early onset alzheimer’s disease
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2022 ◽  
Author(s):  
Jia Li ◽  
Jingqi Feng ◽  
Hang Su ◽  
Jiajun Chen

Abstract Background: Early-onset Alzheimer's disease is defined as Parkinson's disease that begins at an age of 65 or younger. Currently, among the reports on early-onset Alzheimer's disease related genes, mutations of APP, PSEN1 and PSEN2 genes are relatively common, However, the mutation of MAPT P301L causes early-onset Alzheimer's disease, which has not been reported so far. Case report: We have found a clinical case of a 30-year-old male who suddenly developed cognitive impairment and progressed rapidly within 2 years, leaving him unable to take care of himself. The patient underwent examinations of blood and cerebrospinal fluid routine, biochemistry and immunoassay, as well as imaging examinations of MRI, FDGPET and PIBPET. PIB-PET indicated diffuse heterogeneous radionuclivity in cerebral cortex, and positive PIB imaging was considered. Sequencing results suggested that there was a heterozygous mutation in the MAPT gene of the patient, which was located in Chr17-44087755, and c.902C>T. Conclusion: We speculated that EOAD of this patient may be related to the P301L mutation on MAPT.


2021 ◽  
Author(s):  
Kevin M Knox ◽  
Megan Beckman ◽  
Carole L Smith ◽  
Suman Jayadev ◽  
Melissa Barker-Haliski

Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with variants in presenilin 2 (PSEN2). Like patients with epilepsy, untreated seizures may also worsen cognitive function in AD. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p<0.02; females: p<0.02). Chronic seizures more significantly worsened anxiety-like behaviors of female PSEN2 KO mice as measured by percentage of total time exploring the center of an OF. TM performance was significantly worsened in kindled female (p=0.024), but not male, PSEN2 KO mice. Male BM performance was generally worsened by seizures (p=0.038), but not by genotype. Conversely, kindled PSEN2 KO females made the most BM errors (p=0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. This study demonstrates that hippocampus-dependent cognitive function may be only worsened by uncontrolled chronic seizures in female, but not male, PSEN2 KO mice. Our work aligns with clinical evidence of sex-specific worsening of AD burden and supports sex-specific anticonvulsant interventions in AD.


2021 ◽  
Vol 12 ◽  
Author(s):  
Karin Windsperger ◽  
Stefanie Hoehl

Down syndrome (DS) is the most prevalent neurodevelopmental disorder, with a known genetic cause. Besides facial dysmorphologies and congenital and/or acquired medical conditions, the syndrome is characterized by intellectual disability, accelerated aging, and an increased likelihood of an early onset Alzheimer's disease in adulthood. These common patterns of DS are derived from the long-held standard in the field of DS research, that describes individuals with DS as a homogeneous group and compares phenotypic outcomes with either neurotypical controls or other neurodevelopmental disorders. This traditional view has changed, as modern research pinpoints a broad variability in both the occurrence and severity of symptoms across DS, arguing for DS heterogeneity and against a single “DS profile.” Nevertheless, prenatal counseling does not often prioritize the awareness of potential within-group variations of DS, portraying only a vague picture of the developmental outcomes of children with DS to expectant parents. This mini-review provides a concise update on existent information about the heterogeneity of DS from a full-spectrum developmental perspective, within an interdisciplinary context. Knowledge on DS heterogeneity will not only enable professionals to enhance the quality of prenatal counseling, but also help parents to set targeted early interventions, to further optimize daily functions and the quality of life of their children.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Taylor Diedrich ◽  
Dustin Hammers ◽  
Sára Nemes

