Movement-related cortical potentials preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy

To determine the influence of cerebellar involvement on the preparatory state of the cerebral cortex for voluntary movements, we studied the movement-related cortical potentials (Bereitschaftspotential, BP) preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy (CA). The first task (paradigm 1) consisted of a sequential finger movement at a self-placed rate of every 3 sec or longer, in which patients and control subjects pushed rapidly 7 keys on a keyboard in a sequence visually predetermined on a screen. The second task (paradigm 2) consisted of a goal-directed self-paced movement with visual feedback on a screen. In both paradigms, control subjects and patients had distinct movement-related cortical potentials, but peak amplitudes (close to movement onset) were reduced in the patient group (paradigm 2), whereas in the overall analysis the mean amplitude 600–800 msec before movement onset (NS1) was larger in the patient group (paradigms 1 and 2). Accordingly, the difference (NS2) between peak amplitude and NS1 was smaller in the patient group (paradigms 1 and 2). Whereas control subjects' peak amplitude (paradigm 2) and NS2 (paradigm 1) were focused at Cz, this topographical differentiation was abolished in the patient group. The onset of the BP was earlier in the patients than in the control subjects (paradigms 1 and 2). Our results suggest that pathways from the cerebellum to the cortex do play a role in generating movement-related cortical potentials. A strong input from the cerebellum seems to be crucial for the generation of a normal motor potential close to the movement onset, reflecting a specific deficit in patients with CA. Patients with CA may try to compensate for their motor deficits by a longer cortical activation preceding voluntary movements (earlier onset of the BP). The increased NS1 could be the result of larger effort, by which patients try to compensate for their motor deficits as well.     

Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry

Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices.     

In Vivo High-Resolution 7 Tesla MRI Shows Early and Diffuse Cortical Alterations in CADASIL

Background and Purpose

Recent data suggest that early symptoms may be related to cortex alterations in CADASIL (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic model of cerebral small vessel disease (SVD). The aim of this study was to investigate cortical alterations using both high-resolution T2* acquisitions obtained with 7 Tesla MRI and structural T1 images with 3 Tesla MRI in CADASIL patients with no or only mild symptomatology (modified Rankin’s scale ≤1 and Mini Mental State Examination (MMSE) ≥24).

Methods

Complete reconstructions of the cortex using 7 Tesla T2* acquisitions with 0.7 mm isotropic resolution were obtained in 11 patients (52.1±13.2 years, 36% male) and 24 controls (54.8±11.0 years, 42% male). Seven Tesla T2* within the cortex and cortical thickness and morphology obtained from 3 Tesla images were compared between CADASIL and control subjects using general linear models.

Results

MMSE, brain volume, cortical thickness and global sulcal morphology did not differ between groups. By contrast, T2* measured by 7 Tesla MRI was significantly increased in frontal, parietal, occipital and cingulate cortices in patients after correction for multiple testing. These changes were not related to white matter lesions, lacunes or microhemorrhages in patients having no brain atrophy compared to controls.

Conclusions

Seven Tesla MRI, by contrast to state of the art post-processing of 3 Tesla acquisitions, shows diffuse T2* alterations within the cortical mantle in CADASIL whose origin remains to be determined.     

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.     

Cortical gyrification and sulcal spans in early stage Alzheimer's disease

Alzheimer's disease (AD) is characterized by an insidious onset of progressive cerebral atrophy and cognitive decline. Previous research suggests that cortical folding and sulcal width are associated with cognitive function in elderly individuals, and the aim of the present study was to investigate these morphological measures in patients with AD. The sample contained 161 participants, comprising 80 normal controls, 57 patients with very mild AD, and 24 patients with mild AD. From 3D T1-weighted brain scans, automated methods were used to calculate an index of global cortex gyrification and the width of five individual sulci: superior frontal, intra-parietal, superior temporal, central, and Sylvian fissure. We found that global cortex gyrification decreased with increasing severity of AD, and that the width of all individual sulci investigated other than the intra-parietal sulcus was greater in patients with mild AD than in controls. We also found that cognitive functioning, as assessed by Mini-Mental State Examination (MMSE) scores, decreased as global cortex gyrification decreased. MMSE scores also decreased in association with a widening of all individual sulci investigated other than the intra-parietal sulcus. The results suggest that abnormalities of global cortex gyrification and regional sulcal span are characteristic of patients with even very mild AD, and could thus facilitate the early diagnosis of this condition.     

