Journals
2025 EN
Rached Noor Abi · McManus Morgan N · Lopez Zuliany
+3 more
Abstract Background Caregivers of people living with dementia (PLWD) face burdens and stressors despite the existence of caregiving resources in the community, which sometimes remain underutilized. The Telemedicine Cognitive Geriatric Program (TCGP) of the NYC Health and Hospitals Bellevue serves culturally diverse PLWD and provides caregiver support. We aim to understand the needs and preferences for support delivery of our caregiver population. Method We retrospectively reviewed the services provided by the Social Worker (SW) to caregivers referred from the TCGP from May to December 2024. Using the electronic medical record, we identified all patients in the program. We administered a phone survey to caregivers, collected demographic information, past experiences with caregiver support, interest in future support, and preferences for support type (informational, emotional support, or tangible) and formats (individual vs. group, in person vs. virtual, open discussion vs. structured). Result Of 85 patients receiving care, 26 have Mild Cognitive Impairment, 47 dementia (20 mild, 12 moderate, 15 severe). SW connected with 48 out of 54 caregivers identified. In addition to emotional support and psychoeducation, SW assisted 44% with obtaining an increase in home care services hours, 17% with acquiring durable medical equipment, connected 12% to transportation resources, and referred 64.5% to community programs. Among 31 caregivers reached for the survey, 83.9% were female, 74.2% Hispanic, 9.7% African American, 9.7% Asian, 6.4% White. Most caregivers (61.3%) were children of the PLWD. About half (51.1%) received prior caregiver support, 77.4% expressed interest in future support with 75% preferring a mix of informational, emotional, and instrumental support. Most (41.7%) preferred individual support, 29.1% preferred group only, and 29.2% had no preference. Highlighted topics included managing behaviors, progression of dementia, and navigating home health and hospice services. Reasons for declining support were cultural differences, nature of familial bonds, and length of time and experience as a caregiver. Conclusion These findings highlight the need for comprehensive and culturally responsive caregiver support programs. Providing practical assistance and addressing issues such as navigating healthcare services may improve engagement of culturally diverse caregivers. Future research should examine which components of these support programs influence caregiver well‐being and patient outcomes.
Journals
2025 EN
Taillie Dominique · Cha Diana · Ferraro Gina
+4 more
Abstract Background Amyloid‐beta precursor protein (APP) is the source of all amyloid‐beta (Aβ), the amyloidogenic peptide that aggregates in Alzheimer’s disease (AD). Lowering APP mRNA expression with RNA interference (RNAi) is a novel treatment strategy under investigation for AD. The 5xFAD mouse model of AD overexpresses APP and PSEN1 with five familial AD mutations, resulting in robust pathology, including amyloid plaques, microgliosis, inflammation, synaptic loss, neuronal loss, and behavioral changes. This work evaluates the effects of early and late intervention with an APP‐lowering small interfering RNA (siRNA) in this established AD model. Method APP‐targeting siRNAor artificial CSF (aCSF; control) was administered by intracerebroventricular injection in 5xFAD mice at late (8‐months‐old) and early (12‐weeks‐old) disease stages, and in age‐matched wild‐type mice. Late intervention mice received either aCSF or 300µg single dose. Early intervention mice received one of four dose regimens: control (aCSF:aCSF), transient lowering (75µg APP siRNA:aCSF), moderate sustained lowering (75µg APP siRNA:75µg APP siRNA), or robust sustained lowering (300µg APP siRNA:300µg APP siRNA). The impact of late and early siRNA intervention on molecular, biochemical, histological, and disease‐related behavioral outcomes (assessed using the elevated plus‐maze and open‐field assay) were assessed in 12‐month‐old mice (Figure 1). Result Treatment in the late intervention group lowered amyloid burden to levels below the 8‐month baseline (Figure 2A, 2B). Compared with age‐matched aCSF mice, late treatment decreased pathogenic amyloid species, Aβ40 and Aβ42, in CSF and tissue, reduced markers of glial inflammation, and reduced plasma neurofilament light chain (NfL). No significant behavioral changes were noted (Figure 3A). Treatment in early intervention groups lowered amyloid burden in tissue (Figure 2C, 2D), reduced markers of glial inflammation, reduced plasma NfL, and decreased anxiety‐like behavior, all in a dose‐dependent manner. Notably, robust, sustained lowering of APP completely prevented the emergence of disease‐associated anxiety‐like behavior (Figure 3B). Conclusion Treatment with APP‐lowering siRNA reduced AD pathology in the 5xFAD mouse model. Early intervention with the highest dose regimen prevented the emergence of behavioral deficits and substantially improved many aspects of disease phenotype. These results support the continued development of mivelsiran, an investigational, first‐in‐class APP‐lowering RNAi therapeutic, in patients with AD (NCT05231785).
