Expression of glial fibrillary acidic protein and glutamine synthetase genes in the natural scrapie of sheep

Gene expression of two astroglial markers, glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS), was investigated in cerebellum and brainstem from scrapie-affected sheep. The GFAP and GFAP-mRNA concentrations were increased in the two cerebral regions studied in the scrapie-affected animals as compared to the controls. The good correlation between the increase in GFAP and GFAP-mRNA concentrations found in scrapie-affected sheep indicates a significantde novo synthesis of GFAP in this pathology. In contrast to these results, in scrapie no significant differences in GS-mRNA content appeared in either brain area from scrapie-affected sheep as compared to the controls. This fact could suggest some specificity of GFAP expression changes in this pathology. The over-expression of GFAP gene could be related to a possible interaction between GFAP and scrapie infectious agent in astrocytes. The relative increase in the GFAP and its encoding message in affected animals was higher in the cerebellum than in the brainstem, which would suggest regional comparative differences in the effect here described.     

Activity and acceptability of piribedil in Parkinson's disease: a multicentre study

Several controlled trials have shown that the dopamine agonist, Trivastal (piribedil), is active in the treatment of Parkinson's disease, particularly with regard to tremor. To determine its efficacy as monotherapy in patients previously untreated with levodopa, a 3-month multicentre study was conducted with Trivastal 50 mg LP in 113 patients with idiopathic Parkinson's disease. The study population consisted of 66 men and 47 women, aged 63.1, SD 0.6 (43–79) years with a 2.1, SD 0.2 (1–15) year history of Parkinson's disease. Mean disease stage was 1.82 (1–4) by the Hoehn and Yahr classification. Tremor was the predominant clinical feature in 42 patients; the remaining 71 patients displayed the full parkinsonian syndrom. Trivastal 50 mg LP was prescribed stepwise up to doses of 150–250 (207, SD 6.4) mg/day at the end of 3 months. No concomitant antiparkinsonian medication was given. Patients were clinically assessed at 1, 2 and 3 months on the Webster scale, a specific tremor scale and the HARD depression scale. Mean results were as follows in the 90 patients completing the study. On the Webster scale, tremor fell from 1.7 to 1 (–41%,P<0.001), bradykinesia=" from=" 1.5=" to=" 0.8=">P<0.001) and=" rigidity=" from=" 1.3=" to=" 0.9=">P < 0.001);=" on=" the=" specific=" scale,=" rest=" tremor=" decreased=" in=" daily=" duration=" and=" amplitude=" from=" 3.9=" to=" 2.4=">P < 0.001)=" and=" from=" 2.9=" to=" 2.1=">P < 0.001),=" respectively.=" the=" 32=" patients=" in=" whom=" tremor=" was=" the=" predominant=" feature=" improved=" their=" total=" score=" on=" the=" webster=" scale=" from=" 5.8=" to=" 4.7=">P<0.05) and=" their=" tremor=" score=" from=" 1.7=" to=" 1.2=">P < 0.05).=" the=" 58=" patients=" with=" the=" full=" parkinsonian=" syndrom=" improved=" their=" total=" webster=" score=" from=" 11.8=" to=" 6.9=">P < 0.001).=" eight=" of=" the=" ten=" items=" on=" the=" scale=" were=" significantly=" reduced,=" from=" between=" 33%=" (facial=" expression)=" to=" 53%=" (manual=" bradykinesia).=" the=" depression=" rating=" fell=" from=" 10.2=" to=" 7.3=">P < 0.001),=" the=" most=" marked=" improvement=" being=" in=" mood=" and=" inhibition.=" in=" conclusion,=" monotherapy=" with=" trivastal=" 50=" mg=" lp=" at=" a=" mean=" dose=" of=" 200=" mg/day=" is=" effective=" within=" 1=" month=" regarding=" the=" major=" features=" of=" parkinson's=">     

mRNA levels of Ca2+-independent forms of protein kinase C in postischemic gerbil brain by Northern blot analysis

