The future of alzheimer disease immunotherapies in Saudi Arabia: Consensus statement of the Saudi Chapter of Cognitive and Behavioral Neurology.

Alzheimer Disease (AD) constitutes a major global healthcare problem. Standard AD pharmacotherapies offer only modest transient cognitive and behavioral benefits. Aducanumab, an amyloid monoclonal antibody, was the first disease modifying agent to be approved for AD treatment. However, concerns about its efficacy and side effects led regulatory institutions around the world to restrict its use. Lecanemab was the second amyloid antibody to receive accelerated approval for use in early AD. This review and consensus statement was prepared by the Saudi Chapter of Cognitive and Behavioral Neurology to review the current developments in AD immunotherapies from a Saudi perspective. We outline recommendations with regards to offering aducanumab and other future immunotherapies to Saudi AD patients. We describe resources, infrastructure, research, and clinical practice changes that must be attained to transform the patient journey and clinical pathways of AD in Saudi Arabia to enable offering AD immunotherapies in Saudi Arabia.

A Comprehensive Analysis of Unique and Recurrent Copy Number Variations in Alzheimer's Disease and its Related Disorders.

BACKGROUND: Copy number variations (CNVs) play an important role in the genetic etiology of various neurological disorders, including Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) were shown to have share mechanisms and signaling pathways with AD. OBJECTIVE: We aimed to assess CNVs regions that may harbor genes contributing to AD, T2DM, and MDD in 67 Saudi familial and sporadic AD patients, with no alterations in the known genes of AD and genotyped previously for APOE. METHODS: DNA was analyzed using the CytoScan-HD array. Two layers of filtering criteria were applied. All the identified CNVs were checked in the Database of Genomic Variants (DGV). RESULTS: A total of 1086 CNVs (565 gains and 521 losses) were identified in our study. We found 73 CNVs harboring genes that may be associated with AD, T2DM or MDD. Nineteen CNVs were novel. Most importantly, 42 CNVs were unique in our studied cohort existing only in one patient. Two large gains on chromosomes 1 and 13 harbored genes implicated in the studied disorders. We identified CNVs in genes that encode proteins involved in the metabolism of amyloid-ß peptide (AGRN, APBA2, CR1, CR2, IGF2R, KIAA0125, MBP, RER1, RTN4R, VDR and WISPI) or Tau proteins (CACNAIC, CELF2, DUSP22, HTRA1 and SLC2A14). CONCLUSION: The present work provided information on the presence of CNVs related to AD, T2DM, and MDD in Saudi Alzheimer's patients.

Neuromyelitis optica spectrum disorders in the Arabian Gulf: challenges and growing experience.

Neuromyelitis optica spectrum disorders (NMOSD) have been studied in different ethnic groups, including Asians, African-Americans, and Caucasians. Demonstrating the clinical features among diverse communities is important to understand the variable disease phenotypes, which will lead to further classification and better clinical management. Testing for antibody against aquaporin-4 (AQP4), the most common target antigen in NMOSD, is not available in many countries and tests use different methods, with variable sensitivity. With negative antibody results, the diagnosis of NMOSD becomes challenging and may affect the outcomes of patients with NMOSD. There are no adequate studies that assess NMOSD cohorts in the Arabian Gulf region, despite the increasing number of diagnosed cases. It is worth assessing NMOSD cohorts in the Arabian Gulf population to study the natural history of disease and to establish an epidemiological background for future perspectives. Various challenges to implement such a mission are outlined, including disease rarity, overlapping presenting symptoms and signs, which posed the issue of mimickers in the differential diagnosis, lack of specialized clinics, absence of highly sensitive testing methods for diagnosis, and the indefinite agreement on the negative AQP4 NMOSD criteria. Collaborative efforts started to take a place among many experts in the region to establish a registry of NMOSD patients for better perception of the disease pattern.

Genetic Study of Alzheimer's Disease in Saudi Population.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurological disorder associated with mental decline and dementia. Several studies focused on investigating the molecular basis of the disease that led to the identification of several causative genes and risk associated alleles. Replication of these studies and findings from different populations is very important. OBJECTIVE: Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia. METHODS: Comprehensive screening for point mutations was carried out by direct sequencing of coding regions in the three known AD causative genes: PSEN1, PSEN2, APP, as well as the AD associated gene SORL1. All patients were also genotyped for APOE alleles. In silico 3D protein structure analysis was performed for two novel SORL1 variants. RESULTS: We identified a total of eight potential pathogenic missense variants in all studied genes. Five of these variants were not previously reported including four in SORL1 (p.Val297Met, p.Arg1084Cys, p.Asp1100Asn, and p.Pro1213Ser) and one in APP (p.Glu380Lys). The frequency of APOE-ɛ4 allele was 21.37% of total investigated cases. In silico 3D protein structure analysis of two SORL1 novel missense variants (p.Pro1213Ser and p.Arg1084Cys) suggested that these variants may affect the folding of the proteins and disturb their structure. CONCLUSIONS: Our comprehensive analysis of the open reading frame of the known genes have identified potential pathogenic rare variants in 18/117 cases. We found that point mutations in AD main genes (PSEN1, PSEN2, and APP) were underrepresented in our cohort of patients. Our results confirm involvement of SORL1 in familial and sporadic AD cases.

Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic. OBJECTIVE: To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation. METHODS: The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing. RESULTS: Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts. CONCLUSION: This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients.

Natural course of epilepsy concomitant with CNS tuberculomas.

BACKGROUND: Epilepsy is relatively common in CNS tuberculomas, but its natural course is unclear. AIM: To determine the prevalence and prognosis of epilepsy in patients with seizures related to CNS tuberculomas. METHODS: We retrospectively reviewed the charts of patients with CNS tuberculomas who presented at our institution between 1983 and 2001. RESULTS: Seizures occurred in 22 of 93 (23.6%) of the patients with CNS tuberculomas. These patients were treated with standard antituberculous therapy for a period varying between 6 and 20 months. Sixty-three out of 93 patients were cured of tuberculosis, and 21 of the 63 (33%) who had concomitant epilepsy became seizure-free. TB recurred in 3 patients, and 1 out of 22 who had concomitant epilepsy continued to have seizures; 3 died and 24 were lost to follow-up. Anti-epileptic medications were discontinued after completion of the anti-TB course. CONCLUSION: Seizures are commonly associated with CNS tuberculomas and most often resolve after successful treatment of the underlying CNS tuberculosis.

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.