Journals
2025 EN
Janssen Niels · Paauw Dominique · Bakker Lieke
+3 more
Abstract Background Around 45% of dementia cases is likely attributable to modifiable risk factors, such as hypertension and high cholesterol. It is therefore important to increase awareness on the potential of dementia risk reduction on a population level. Herein, people with low socioeconomic position or migration background are often underrepresented. We assessed levels of awareness for dementia risk reduction in the general population and underrepresented groups. Method Online surveys and street interviews were conducted to test awareness about dementia risk being modifiable and knowledge regarding individual risk factors in the regions of South Limburg ( n = 1619) and Groningen ( n = 505), the Netherlands. In addition, two local districts characterized by low‐socioeconomic position ( n = 120) or migration background ( n = 330) were assessed. This was part of a baseline assessment within the Netherlands Dementia Prevention Initiative (NDPI) assessment, in which a newly designed awareness campaign will run from February 2025 for a total duration of 12 months in these regions and districts. The local campaigns will be implemented using a participatory, bottom‐up approach. Various activities are planned, including the use of mass media and public events. Result Initial results of measurements before the start of the campaign show that most participants rated their own knowledge about dementia as ‘fair’ (47% and 52%). Between 49% and 71% of all respondents are aware of the potential of risk reduction. Of all statements on risk and protective factors, maintaining cognitive activity (‘stimulating your brain reduces dementia risk’) was identified most often in three samples, ranging between 88% and 91%. In the district sample including mainly people with a migration background, physical activity and depression (both 75%) were identified most often. The risk factors chronic kidney disease (between 15% and 42%) and hearing impairment (between 19% and 32%) were least identified. Conclusion Educating the general population by raising awareness on protective and risk factors for brain health is essential. Maximizing reach and engagement of underrepresented groups is invaluable for developing interventions that help minimizing social inequalities in brain health. A dedicated awareness campaign is currently being conducted in NDPI to promote an inclusive dementia risk reduction strategy.
Journals
2025 EN
Li Chenyang · Pang Huize · Li Annie
+6 more
Abstract Background To interpret clinical Alzheimer’s disease (AD) pathology, postmortem MRI is frequently used to provide crucial insights into brain structure and vasculature, bridging in vivo imaging and histopathological validation. However, imaging blood and vascular changes after death and fixation remains poorly understood. Traditional vascular contrast agents are ineffective in postmortem imaging studies due to lack of circulation, posing challenges for vascular mapping of postmortem tissues. This study is to explore how blood clots can be used as contrast media to enhance postmortem vascular MRI. Method We studied three human brain tissues with postmortem diagnosis of epilepsy, Parkinson’s Disease and AD, acquired from the NYU ADRC. The brain hemisphere was scanned first using human whole‐body 7T scanner. This is followed by cutting the hemisphere into smaller tissue chunks, including the prefrontal cortex and hippocampus, for high resolution preclinical MRI on animal scanners. Subsequently, histopathological staining, using hematoxylin and eosin (H&E) and Luxol fast blue stains (LFB), were performed to evaluate the vascular morphology and blood clot formation. Result High resolution susceptibility weighted imaging (SWI) of post‐mortem brain revealed clear small vessel contrast in grey matter and white matter, comparable to in vivo USPIO‐enhanced 7T MRI (Figure 1A and C). Moreover, intrahippocampal vasculatures were well illustrated in postmortem MRI, closely resembling USPIO‐enhanced clinical MRI findings (Figure 2E‐FC). Histopathology staining (HE and LFB staining) of hippocampal tissue demonstrated the blood clot vascular structures in the white matter, hippocampus and cortical regions (red arrow in Figure 3). Conclusion This study demonstrates the use of postmortem coagulated blood as an intrinsic contrast agent on T2*‐weighted images for visualizing small vasculatures, establishing a method for detailed vascular mapping in postmortem specimens alongside histopathological analysis. This approach can help to enhance our understanding of in vivo vascular imaging findings of vascular contributions to AD and AD‐related dementia and their underlying pathological substrates. Figure 1. Comparison of high‐resolution T2*‐weighted data between postmortem and in vivo MRI . Figure 2. Multi‐contrast MRI of post‐mortem hippocampus compared with histopathology and in vivo vascular MRI. Figure 3. Blood clot formation (arrows) in postmortem brain tissue on T2*‐weighted imaging and histological staining.
Journals
2025 EN
ElChoueiry Michel · Sidhu Harsimran · Lévesque Maude
+10 more
Abstract Background Most mutations in the COL6A3 gene lead to collagen VI‐related myopathies. This is due to a reduced expression or mislocalization of the COL6A3 protein. Therefore, studying the consequence of knocking out the Col6a3 gene in mouse models is relevant, but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression. Methods Here, we present the development, validation and preliminary phenotypic characterization of a novel CRISPR‐based knockout mouse model targeting Col6a3 exon 3 ( Col6a3 d3/d3 ). Results In this mouse model, Col6a3 mRNA is still expressed at a similar level to wild‐type littermates, although the expected protein is undetectable by mass spectrometry. Histological analysis of Col6a3 d3/d3 quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells, consistent with a myopathy phenotype. Interestingly, Col6a3 d3/d3 mice are smaller in size, with their fat, muscle, and bone kept proportional compared to wild‐type littermates. Conclusions In summary, we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI‐associated diseases.
