Juan J. Zarranz

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.

A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease

Background: Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene. Methods: The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed. Results: Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick’s bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa. Conclusion: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

Phenotypic variability in familial prion diseases due to the D178N mutation

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Use of ziprasidone in parkinsonian patients with psychosis.

Twelve patients with Parkinson disease and psychosis were included in an open-label 12-week trial of ziprasidone. Two patients withdrew from the treatment because of adverse effects. The remaining 10 patients reported a significant improvement in psychiatric symptoms. Altogether, there was no deterioration of motor symptoms (UPDRS III score: basal 40.4 ± 11, 1, first month 41.1 ± 10.8; final visit, 37.7 ± 13.3). Two patients (20%) suffered a slight deterioration in motor symptoms and another patient suffered deterioration of gait. No analytic alterations or serious adverse effects that could limit the use of ziprasidone were observed. Although controlled trials are needed, the findings suggest that ziprasidone may be effective in parkinsonian patients with psychosis.

High-affinity choline uptake carrier in Alzheimer's disease: implications for the cholinergic hypothesis of dementia.

We examined the density and the state of affinity of [3H]hemicholinium-3 ([3H]HC-3) binding sites, a marker of the presynaptic high-affinity choline uptake (HACU) carrier, in 4 representative regions of 13 postmortem Alzheimers disease (AD) brains, as well as in 12 matched control brains. Significant reductions in the densities of [3H]HC-3 binding sites were found both in frontal cortex (-44.7%) and hippocampus (-36.5%) of AD brains in comparison to controls. On the other hand the densities of [3H]HC-3 binding sites in AD brains in caudate-putamen and cerebellar cortex showed no significant differences when compared to controls. No significant change in the state of affinity of these sites could be observed in the saturation assays carried out in hippocampus and frontal cortex. Our findings concur with the reported data by using other presynaptic cholinergic markers in AD and confirm that some degree of cholinergic degeneration, highly specific for the basal forebrain neurons, occurs in AD. However, these results, obtained in a group of AD brains belonging to severely demented patients, do not show a dramatic loss of the HACU in many AD brains. Although this fact could be due to the existence of a compensatory mechanism, our results probably suggest that dementia in AD cannot be explained only by the loss of neocortical cholinergic presynaptic terminals arising from the basal forebrain and also may clarify as to why the acetylcholine precursors or the muscarinic agonists are not effective in AD dementia.

Cardiac sympathetic denervation precedes nigrostriatal loss in the E46K mutation of the α-synuclein gene (SNCA)

IntroductionHere we report the case of an asymptomatic carrier of the E46K substitution in α-synuclein gene where we have documented that cardiac sympathetic denervation precedes nigrostriatal dopaminergic loss.Material and methodsShe has been followed up regularly with standard neurological examination, UPDRS, neuropsychological formal testing, parkinson disease sleep scale-PDSS, Epworth scale, Hamilton-D scale, SCOPA Aut, orthostatic hypotension test, brief smell identification test, polysomnography, cerebral 123-I-FP-CIT SPECT, and, 123I-MIBG cardiac scintigraphy.ResultsShe shows no presence of orthostatic hypotension. Olfactory test results demonstrate normal limits. In the PSG the nocturnal sleep shows mild abnormalities although the sleep efficiency and stage proportion remain under normal limits. The 123-I-FP-CIT SPECT is normal; in contrast, the 123I-MIBG cardiac scintigraphy shows a complete lack of isotopic uptake compatible with a severe sympathetic myocardial denervation.ConclusionThis example of monogenic autosomal dominant parkinsonism due to an α-synuclein mutation favours the hypothesis that peripheral autonomous nervous system involvement occurs earlier than the CNS degeneration.

Parkinson's disease‐like presentation of multiple system atrophy with poor response to STN stimulation: A clinicopathological case report

We report on a clinicopathological case of multiple system atrophy with good response to levodopa and subsequent development of motor complications. Because the subject complied with all the inclusion criteria (Core Assessment Program for Surgical Interventional Therapies in Parkinsons Disease), bilateral subthalamic nucleus deep brain stimulation electrodes were implanted.