Background: The Learning Ratio (LR) is a novel marker of learning capacity. Unlike traditional raw learning scores (RLS), LR controls for the number of words learned by participants after the first trial, thus avoiding a common confound with learning slope research. While investigation has been conducted on the relationship between LR and late-onset Alzheimer’s Disease, little to no information on LR in the context of early-onset Alzheimer’s Disease (EOAD) exists. The goal of this study was to establish criterion validity for the LR by showing that it outperforms the traditional RLS in EOAD. Methods: Rey Auditory Verbal Learning Test individual trial scores (Trials 1-5) were obtained from 314 participants (82 cognitively normal [CN], 168 EOAD, and 64 Early-Onset Non-Alzheimer’s Disease [EOnonAD]) enrolled in the Longitudinal Early-Onset Alzheimer’s Disease Study. RLS for each participant was calculated as follows: Highest Trial score (of Trials 2 through 5) – Trial One score. LR was calculated as follows: RLS / (Maximum trial score possible – Trial One score). In essence, LR is the proportion of available information learned after Trial 1. Results: When controlling for age, education, sex, and ethnicity, significant differences were observed between groups for both LR (p<0.001, η=0.485) and RLS (p<0.001, η=0.325). For both LR and RLS, CN participants performed better than EOnonAD participants, who performed better than EOAD participants. Upon direct comparison, the magnitude of the effect for LR was stronger than for RLS. Conclusion: Results support criterion validity for LR by establishing that LR values are consistently lower for more severe disease states to a greater extent than a traditional learning metric. Such a finding suggests that LR is useful for measuring learning for those with EOAD.


2021 ◽  
Vol 17 (S6) ◽  
Author(s):  
Jorge J Llibre‐Guerra ◽  
Leonardo Iaccarino ◽  
Yan Li ◽  
Lauren Edwards ◽  
Eric McDade ◽  
...  

2021 ◽  
pp. 1-12
Author(s):  
Sarah Haoudy ◽  
Thérèse Jonveaux ◽  
Salomé Puisieux ◽  
Jonathan Epstein ◽  
Lucie Hopes ◽  
...  

Background: Epilepsy seems to be an important comorbidity in patients with early onset Alzheimer’s disease (EOAD). Currently, seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Objective: To better define the epileptic disorders observed in patients with EOAD. Methods: All patients diagnosed as EOAD in our hospital between 2013 and 2019 and with positive CSF biomarkers for AD were selected. The usual follow-up was extended with a 3 h EEG and a consultation with an epilepsy expert. Information on epilepsy and AD were collected and analyzed. Results: Among the 25 included patients, 10 (40%) were classified as epileptic. Considering the seizure types, patients presented tonic-clonic seizures (n = 3), typical temporal seizures (n = 3), myoclonus (n = 3), focal extra-temporal seizures (n = 1), and other seizure types (n = 2). AD-E patients had a significant lower MMSE (15.3±8.4 AD-E versus 22.1±5.1 AD-NE, p = 0.036) and a lower autonomy (IADL 4.1±2.7 AD-E versus 6.4±1.9 AD-NE, p = 0.046) at AD diagnosis with comparable ages between AD-E and AD-NE. Epileptic patients seemed to present a faster cognitive decline compared to AD patients without seizures ([ΔMMSE per year 1.7±1.3 AD-E versus 0.9±1.4 AD-NE; p = 0.09). All patients with severe cognitive impairment (MMSE ≤ 10) had an epileptic comorbidity. Conclusion: Epilepsy is a frequent comorbidity in EOAD patients, with a percentage of 40% in our study. This comorbidity may be associated with a severe form of EOAD. The role of epilepsy in the acceleration of cognitive decline and the positive impact of antiepileptic drugs on cognition need further research.


2021 ◽  
Vol 14 (11) ◽  
pp. 1170
Author(s):  
Wenche Stensen ◽  
Ulli Rothweiler ◽  
Richard Alan Engh ◽  
Melissa R. Stasko ◽  
Ilya Bederman ◽  
...  

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.


2021 ◽  
Vol 1 (2) ◽  
pp. 121-126
Author(s):  
Alberto Pérez-Mediavilla ◽  
Marta Zamarbide

Familial early-onset Alzheimer’s disease (AD) is more probable in individuals coming from mothers diagnosed with AD than from fathers diagnosed with AD. Studies in animal models have shown maternal imprinting due to the transmission to the embryo of altered material in the ovum. In the case of transgenic animals harboring a mutated form of the human amyloid precursor protein (APP), offspring from crosses with wild-type (WT) fathers and transgenic mothers display more abnormalities than offspring from crosses with transgenic fathers and WT mothers. Expression of the mutated APP in the ovum may lead to alterations that may be genetic and/or epigenetic in the nuclear and/or the mitochondrial DNA. These modifications that are transmitted to the new living beings affect more mitochondrial proteins and, therefore, the mitochondrial function may be affected in adulthood by trends present in the ovum.


Author(s):  
José Contador ◽  
Agnès Pérez-Millan ◽  
Nuria Guillen ◽  
Adrià Tort-Merino ◽  
Mircea Balasa ◽  
...  

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