Journals
2025 EN
Blackburn Patrick R. · Ebstein Frédéric · Hsieh TzungChien
+76 more
Objective De novo variants in cullin‐3 ubiquitin ligase ( CUL3 ) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3 , describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism. Methods Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells. Results We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells. Interpretation Our study further refines the clinical and mutational spectrum of CUL3 ‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89
Journals
2025 EN
Houdayer Clara · Phillips A. Marie · Chabbert Marie
+50 more
Objective We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in HCN2 , encoding for the hyperpolarization‐activated cyclic nucleotide (HCN) gated channel 2. Methods GeneMatcher facilitated the recruitment of 21 individuals with HCN2 variants from 15 unrelated families, carrying HCN2 variants. In vitro functional studies were performed by electrophysiology with Xenopus laevis oocytes and membrane trafficking was investigated in HEK cells by confocal imaging. Structural 3D‐analysis of the HCN2 variants was performed. Results The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21). Thirteen pathogenic variants (12 new and 1 already described) were identified: 11 missense (8 monoallelic and 3 biallelic), 1 recurrent inframe deletion (monoallelic), and 1 frameshift (biallelic). Functional analysis of p.(Arg324His) variant showed a strong increase of HCN2 conductance, whereas p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D‐analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability. Interpretation Our findings broadened the HCN2 disease clinical spectrum to include DD/ID with or without epilepsy. Functional analysis in cellular models reveal that pathogenic HCN2 variants can cause either loss‐of‐function or gain‐of‐function, providing critical information for the development of targeted therapies for HCN2 ‐related disorders. ANN NEUROL 2025;98:573–589
Journals
2025 EN
Shuttleworth Hannah A. · Kuzovnikov Mikhail A. · Conway Lewis J.
+11 more
Abstract Carbon, nitrogen, and hydrogen are among the most abundant elements in the solar system, and our understanding of their interactions is fundamental to prebiotic chemistry. CH 4 and N 2 are the simplest archetypical molecules formed by these elements and are both markedly stable under extremes of pressure. Through a series of diamond anvil cell experiments supported by density functional theory calculations, we observe diverse compound formation and reactivity in the CH 4 ‐N 2 binary system at high pressure. Above 7 GPa two concentration‐dependent molecular compounds emerge, (CH 4 ) 5 N 2 and (CH 4 ) 7 (N 2 ) 8 , held together by weak van der Waals interactions. Strikingly, further compression at room temperature irreversibly breaks the N 2 triple bond, inducing the dissociation of CH 4 above 140 GPa, with the near‐quenched samples revealing distinct spectroscopic signatures of strong covalently bonded C−N−H networks. High temperatures vastly reduce the required pressure to promote the reactivity between CH 4 and N 2 , with NH 3 forming together with longer‐chain hydrocarbons at 14 GPa and 670 K, further decomposing into powdered diamond when temperatures exceed 1200 K. These results exemplify how pressure‐driven chemistry can cause unexpected complexity in the most simple molecular precursors.
Journals
2025 EN
Huang Wengang · Xue WenLong · Chen Peng
+13 more
Abstract Modulating the liquid phase of metal–organic frameworks (MOFs) presents new opportunities for functionalizing glassy MOFs, expanding the fundamental science and practical application for this emerging family of materials. Herein, we report the fabrication of a bimetallic glassy MOF via a liquid–liquid transition process. This is achieved by introducing a robust Schiff base–cobalt functional group into Zn‐ZIF‐62, which attracts negatively charged imidazolate ligands, facilitating low‐temperature melting. This ultimately leads to the formation of a bimetallic glassy MOF (Co/Zn‐a g ZIF‐62‐ipy) upon melt‐quenching. The material features an exceptionally high glass‐forming capability, uniformly distributed bimetallic ions, and a markedly enhanced visible light photogeneration efficiency of enzymatically active nicotinamide adenine dinucleotide (NADH) when compared with Co‐doped ZIF‐62 glass. These findings offer novel insights into modulating the liquid phase of an MOF to develop functional glassy MOF photocatalysts for coenzyme NADH regeneration and other advanced applications.
Journals
2025 EN
Huang Wengang · Xue WenLong · Chen Peng
+13 more
In their Research Article ( e202506570 ), Jingwei Hou, Wengang Huang and co‐workers developed a bimetallic MOF glass (Co/Zn‐agZIF‐62‐ipy) via a liquid–liquid transition, incorporating Schiff base–Co units. The resulting glass shows high glass‐forming ability, uniform metal dispersion, and enhanced visible‐light‐driven NADH regeneration. This work presents a novel strategy to tune MOF liquid phases for stable, non‐noble metal photocatalysts mimicking enzymatic function.