Isabel Lamet

Homocysteine and cognitive impairment in Parkinson's disease: A biochemical, neuroimaging, and genetic study

The role of the plasma level of homocysteine (Hcy), as a primary outcome, and the effect of silent cerebrovascular lesions and genetic variants related to Hcy metabolism, as secondary outcomes, in the cognitive decline and dementia in Parkinsons disease (PD) were studied. This case–control study focused on 89 PD patients of minimum 10 years of evolution and older than 60 years, who were neuropsychologically classified either as cognitively normal (n = 37), having mild cognitive impairment (Petersen criteria) (n = 22), or suffering from dementia (DSM‐IV) (n = 30), compared with cognitively normal age‐matched control subjects (n = 30). Plasma levels of Hcy, vitamins B12 and B6, folic acid, polymorphisms in genes related to Hcy metabolism (MTHFR, MTR, MTRR, and CBS) and silent cerebrovascular events were analyzed. Plasma levels of Hcy were increased in PD patients (P = 0.0001). There were no differences between the groups of patients. The brain vascular burden was similar among PD groups. There was no association between polymorphisms in the studied genes and the Hcy plasma levels or cognitive status in PD patients. We found no evidence for a direct relationship between Hcy plasma levels and cognitive impairment and dementia in PD. No indirect effect through cerebrovascular disease or genetic background was found either.

Posterior parietooccipital hypometabolism may differentiate mild cognitive impairment from dementia in Parkinson’s disease

PurposePatients with Parkinson’s disease (PD) may have normal cognition, mild cognitive impairment (MCI) or dementia. We investigated differences in cerebral metabolism associated with these three cognitive states and the relationship between metabolism and cognitive dysfunction.MethodsFDG PET and a battery of neuropsychological tests were used to study PD patients with dementia (n = 19), MCI (n = 28) and normal cognition (n = 21), and control subjects (n = 20). Regional glucose metabolism in patients and controls was analysed using statistical parametric mapping (SPM8) corrected for age, motor severity and depression. Correlations between the mini-mental state examination score and Z-score values of the different cognitive domains with respect to cerebral FDG uptake were assessed using SPM8.ResultsPD patients with MCI (PD-MCI patients) exhibited decreased FDG uptake in the frontal lobe, and to a lesser extent in parietal areas compared with cognitively normal patients. Patients with dementia showed reduced metabolism in the parietal, occipital and temporal areas and a less extensive reduction in the frontal lobe compared with PD-MCI patients, while widespread hypometabolism was seen in comparison with patients with normal cognition. PD-MCI patients exhibited reduced FDG uptake in the parietal and occipital lobes and in localized areas of the frontal and temporal lobes compared with controls, whereas patients with dementia showed a widespread reduction of cortical metabolism. Mini-mental state examination score correlated positively with metabolism in several lobes, executive function with metabolism in the parietooccipitotemporal junction and frontal lobe, memory with temporoparietal metabolism, visuospatial function with occipitoparietal and temporal metabolism, and language with frontal metabolism.ConclusionPD patients with MCI exhibited hypometabolism in several cortical regions compared with controls, and in the frontal and parietal regions compared with cognitively normal patients. Hypometabolism was higher in patients with dementia than in those with MCI, mainly in the posterior cortical areas where it was correlated with visuospatial, memory and executive functions.

Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population.

Alzheimers disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.

The impact of silent vascular brain burden in cognitive impairment in Parkinson's disease

Background and purpose:  White matter hyperintensities (WMHs) detected by magnetic resonance imaging (MRI) of the brain are associated with dementia and cognitive impairment in the general population and in Alzheimer’s disease. Their effect in cognitive decline and dementia associated with Parkinson’s disease (PD) is still unclear.

The Effect of MAPT H1 and APOE ε4 on Transition from Mild Cognitive Impairment to Dementia

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimers disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition.

Frontobasal gray matter loss is associated with the TREM2 p.R47H variant

A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimers disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimers Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H.