Reduction of Noradrenaline in Cerebellum of Patients with Olivopontocerebellar Atrophy

Noradrenaline (NA) was measured in postmortem cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The mean cerebellar cortical NA level was significantly reduced (by 40%) in OPCA as compared with control values. The NA deficit most likely reflects a degeneration of the locus caeruleus noradrenergic system that is known to occur in some patients with OPCA. The relationship between the altered cerebellar NA levels and the clinical symptomatology of OPCA remains to be determined.     

'MRI-negative PET-positive' temporal lobe epilepsy (TLE) and mesial TLE differ with quantitative MRI and PET: a case control study

Background

'MRI negative PET positive temporal lobe epilepsy' represents a substantial minority of temporal lobe epilepsy (TLE). Clinicopathological and qualitative imaging differences from mesial temporal lobe epilepsy are reported. We aimed to compare TLE with hippocampal sclerosis (HS+ve) and non lesional TLE without HS (HS-ve) on MRI, with respect to quantitative FDG-PET and MRI measures.

Methods

30 consecutive HS-ve patients with well-lateralised EEG were compared with 30 age- and sex-matched HS+ve patients with well-lateralised EEG. Cerebral, cortical lobar and hippocampal volumetric and co-registered FDG-PET metabolic analyses were performed.

Results

There was no difference in whole brain, cerebral or cerebral cortical volumes. Both groups showed marginally smaller cerebral volumes ipsilateral to epileptogenic side (HS-ve 0.99, p = 0.02, HS+ve 0.98, p < 0.001). In HS+ve, the ratio of epileptogenic cerebrum to whole brain volume was less (p = 0.02); the ratio of epileptogenic cerebral cortex to whole brain in the HS+ve group approached significance (p = 0.06). Relative volume deficits were seen in HS+ve in insular and temporal lobes. Both groups showed marked ipsilateral hypometabolism (p < 0.001), most marked in temporal cortex. Mean hypointensity was more marked in epileptogenic-to-contralateral hippocampus in HS+ve (ratio: 0.86 vs 0.95, p < 0.001). The mean FDG-PET ratio of ipsilateral to contralateral cerebral cortex however was low in both groups (ratio: HS-ve 0.97, p < 0.0001; HS+ve 0.98, p = 0.003), and more marked in HS-ve across all lobes except insula.

Conclusion

Overall, HS+ve patients showed more hippocampal, but also marginally more ipsilateral cerebral and cerebrocortical atrophy, greater ipsilateral hippocampal hypometabolism but similar ipsilateral cerebral cortical hypometabolism, confirming structural and functional differences between these groups.

     

CAG repeats determine brain atrophy in spinocerebellar ataxia 17: a VBM study

Background

Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17).

Methodology/Principal Findings

To determine whether specific structural brain degeneration and rate of disease progression in SCA17 might be associated with the CAG repeat size, observer-independent voxel-based morphometry was applied to high-resolution magnetic resonance images of 16 patients with SCA17 and 16 age-matched healthy controls. The main finding contrasting SCA17 patients with healthy controls demonstrated atrophy in the cerebellum bilaterally. Multiple regression analyses with available genetic data and also post-hoc correlations revealed an inverse relationship again with cerebellar atrophy. Moreover, we found an inverse relationship between the CAG repeat length and rate of disease progression.

Conclusions

Our results highlight the fundamental role of the cerebellum in this neurodegenerative disease and support the genotype-phenotype relationship in SCA17 patients. Genetic factors may determine individual susceptibility to neurodegeneration and rate of disease progression.     

Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by unstable expansion of a CAG repeat in the DRPLA gene. We performed detailed quantitative analysis of the size and the size distribution (range) of the expanded CAG repeats in various regions of the CNS of eight autopsied patients with DRPLA. Expanded alleles (AE) showed considerable variations in size, as well as in range, depending on the region of the CNS, whereas normal alleles did not show such variations, which indicates the occurrence of somatic mosaicism of AE in the CNS. The AE in the cerebellar cortex were consistently smaller by two to five repeat units than those in the cerebellar white matter. Moreover, the AE in the cerebral cortex were smaller by one to four repeat units than those in the cerebral white matter. These results suggest that the smaller AE in the cerebellar and cerebral cortices represent those of neuronal cells. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter showed considerable variation ranging from 9 to 23 repeat units, whereas those in the cerebellar cortex showed little variance and were approximately 7 repeat units. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter were much broader in patients with higher ages at death than they were in patients with lower ages at death, raising the possibility that the range of AE increases with time, as the result of mitotic instability of AE.     

Reduced cortical thickness in mental retardation

Mental retardation is a developmental disorder associated with impaired cognitive functioning and deficits in adaptive behaviors. Many studies have addressed white matter abnormalities in patients with mental retardation, while the changes of the cerebral cortex have been studied to a lesser extent. Quantitative analysis of cortical integrity using cortical thickness measurement may provide new insights into the gray matter pathology. In this study, cortical thickness was compared between 13 patients with mental retardation and 26 demographically matched healthy controls. We found that patients with mental retardation had significantly reduced cortical thickness in multiple brain regions compared with healthy controls. These regions include the bilateral lingual gyrus, the bilateral fusiform gyrus, the bilateral parahippocampal gyrus, the bilateral temporal pole, the left inferior temporal gyrus, the right lateral orbitofrontal cortex and the right precentral gyrus. The observed cortical thickness reductions might be the anatomical substrates for the impaired cognitive functioning and deficits in adaptive behaviors in patients with mental retardation. Cortical thickness measurement might provide a sensitive prospective surrogate marker for clinical trials of neuroprotective medications.     

Altered Oscillation and Synchronization of Default-Mode Network Activity in Mild Alzheimer’s Disease Compared to Mild Cognitive Impairment: An Electrophysiological Study

Some researchers have suggested that the default mode network (DMN) plays an important role in the pathological mechanisms of Alzheimer’s disease (AD). To examine whether the cortical activities in DMN regions show significant difference between mild AD from mild cognitive impairment (MCI), electrophysiological responses were analyzed from 21 mild Alzheimer’s disease (AD) and 21 mild cognitive impairment (MCI) patients during an eyes closed, resting-state condition. The spectral power and functional connectivity of the DMN were estimated using a minimum norm estimate (MNE) combined with fast Fourier transform and imaginary coherence analysis. Our results indicated that source-based EEG maps of resting-state activity showed alterations of cortical spectral power in mild AD when compared to MCI. These alterations are characteristic of attenuated alpha or beta activities in the DMN, as are enhanced delta or theta activities in the medial temporal, inferior parietal, posterior cingulate cortex and precuneus. With regard to altered synchronization in AD, altered functional interconnections were observed as specific connectivity patterns of connection hubs in the precuneus, posterior cingulate cortex, anterior cingulate cortex and medial temporal regions. Moreover, posterior theta and alpha power and altered connectivity in the medial temporal lobe correlated significantly with scores obtained on the Mini-Mental State Examination (MMSE). In conclusion, EEG is a useful tool for investigating the DMN in the brain and differentiating early stage AD and MCI patients. This is a promising finding; however, further large-scale studies are needed.     

