Genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome: A Next Generation Sequencing study.

OBJECTIVE: To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome. METHODS: A Next Generation Sequencing - based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis). RESULTS: Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes. CONCLUSIONS: Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions.

Lower serum uric acid is associated with mild cognitive impairment in early Parkinson's disease: a 4-year follow-up study.

Cognitive deficits are common in Parkinson's disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

Normative data for the Montreal Cognitive Assessment in an Italian population sample.

The Montreal Cognitive Assessment (MoCA) is a rapid screening battery, also including subtests to assess frontal functions such as set-shifting, abstraction and cognitive flexibility. MoCA seems to be useful to identify non-amnestic mild cognitive impairment (MCI) and subcortical dementia; it has high sensitivity and specificity in distinguishing MCI from mild Alzheimer's Disease. Previous studies revealed that certain items of MoCA may be culturally biased and highlighted the need for population-based norms for the MoCA. The aim of present study was to collect normative values in a sample of Italian healthy subjects. Four hundred and fifteen Italian healthy subjects (252 women and 163 men) of different ages (age range 21-95 years) and educational level (from primary to university) underwent MoCA and Mini Mental State Examination (MMSE). Multiple linear regression analysis revealed that age and education significantly influenced performance on MoCA. No significant effect of gender was found. From the derived linear equation, a correction grid for MoCA raw scores was built. Inferential cut-off score, estimated using a non-parametric technique, is 15.5 and equivalent scores were computed. Correlation analysis showed a significant but weak correlation between MoCA adjusted scores with MMSE adjusted scores (r = 0.43, p < 0.001). The present study provided normative data for the MoCA in an Italian population useful for both clinical and research purposes.

Apathy and related executive syndromes in dementia associated with Parkinson's disease and in Alzheimer's disease.

Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer's disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A- and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy. The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-A- on frontal tasks. The AD-A+ had poorer performance than AD-A- on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales.The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an 'apathetic syndrome', characterized by specific cognitive and psychological symptoms.