Selective Brain Gray Matter Atrophy Associated with APOE ε4 and MAPT H1 in Subjects with Mild Cognitive Impairment

The aim of our study was to elucidate whether specific patterns of gray matter loss were associated with apolipoprotein E ε4 (APOE ε4) and microtubule-associated protein tau (MAPT)-H1) genetic variants in subjects with mild cognitive impairment (MCI) at a baseline visit. Gray matter voxel-based morphometry analysis of T1 magnetic resonance imaging scans were performed in 65 amnestic-MCI subjects. MCI APOE ε4 carriers compared with non-carriers showed increased brain atrophy in right hippocampus and rostral amygdala, superior and middle temporal gyrus, and right parietal operculum, including inferior frontal gyrus, inferior parietal, and supramarginal gyrus. MAPT-H1/H1 MCI carriers showed an increased bilateral atrophy in superior frontal gyri (including frontal eye fields and left prefrontal cortex) and precentral gyrus but also unilateral left atrophy in the inferior temporal gyrus and calcarine gyrus. In addition, MCI subjects carrying both APOE ε4 and MAPT-H1/H1 variants showed gray matter loss in the supplementary motor area and right pre- and postcentral gyri. The effect of APOE ε4 on gray matter loss in right hippocampus suggests that, at least in some AD sub-types, the neuronal vulnerability could be increased in the right hemisphere. The pattern of frontal gray matter loss observed among MCI MAPT H1/H1 carriers has also been found in other tauopathies, suggesting that MCI may share etiological factors with other tauopathies. Frontal and parietal cortex vulnerability was found when adding MAPT H1/H1 and APOE ε4 effects, suggesting a synergistic effect of these variants. These results could be due to changes in APOE ε4 and MAPT expression.

Paraneoplastic encephalitis presenting as pure word deafness in a patient with small cell lung cancer

Pure word deafness (PWD) is a rare neuropsychologic syndrome characterized by the inability to comprehend and repeat speech and defective writing to dictation with preserved ability to identify nonverbal sounds [1]. A 52-year-old right-handed man with a history of 105-pack-year smoking history presented with suddenonset difficulties understanding spoken language since 10 days before. Additionally, he had experienced two episodes of tingling in the right hemibody and auditory hallucinations (musical tones) that lasted for 30 s. Cranial nerves, strength, sensation, gait, coordination, and reflexes were intact. He was alert and oriented. Speech was fluent, and grammatically correct. Verbal and visual memory, praxis, right-left discrimination, finger identification, and executive function skills were within normal limits. He was able to recognize music and non-verbal sounds. Oral tests were altered, including yes/no questions, oral commands, and completion of sentences. Repetition was slightly altered. Nomination, calculation, reading aloud, and reading comprehension were conserved. He made no mistakes in writing spontaneously, copying, and answering written questions. Pure tone threshold audiometry, brainstem auditoryevoked potentials, and contrast-enhanced brain MRI revealed no abnormalities. EEG showed slow waves and sharp spikes in the left temporal region (T3, F7, T5). Blood tests were within normal limits. Cerebrospinal fluid (CSF) analysis showed increased cells (32 lymphocytes/ll, no malignant cells), oligoclonal bands with increased IgG and IgM, normal proteins (50 mg/dl), and normal glucose (84 mg/dl). These results were consistent with infectious or paraneoplastic encephalitis, hence, empirical treatment with ganciclovir 5 mg/kg/12 h, ceftriaxone 2 g/12 h, and metronidazole 500 mg/8 h was started. Gabapentin 800 mg/day was also started. A whole-body 18-fluoro-deoxy-glucose-positron emission tomography (FDG-PET) found hypermetabolic foci in the hilum of the right lung (SUVmax: 8), and the lower lobe of the left lung (SUVmax: 3.8). There was also decreased metabolism in the anterior-lateral area of the left temporal lobe, including the insular cortex, with spared primary language areas and primary auditory cortex, consistent with encephalitis (Fig. 1a). Thoracic CT scan disclosed a nodular adenopathy in the right hilum and a hypodense nodular lesion in the lingula. Cytologic examination of material obtained by endobronchial brushing revealed malignant cells consistent with small cell lung cancer (SCLC). CSF cultures and PCR for herpes simplex, varicella-zoster, and enteroviruses resulted negative, and antibiotic and antiviral treatment were withdrawn. Serum and CSF paraneoplastic panel (anti-Hu, anti-Yo, anti-Ri, anti-CV2, antiMa, anti-VGKC, anti-GAD, and anti-amphiphysin) resulted negative. He then received the first dose of chemotherapy. At discharge, episodes of tingling and hallucinations had remitted, but language disturbance remained. He subsequently received three additional cycles of chemotherapy and prophylactic holocraneal and thoracic radiotherapy. At 6-month follow-up, neuropsychological examination was normal except for slight J.-A. Palma I. Lamet M. Riverol (&) Department of Neurology, University Clinic of Navarra, 31008 Pamplona, Spain e-mail: mriverol@unav.es