Aβ removal and describe the possible advantages and rationale supporting this hypothesis.
Reference: Front. Neurol., 18 October 2019 | https://doi.org/10.3389/fneur.2019.01036