To investigate the role of Ca²⁺-independent forms of protein kinase C (PKC) in ischemic neuronal injury, mRNA expression of PKC was studied by Northern blot analysis. Ischemia was produced in gerbils by 10-min bilateral carotid artery occlusion and was followed by recirculation for 15 min, 6 h, and 24 h. Brains of postischemic and sham-operated animals were removed, forebrains fresh frozen, and processed for Northern blot analysis. Three synthetic oligonucleotide probes based on published cDNA sequences of rat brain PKC for the isozymes δ, ε, and ζ were utilized for hybridization. Northern blot analysis showed increased hybridization signal for all three PKC isozymes examined in the 6- and 24-h postischemic groups. Of these, the twofold increases in the expression of PKC δ and ζ were statistically significant in comparison to the control. These results suggest that the mRNA levels of Ca²⁺-independent forms of PKC, in particular, δ and ζ, are temporally stimulated by ischemic injury in the brain and may imply an important role of the enzyme in postischemic neuronal damage. However, since the protein itself was not examined in this study, the significance of the increased expression cannot be ascertained. However, it may reflect a compensatory response to the loss of PKC reported to occur in the reperfusion phase.     

Neuropeptide Y immunoreactive neurons in murine trisomy 16 cortical cultures

Neuropeptide Y (NPY)-containing neurons are depleted in the cortices of individuals with Alzheimer disease (AD), yet spared in the striatum of patients with Huntington chorea. It is unknown whether this neuronal phenotype is inherently susceptible to the neurodegenerative processes that are a hallmark of AD. To study this question, the murine trisomy 16 model of Down syndrome and Alzheimer disease was investigated. Since trisomic fetuses diein utero, studies were carried out on primary cultures of dissociated cortical neurons. These were prepared from 15-d gestational trisomy 16 fetuses and their littermate euploid controls, and examined by immunocytochemical staining for neuropeptide Y at 7 and 12 d in vitro. Trisomy 16 neurons were also grown on euploid glial carpets, whereas euploid neurons were grown on trisomic glia. The results demonstrate a significant increase in the number of NPY neurons and a stunting in the dendritic arbor of these neurons in trisomic vs euploid cortex. Both of these parameters could be normalized by direct contact with euploid glia. When euploid cortex was plated on trisomic glia, the number of NPY neurons and their morphology were altered so that they began to resemble trisomic NPY cortical neurons. These results indicate a dysregulation of NPY neuronal expression and differentiation in trisomy 16 cortex that are modifiable by interaction with euploid glia and imply an abnormal trophic (glial) environment in trisomic cortex.     

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

Background

Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.^1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles^{4,5,6,7,8,9,10,11,12,13,14,15,16} (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33} We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.³⁴     

Anomalous binding of radiolabeled oligonucleotide probes to plaques and tangles in Alzheimer disease hippocampus

Several reports indicate that Alzheimer disease (AD) brain contains elevated levels of heat shock 70 proteins. To determine the cellular localization of the heat shock 70mRNAs, specific oligonucleotide probes werein situ hybridized to AD and control brains. When oligonucleotides werein situ hybridized to brain sections with no AD neuropathology, hybridization was cell-specific and prior ribonuclease (RNase) treatment of adjacent sections resulted in no hybridization signal. However,in situ hybridization to AD hippocampus resulted in heavy grain deposition over senile plaques and neurofibrillary tangles. Despite altering a number of experimental variables, we observed a similar pattern of grain deposition with most of the oligonucleotides tested, including one oligonucleotide specific for glutamic acid decarboxylase mRNA.In situ hybridization with either an RNA probe for glutamic acid decarboxylase or an oligonucleotide probe specific for 18S rRNA did not show this pattern of grain deposition. In control studies a sense hsc70 oligonucleotide showed no grain deposition in either cerebellum or hippocampus. Sections from AD hippocampus pretreated with RNase prior toin situ hybridization demonstrated enhanced grain deposition with the majority of probes tested. Anomalousin situ hybridization to AD hippocampus was usually eliminated by removing formamide from the posthybridization weshes, although post-RNase sticking often remained intense. These findings indicate that artifactual probe binding to senile plaques and neurofibrillary tangles may complicate the analysis ofin situ hybridization studies using oligonucleotide probes to determine mRNA distribution in AD brain.     

