Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer's Disease or Frontotemporal Dementia.

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.

Investigation of neuropsychological characteristics of very mild and mild dementia with Lewy bodies.

INTRODUCTION: The study aimed to compare the profile of very mild and mild dementia with Lewy bodies (DLB) patients with disease duration up to 5 years in order to find markers for faster progression in this early stage. METHOD: We investigated 45 DLB patients with disease duration up to 5 years and 22 normal controls. DLB patients were divided into two subgroups on the basis of the Mini-Mental State Examination (MMSE): very mild and mild. RESULTS: Compared to normal controls, very mild DLB patients show significant deficits on tests for attention/executive functions, language, visuospatial/constructional abilities, and retrieval of the episodic memory. In addition, mild DLB (mDLB) patients show a significantly lower score on recall and recognition of the Free and Cued Selective Reminding Test (FCSRT), Trail Making Test Part B (TMT-B), Stroop test, verbal fluency, and Clock Drawing Test than did very mild DLB (vmDLB) patients. Patients with mDLB also have more visual hallucinations, but not significant motor differences compared to vmDLB. CONCLUSIONS: In the present work we found that faster progression to the mild DLB stage in the first few years of the disease is mainly related to deterioration of memory, attention/executive functions, and visuospatial abilities, as well as an increased frequency of visual hallucinations.

Executive functions deficit in Parkinson's disease with amnestic mild cognitive impairment.

Recent studies suggest that onset of dementia in Parkinson's disease (PD) is preceded by a phase known as mild cognitive impairment (MCI). Different clinical subtypes of MCI in PD were found. The objective of this study was to investigate whether patients with PD diagnosed with amnestic MCI (aPD-MCI) have also subtle deficits in other cognitive domains and especially in attention/executive functions and, therefore to clarify whether all subcomponents of executive control are equally affected in aPD-MCI. We investigated 23 patients with aPD-MCI (modified Petersen's criteria) and 25 normal controls. Relative to controls, the aPD-MCI group showed significant deficits with reference to tasks that encompass various aspects of attention/executive functions, including Trail Making Test, Stroop test, Modified Card Sorting Test, and digit span backward, as well as phonemic and semantic verbal fluency. This suggests that executive dysfunction is consistently presented in PD with MCI, even in ''amnestic'' PD-MCI due to cortical-subcortical dysfunction.