Toward a new nosology of neurodegenerative diseases
New “omic” technologies are revealing shared and distinct biological pathways within and across neurodegenerative diseases (NDDs), allowing a better understanding of endophenotypes that exceeds the boundaries of the current diagnostic criteria. Moreover, a diagnostic framework is needed that can accommodate the co-pathology and the clinical overlap and heterogeneity of NDDs. Apart from dissecting the reasons for a revolution in how we conceive NDD, this article aims to prompt a change in how we diagnose and classify NDD, drafting a general scheme for a new nosology. As identifying a cause is the key to using the term “disease” properly, we propose using a tridimensional classification based on three axes: (1) etiology or pathogenic mechanism, (2) pathology markers and molecular biomarkers, (3) anatomic–clinical; and three hierarchical levels of etiology: (1) genetic/sporadic (2) cellular pathways and processes, and function of fluidic brain systems, and (3) risk factors.
Reference: Menéndez-González, M. Toward a new nosology of neurodegenerative diseases. Alzheimer's Dement. 2023; 1- 7. https://doi.org/10.1002/alz.13041
Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications
Intrathecal pseudodelivery is a specialized drug delivery method where the therapeutic agent is introduced into a reservoir connected to the intrathecal space rather than being directly released into the cerebrospinal fluid (CSF). In this approach, the drug remains within the reservoir, where it interacts with its target, thus altering the composition of the CSF without systemic release of the drug into the body.
Key Points:
- Localized Interaction: The drug interacts with its target within the reservoir, potentially allowing for more controlled and localized treatment effects.
- Minimal Systemic Exposure: By confining the drug to the reservoir and avoiding its release into the broader CSF, this method can reduce systemic side effects and toxicity.
- Enhanced Efficacy: It aims to maximize the efficacy of the drug by ensuring it is delivered precisely where needed while avoiding dispersion throughout the central nervous system (CNS) that might dilute its effectiveness.
Overall, intrathecal pseudodelivery can be advantageous in achieving targeted drug effects within the CNS while minimizing unintended systemic impacts.
Reference: Manuel, M.-G.; Tamba, B.-I.; Leclere, M.; Mabrouk, M.; Schreiner, T.-G.; Ciobanu, R.; Cristina, T.-Z. Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications. Pharmaceutics 2023, 15, 768. https://doi.org/10.3390/pharmaceutics15030768
A variant in GRN of Spanish origin presenting with heterogeneous phenotypes
Introduction
The variant c.1414-1G > T in theGRN gene has been previously reported as probably pathogenic in subjects of Hispanic origin in the American continent.
Methods
We report five families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings.
Results
Phenotypes were strikingly different, including cases presenting with behavioral variant of frontotemporal dementia, with semantic variant of primary progressive aphasia, with rapidly progressive motor neuron disease (pathologically documented), and with tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G > T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11.
Conclusions
We conclude that variant c.1414-1G > Tn the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.
Full text: https://doi.org/10.1016/j.nrleng.2022.10.001
New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease
Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies
The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems
Alzheimer’s disease (AD) is a global health problem, with incidence and prevalence considered to increase during the next decades. However, no currently available effective treatment exists despite numerous clinical trials in progress. Moreover, although many hypotheses are accepted regarding the pathophysiological mechanisms of AD onset and evolution, there are still many unknowns about the disorder. A relatively new approach, based on the amyloid-beta dynamics among different biological compartments, is currently intensely discussed, as it seems to offer a promising solution with significant therapeutic impact. Known as the “cerebrospinal-fluid-sink therapeutic strategy”, part of the “three-sink therapeutic strategy”, this theoretical model focuses on the dynamics of amyloid-beta among the three main liquid compartments of the human body, namely blood, cerebrospinal fluid, and the (brain) interstitial fluid. In this context, this article aims to describe in detail the abovementioned hypothesis, by reviewing in the first part the most relevant anatomical and physiological aspects of amyloid-beta dynamics. Subsequently, explored therapeutic strategies based on the clearance of amyloid-beta from the cerebrospinal fluid level are presented, additionally highlighting their limitations. Finally, the originality and novelty of this work rely on the research experience of the authors, who focus on implantable devices and their utility in AD treatment.
Smoking is associated with age at disease onset in Parkinson's disease
Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients.
Objective
The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk.
Methods
We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results.
Results
Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001).
Conclusions
Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.
Cancer in Parkinson Disease: an approximation to the main risk factors
Impact of Depression and Anxiety on Dimensions of Health-Related Quality of Life in Subjects with Parkinson’s Disease Enrolled in an Association of Patients
A series of cases with Huntington-like phenotype and intermediate repeats in HTT
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.
Background
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.
Methods
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.
Results
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.
Conclusion
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
Genetic variation in APOE, GRN and TP53 are phenotype modifiers in frontotemporal dementia
A role for ATXN1, ATXN2 and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease
Reference: https://doi.org/10.1016/j.neurobiolaging.2019.10.017
The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight
Albumin Exchange in Alzheimer's Disease: Might CSF Be an Alternative Route to Plasma?
Reference: Front. Neurol., 18 October 2019 | https://doi.org/10.3389/fneur.2019.01036
Prevalence of Depression and Anxiety in Parkinson Disease and Impact on Quality of Life: A Community-Based Study in Spain
Full text https://doi.org/10.1177/0891988719874130
Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders
Reference: Journal of Translational Medicine volume 17, Article number: 290 (2019) Full text