Profile of cognitive impairment in dementia associated with Parkinson's disease compared with Alzheimer's disease

Objective

To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).

Methods

Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).

Results

Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.

Conclusion

The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%¹ and a cumulative prevalence close to 80%.² In PD, dementia is associated with rapid motor³ and functional decline,⁴ and increased mortality.⁵Cortical Lewy body pathology correlates best with dementia in PD^6,7,8,9; subcortical pathology¹⁰ and AD‐type pathology¹¹ have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,¹² subsequently involving neocortical areas, including the posterior association cortices.¹³ In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.¹⁴ In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.¹⁵Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.^16,17 AD is characterised by memory loss emerging in the early stages of the disease,¹⁸ primarily involving learning and encoding deficits¹⁹ which are associated with medial temporal lobe pathology.^20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention²⁴ and working memory,^25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual^28,29,30 and visuoconstructional tasks are also frequent.³¹ Memory impairment is often present^26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,³⁵ indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently^36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.³²Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,³³ such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.^38,39     

Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study

Background

Chronic tinnitus is a disabling, almost untreatable, condition, usually accompanied by psychiatric distress. In patients with complex neuropsychiatric diseases, such as chronic pain, with which tinnitus shares pathophysiological similarities, placebo effects may be pronounced. Moreover, it may be difficult to distinguish actual repetitive transcranial magnetic stimulation (rTMS) induced clinical benefits beyond placebo effects in neuropsychiatric patients.

Methods

16 patients with chronic tinnitus underwent a randomised, double blind, crossover, placebo controlled trial of 1 Hz rTMS (120% of motor threshold; 1200 stimuli/day for 5 days) of the left temporoparietal region. Patients were screened for psychiatric comorbidity; additionally, anxiety and depression were monitored throughout the study. Moreover, an original placebo rTMS procedure produced the same activation of ipsilateral face muscles (a condition which may per se change the subjective rating of tinnitus) as the real rTMS.

Results

There were 8 out of 14 responders. Two patients dropped out for transient worsening of tinnitus. Active rTMS induced an overall significant, but transient, improvement (35% of the basal score) of subjective tinnitus perception that was independent of either tinnitus laterality or mood or anxiety changes. No correlations were found between response to rTMS and tinnitus duration, initial subjective score or patient age. When asked after the study was over, 71.4% of patients failed to identify the temporal sequence of the real or sham rTMS interventions.