Decreased density of presynaptic α2-adrenoceptors in postmortem brains of patients with Alzheimer's disease

Abstract: The full agonist [3H]bromoxidine (UK 14304) was used to quantitate α2‐adrenoceptors in postmortem brains of patients with Alzheimers disease. The effects of aging and human serum Cohn fraction IV on [3H]bromoxidine binding were also assessed. In patients with Alzheimers disease, the binding capacity (Bmax) of [3H]bromoxidine was lower in the frontal cortex (37%), hypothalamus (33%), and cerebellum (52%) than in matched controls. In the hippocampus, amygdala, and head of caudate, the binding capacities (Bmax) were unchanged. Quantitative autoradiographic analyses with [3H]bromoxidine confirmed the existence of a marked reduction (55–60%) in α2A‐adrenoceptor density in the frontal cortex (layers I and III). In patients with dementia who did not meet neuropathological criteria for Alzheimers disease, the density of α2‐adrenoceptors was unchanged. In control subjects, the density of α2A‐adrenoceptors in the frontal cortex showed a significant negative correlation with age at death. The inhibitory effect of human serum Cohn fraction IV on [3H]bromoxidine was very similar in control subjects and patients with Alzheimers disease. The observed decrease in the density of brain α2‐adrenoceptors in Alzheimers disease may represent direct biochemical evidence of a presynaptic location of this receptor on noradrenergic nerve terminals in the human CNS.

Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Alzheimers Disease, and its Relationship with Cognitive Impairment

OBJECTIVE The study aimed to describe the prevalence of Neuropsychiatric symptoms (NPS) in Alzheimers disease (AD), amnestic mild cognitive impairment (MCI) and controls using the 12-item Neuropsychiatric Inventory (NPI) and to analyze the relationships between neuropsychiatric symptoms with specific neuropsychological tests. PATIENTS AND METHODS We prospectively studied 485 patients from the Memory Unit in Cruces Hospital (Spain), 344 met the criteria of NINCDS-ADRDA for probable AD (99 were classified as mild and 245 as moderate-severe), 91 for MCI and 50 were controls. Mini-mental State Examination (MMSE) and CDR (Clinical Dementia Rating) were used to evaluate global cognitive function and to classify the severity of cognitive impairment. The neuropsychological test battery included memory test, verbal fluency, visuoespatial skills and daily living scales. The 12-items Neuropsychiatric Inventory (NPI) version was used to assess neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs. RESULTS Apathy and depression were more prevalent NPS in moderate-severe AD (78.4% and 44.1%, respectively), mild AD (64.6% and 41.4%, respectively) and MCI (50.5% and 33%, respectively) patients than in controls (6% and 8%, respectively). The prevalence and the mean scores of all symptoms increased along the severity of the disease, except for sleep and appetite disorders. In patients with mild AD a relationship was found between the presence of NPS and RDRS-2 scale (p = 0.003); and between NPS and RDRS-2 (p = 0.029) and SS-IQCODE scales (p = 0.039) in moderate-severe patients. CONCLUSIONS NPS were more prevalent in AD and MCI patients than in controls. In AD and MCI patients apathy and depression were the most prevalent NPS. The prevalence and the mean scores of all symptoms gradually increased along the severity of the disease, except for sleep and appetite disorders. We have no found a relationship between neuropsycological test and the presence of NPS, but in patients with mild and moderate-severe AD there is a relationship with daily living scales.

Sleep complaints and their relation with drug treatment in patients suffering from Parkinson's disease.

The aim of this research was to quantify sleep problems in patients suffering from Parkinsons disease by means of the new Parkinsons Disease Sleep Scale (PDSS) and to correlate such problems with the possible influence of current drug treatment. A total of 70 patients (36 men and 34 women) with a diagnosis of Parkinsons disease were enrolled. Their mean age was 69.7 ± 8.2 years, and duration of disease was 7.4 ± 4.8 years. All patients completed the PDSS and the Unified Parkinsons Disease Rating Scale (UPDRS Parts I–IV). Drug consumption and doses were registered. The mean score on the PDSS scale was 109.23 ± 19.75 and on the UPDRS III scale was 25.24 ± 11.35. The lowest scores were obtained in Item 3 (sleep fragmentation): 5.53 (2.46); and in Item 8 (nocturia): 5.75 (2.91). There was a weak correlation between the PDSS and UPDRS III (cc = −0.355, P = 0.003), PDSS and UPDRS I (cc = −0.272, P = 0.02), and PDSS and UPDRS IV (cc = −0.416, P < 0.001). Motor conditions, mental state, and drug complications influence sleep quality. Although this effect was significant, it was not of a great magnitude. Dopaminergic drugs did not increase daytime sleepiness. As a whole, sleep quality in patients who took dopaminergic agonists did not differ from that of patients who took levodopa in monotherapy.