Association between Proton Magnetic Resonance Spectroscopy Measurements and CAG Repeat Number in Patients with Spinocerebellar Ataxias 2, 3, or 6

The aim of this study was to correlate magnetic resonance spectroscopy (MRS) measurements, including that for the N-acetyl aspartate (NAA)/creatine (Cr) ratio in the vermis (denoted V-NAA), right cerebellar hemisphere (R-NAA), and left (L-NAA) cerebellar hemisphere, with the clinical scale for the assessment and rating of ataxia (SARA) score for patients with spinocerebellar ataxia (SCA) types 2, 3, and 6. A total of 24 patients with SCA2, 48 with SCA3, and 16 with SCA6 were recruited; 12 patients with SCA2, 43 with SCA3, and 8 with SCA6 underwent detailed magnetic resonance neuroimaging. Forty-four healthy, age-matched individuals without history of neurologic disease served as control subjects. V-NAA and patient age were used to calculate the predicted age at which a patient with SCA2 or SCA3 would reach an onset V-NAA value. Results showed the following: the NAA/Cr ratio decreased with increasing age in patients with SCA but not in control subjects; the SARA score increased progressively with age and duration of illness; V-NAA showed a better correlation with SARA score than R-NAA in patients with SCA2 or SCA3; the ratio of age to V-NAA correlated well with CAG repeat number; the retrospectively predicted age of onset for SCA2 and SCA3 was consistent with patient-reported age of onset; R-NAA showed a better correlation with SARA score than V-NAA in patients with SCA6; V-NAA and R-NAA correlated with clinical severity (SARA score) in patients with SCA. The correlation between CAG repeat number and age could be expressed as a simple linear function, which might explain previous observations claiming that the greater the CAG repeat number, the earlier the onset of illness and the faster the disease progression. These findings support the use of MRS values to predict age of disease onset and to retrospectively evaluate the actual age of disease onset in SCA.     

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

High levels of phenylalanine (Phe) are the biochemical hallmark of phenylketonuria (PKU), a neurometabolic disorder clinically characterized by severe mental retardation and other brain abnormalities, including cortical atrophy and microcephaly. Considering that the pathomechanisms leading to brain damage and particularly the marked cognitive impairment in this disease are poorly understood, in the present study we investigated the in vitro effect of Phe, at similar concentrations as to those found in brain of PKU patients, on important parameters of oxidative stress in the hippocampus and cerebral cortex of developing rats. We found that Phe induced in vitro lipid peroxidation (increase of TBA-RS values) and protein oxidative damage (sulfhydryl oxidation) in both cerebral structures. Furthermore, these effects were probably mediated by reactive oxygen species, since the lipid oxidative damage was totally prevented by the free radical scavengers α-tocopherol and melatonin, but not by L-NAME, a potent inhibitor of nitric oxide synthase. Accordingly, Phe did not induce nitric oxide synthesis, but significantly decreased the levels of reduced glutathione (GSH), the major brain antioxidant defense, in hippocampus and cerebral cortex supernatants. Phe also reduced the thiol groups of a commercial GSH solution in a cell-free medium. We also found that the major metabolites of Phe catabolism, phenylpyruvate, phenyllactate and phenylacetate also increased TBA-RS levels in cerebral cortex, but to a lesser degree. The data indicate that Phe elicits oxidative stress in the hippocampus, a structure mainly involved with learning/memory, and also in the cerebral cortex, which is severely damaged in PKU patients. It is therefore presumed that this pathomechanism may be involved at least in part in the severe cognitive deficit and in the characteristic cortical atrophy associated with dysmyelination and leukodystrophy observed in this disorder.     

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.     

Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease

We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.     

脊髓小脑共济失调第7型的临床特征及基因突变研究

对一脊髓小脑性共济失调(Spinocerebellar ataxia, SCA)家系的患者进行临床特征及相关基因突变研究。对该家系进行详细的病史采集, 并对患者行视力、眼底血管造影、眼底拍照、视觉诱发电位、视网膜电图以及头颅MRI等辅助检查; 采用聚合酶链反应分别扩增SCA1、SCA2、SCA3、SCA6、SCA7、SCA17及DRPLA基因的CAG重复序列, 用8%变性聚丙烯酰胺凝胶电泳及直接测序进行突变分析。结果2名患者主要表现为小脑性共济失调、视力下降、眼底视网膜色素变性、小脑和脑干萎缩; 并存在SCA7基因的突变, 而未发现SCA1、SCA2、SCA3、SCA6、SCA17及DRPLA基因突变。说明该家系为SCA7突变家系, SCA7基因中CAG三核苷酸重复拷贝数的异常扩增是其致病原因。     