Conclusion

The beneficial effects of rTMS on tinnitus are independent of mood changes. Moreover, they appear in the context of an original placebo stimulation designed to more closely replicate the somatic sensation of active stimulation. Because of the limited temporal duration of the clinical benefit, these neuromodulatory effects could be mediated by transient functional changes taking place in the neural circuits underlying tinnitus processing.Tinnitus is a subjective auditory perception of sounds or noise, not triggered by external auditory stimuli, which affects millions of people.¹ It is estimated that in 1–3% of the general population tinnitus becomes chronic and sufficiently intrusive to interfere with the patient''s quality of life, mainly because of psychiatric distress, including sleep disturbances, thereby leading to work impairment.² Pharmacological and physical/behavioural treatments in severe cases are generally unsatisfactory.³Experimental data based on transection of⁴ or drug effects on⁵ the cochlear nerve, and in vivo human brain imaging studies,^6,7,8 converge in suggesting that tinnitus could be associated with maladaptive plastic brain reorganisations, taking place at multiple brain levels following—and thereafter being maintained independently by—an initial cochlear dysfunction.⁹ Functional brain changes associated with tinnitus showed hyperactivity of discrete temporoparietal regions, including both the primary auditory cortex (AC)^10,11,12,13 and the secondary, or associative, AC.^{7,11,14,15,16,17,18} More comprehensive views on the generation and maintenance of tinnitus indicate involvement of a broader neural network, most likely including the primary and associative AC (although it is difficult to disentangle the relative contribution of these two areas by positron emission tomography (PET) scans¹⁹), part of the limbic system,¹⁷ the anterior cingulated cortex¹⁸ and higher order processing areas.^20,21More direct evidence for the key role played by the AC in the perception/elaboration of tinnitus comes from studies with repetitive transcranial magnetic stimulation (rTMS), a technique that transiently modulates/disrupts the brain function of the targeted area(s) in several perceptive, motor and cognitive domains²²: high‐frequency rTMS (ie, 10 Hz or more for 2 s or less) applied on the scalp overlying the hyperactive left AC produced an intense, short lived tinnitus attenuation (see table 1​1).^16,12,23,24 Although these studies were not designed to “treat” tinnitus, they demonstrate that the AC is definitely involved in the expression of tinnitus. Interestingly, high frequency rTMS has been applied successfully to produce transient clinical benefits in other deafferentation induced disorders, such as chronic neurogenic pain,^25,26 which shares pathophysiological similarities with tinnitus in terms of maladaptive plastic changes at the cortical level.²⁷Table 1 Full papers on repetitive transcranial magnetic stimulation studies (single case reports are not considered) in chronic tinnitus

Ganglioside conjugate vaccines

Gangliosides are known to be suitable targets for immune attack against cancer but they are poorly immunogenic. Active immunization with ganglioside/BCG or liposome vaccines results in moderate titer IgM antibody responses of short duration. Covalent attachment of poorly immunogenic antigens to immunogenic proteins is a potent method for inducing an IgG antibody response. GD3, a dominant ganglioside on malignant melanoma, was modified by ozone cleavage of the double bond in the ceramide backbone, an aldehyde group introduced and used for coupling via reductive amination to ε-aminolysyl groups of proteins. Utilizing this method, GD3 conjugates were constructed with:

1. Synthetic multiple antigenic peptide (MAP) constructs expressing 4 repeats of a malaria T-cell epitope;
2. Outer membrane proteins (OMP) ofNeisseria meningitidis;
3. Cationized bovine serum albumin;
4. Keyhole limpet hemocyanin (KLH); and
5. Polylysine.

In addition, conjugates containing only the GD3 oligosaccharide were synthesized. All constructs were tested for antigenicity using anti-GD3 antibody R24, and for immunogenicity in mice. Serum antibody levels were analyzed by ELISA and immune thin-layer chromatography. Results in the mouse show a significant improvement in the IgM antibody response and a consistent IgG response against GD3 using GD3-KLH conjugates. Other carrier proteins and the use of GD3 oligosaccharide were significantly less effective. If improved immunogenicity and clinical benefit with conjugate vaccines can be demonstrated in patients with melanoma, this approach may be applicable to patients with other tumors of neuroectodermal origin, including gliomas, glioblastomas, astrocytomas, and neuroblastomas.     

Reliability of the French-Canadian adaptation of the Personality Assessment Inventory: Medical–legal implications

The Personality Assessment Inventory (PAI) is a reliable multidimensional psychometric inventory that is increasingly being used in the medical–legal context. To date, 18 language adaptations of the PAI exist, yet only the Spanish, Greek and German language versions have been examined psychometrically. This study evaluated the psychometric properties of the French-Canadian version of the PAI by comparing mean scale and subscale scores between the French-Canadian and English language versions, and analyzing the internal consistency and mean item inter-correlations (MICs) of each version in a sample of 50 bilingual university students. Cronbach’s alphas ranged from −.57 to .80 in the French-Canadian version and from −1.10 to .83 in the English version, with most scales being below .70, indicating inadequate internal consistency. In addition, most of the MICs were below .20, indicating a lack of item homogeneity. Caution is given to this adaptation of the PAI in the medical–legal context. Key words: bilingual, language adaptation, medical–legal, Personality Assessment Inventory, psychological assessment, psychometrics, reliability

The generalizability of psychological tests with specific populations is an insidious problem in clinical psychology and may have significant implications in the context of a medical–legal examination. For example, if psychologists are asked to objectively substantiate the breadth, severity and veracity of subjective symptomatology and come to a diagnostic opinion, it is essential that such opinions are based on firm scientific grounds in order to meet legal standards and be accepted by the courts. This is especially important since psychologists are asked to suggest/comment on the efficacy of treatment, determine disability benefit or comment on the permanence or seriousness of a psychological injury, all in the ultimate context of assisting the trier of fact in a medical–legal setting. The Standards of Educational and Psychological Testing state that translating a measure into another language does not ensure the construct measured remains comparable to the original test (American Educational Research Association, American Psychological Association & National Council on Measurement in Education, 2014). As such, the examination of language adaptations is an essential part of the study of cultural differences and similarities (Ellis, 1989). This does not, of course, discount the complex and distinct sub-cultural groups who speak the same language (e.g. French speakers who are Moroccan, Congolese, Belgian, etc.). Cheung (2009) explained that personality instruments developed in Western cultures are often generalized to other cultural groups with the faulty assumption that these measures are valid for all groups. When a measure is adapted for a population that differs qualitatively from the one for which it was originally developed, the reliability and validity of the test must be evaluated before it can be clinically utilized (Butcher, Derksen, Sloore, & Sirigatti, 2003; Candell & Hulin, 1986; Cheung, 2009; Geisinger, 1994; Sireci & Berberoglu, 2000) and, hence, employed in the context of a medical–legal examination. Despite these recommendations, research on the language adaptations of the Personality Assessment Inventory (PAI; Morey, 1991, 2007) has been limited.The PAI is a self-report instrument that yields a broad range of clinically relevant information, and is a widely utilized test measure of personality and psychopathology in medical–legal examinations. It was developed using a rational and quantitative method of scale development. The rational criterion emphasizes theoretically informed choices when developing items, as opposed to empirically based instruments such as the Minnesota Multiphasic Personality Inventory–2 (MMPI–2; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989). The PAI consists of 344 items that constitute four sets of non-overlapping scales: (a) four validity scales: Inconsistency, Infrequency, Negative Impression Management and Positive Impression Management; (b) 11 clinical scales: Somatic Complaints, Anxiety, Anxiety-Related Disorders, Depression, Mania, Paranoia, Schizophrenia, Borderline Features, Antisocial Features, Alcohol Problems and Drug Problems; (c) five treatment scales: Aggression, Suicidal Ideation, Stress, Nonsupport and Treatment Rejection; and (d) two interpersonal scales: Dominance and Warmth. Several advantages of the PAI include its brevity, lower reading level requirements, focus on diagnostic concepts and attention to clinical management issues. The acronyms for the scales and subscales are presented in

Immunoreactivity patterns in neurofibrillary tangles of the inferior temporal cortex in Alzheimer disease

The distributions of various immunohistochemical markers of neurofibrillary tangles (NFT) were compared to that of a normal nerve cell cytoskeletal marker, SMI32, in the inferior temporal cortex of Alzheimer brains and normal aged controls. NFT markers included antibodies to the microtubule-associated proteins tau, ubiquitin, or amyloid P component (AP). The results showed that, in our group of patients, the decrease of SMI32 immunoreactivity in the Alzheimer temporal cortex is paralleled by an increase in AP immunoreactivity in neurons and neurofibrillary tangles. This suggests that AP may play an important role in NFT formation or evolution in Alzheimer disease.     