Evidence that glutaric acid reduces glutamate uptake by cerebral cortex of infant rats

The role of excitotoxicity in the cerebral damage of glutaryl-CoA dehydrogenase deficiency (GDD) is under intense debate. We therefore investigated the in vitro effect of glutaric (GA) and 3-hydroxyglutaric (3-OHGA) acids, which accumulate in GDD, on [(3)H]glutamate uptake by slices and synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Glutamate uptake was significantly decreased by high concentrations of GA in cortical slices of 7-day-old rats, but not in cerebral cortex from 15- and 30-day-old rats and in striatum from all studied ages. Furthermore, this effect was not due to cellular death and was prevented by N-acetylcysteine preadministration, suggesting the involvement of oxidative damage. In contrast, glutamate uptake by brain slices was not affected by 3-OHGA exposure. Immunoblot analysis revealed that GLAST transporters were more abundant in the cerebral cortex compared to the striatum of 7-day-old rats. Moreover, the simultaneous addition of GA and dihydrokainate (DHK), a specific inhibitor of GLT1, resulted in a significantly higher inhibition of [(3)H]glutamate uptake by cortical slices of 7-day-old rats than that induced by the sole presence of DHK. We also observed that both GA and 3-OHGA exposure did not alter the incorporation of glutamate into synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Finally, GA in vivo administration did not alter glutamate uptake into cortical slices from 7-day-old rats. Our findings may explain at least in part why cortical neurons are more vulnerable to damage at birth as evidenced by the frontotemporal cortical atrophy observed in newborns affected by GDD.     

Galanin-Like Immunoreactivity Is Increased in the Postmortem Cerebral Cortex from Patients with Alzheimer's Disease

Abstract: Galanin is a peptide that is associated with cholinergic neurons of the basal forebrain and, thus, of interest for the neuropathology of Alzheimer's disease. In the present study, human galanin-like immunoreactivity was measured in postmortem human cerebral cortical tissues by using a homologous radioimmunoassay. In an initial study, six cerebral cortical regions were evaluated from nine elderly controls, 13 neuropathologically verified Alzheimer's disease patients, and 19 elderly schizophrenics. A significant 65% increase in galanin was found in frontal cortex Brodmann area 8 of Alzheimer's disease patients compared with controls. In contrast, cerebral cortical tissues from elderly schizophrenics were not different from those from elderly controls in any region. In a second study, 10 cerebral cortical regions were evaluated from 50 neuropathologically verified Alzheimer's disease patients and nine elderly controls. Concentrations of galanin were increased significantly 26–61% in six of 10 cerebral cortical regions examined (Brodmann areas F8, F44, T20, T21, T36, and P22). Purification of brain extracts by size-exclusion Sephadex G-50 chromatography revealed that human galanin-like immunoreactivity eluted in two peaks of different molecular weights. These studies reveal increased concentrations of galanin in the cerebral cortex of Alzheimer's disease, similar to previous findings in basal forebrain tissue. Because galanin inhibits cholinergic neurotransmission, these findings may have important implications in the understanding of Alzheimer's disease neuropathology and associated cognitive deficits.     

Genetic background of apparently idiopathic sporadic cerebellar ataxia

Disease-causing mutations have been identified in various entities of autosomal dominant ataxia and in Friedreich's ataxia. However, no molecular pathogenic factor is known to cause idiopathic cerebellar ataxias. We investigated the CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2, 3, 6, 7, 8 and 12, and the GAA repeat of the frataxin gene in 124 patients apparently suffering from idiopathic sporadic ataxia, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, a typical Friedreich phenotype, or symptomatic ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age at onset between 13 and 36 years. The SCA6 mutation was present in nine patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in three patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. We did not identify the SCA1, SCA3, SCA7 or SCA12 mutation in idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the MSA subgroup. This study has revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 is the most frequent mutation in late onset cerebellar ataxia. The frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich's ataxia.