Elevated levels of dolichol in the brains of mucopolysaccharidosis and related disorders

The contents of total dolichol were measured in the cerebral cortex of various patients with lysosomal storage disorders, including mucopolysaccharidosis. Strikingly high levels of dolichol were demonstrated in G_M1-gangliosides, Sanfilippo B syndrome, and a severe type of Hunter syndrome as well as neuronal ceroid-lipofuscinosis. An increased level of dolichol in cerebral cortex in neuronal ceroid-lipofuscinosis (NCL) was once regarded as pathognomonic for NCL. Our data, however, suggest that an increased level of dolichol in cerebral cortex is a nonspecific phenomenon related to some lysosomal dysfunction secondary to various neurodegenerative disorders.     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Post-surgical changes in brain metabolism detected by magnetic resonance spectroscopy in normal pressure hydrocephalus: results of a pilot study

Background

Adult normal pressure hydrocephalus (NPH) is one of the few potentially treatable causes of dementia. Some morphological and functional abnormalities attributed to hydrocephalus improve following treatment.

Objectives

We focused on analysis of changes in cerebral metabolites using proton magnetic resonance spectroscopy (¹H‐MRS) after NPH treatment, and its clinical and cognitive correlation.

Methods

¹H‐MRS, neuropsychological and clinical status examinations were performed before and 6 months after shunting in 12 adults with idiopathic NPH. We obtained N‐acetyl‐aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) values.

Results

After surgery, NAA/Cr was significantly increased. Moreover, NAA/Cr values were related to cognitive deterioration.

Conclusion

MRS could be a marker of neuronal dysfunction in NPH.Normal pressure hydrocephalus (NPH) is a potentially treatable cause of dementia,^1,2 characterised by progressive cognitive dysfunction, gait disturbance and urinary incontinence associated with ventricular enlargement and abnormalities in CSF dynamics. In these patients, some morphological and functional abnormalities attributed to hydrocephalus improve after treatment.^3,4,5 Proton magnetic resonance spectroscopy (¹H‐MRS) allows non‐invasive in vivo measurement of brain metabolites. Findings from MRS studies reveal that ¹H‐MRS is a potentially non‐invasive technique with sufficient sensitivity to detect subtle changes in neuronal function in neurodegenerative diseases, allowing investigation of neuronal injury or dysfunction^6,7 and the assessment of treatment efficacy.^8,9,101H‐MRS studies in patients with hydrocephalus are scarce.^{6,7,11,12,13,14,15} Changes in cerebral metabolites after treatment with hydrocephalus using this technique have been analysed in only two studies, which concentrated exclusively on the results of lactate metabolites.^11,12The aim of our study was to describe changes in other major metabolites, using ¹H‐MRS, before and after treatment in idiopathic NPH patients, and to obtain preliminary data on their clinical and cognitive correlation, which could serve as the basis for larger studies with control subjects.     

Brain anatomy of autism spectrum disorders I. Focus on corpus callosum

This brief review aims to examine the structural magnetic resonance imaging (sMRI) studies on corpus callosum in autism spectrum disorders (ASD) and discuss the clinical and demographic factors involved in the interpretation of results.Key words: autism spectrum disorders (ASD), corpus callosum, magnetic resonance imaging (MRI), volumes

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental pathologies whose diagnosis is based on the behavioural symptoms (Muratori et al. 2011) and whose intervention strategies aimed at improving socio-communicative skills as well as daily life abilities (Bellani et al. 2011). The neuroanatomical correlates of ASD are not fully elucidated. However, consistent findings based on structural magnetic resonance imaging (sMRI) data reported widespread cerebral abnormalities that include differences between ASD patients and controls in total brain volume, fronto-parieto-temporal and cerebellar regions. Moreover, a replicated altered corpus callosum (CC) size has been reported in the first sMRI analyses (for a review, see Brambilla et al. 2003). In particular, the altered CC has been considered as an anatomical substrate of processing and integration deficits peculiar to ASD, supporting the hypothesis of abnormal cortical connectivity in autism (Just et al. 2007). The CC is the largest commissural white matter (WM) tract in the human brain, and is conventionally divided into anterior CC, which comprises the rostrum, genu, rostral body, anterior mid-body and posterior CC, which includes the posterior mid-body, isthmus and splenium (Witelson, 1989). This primary WM structure connects homologous and heterotopic cortical areas of the two cerebral hemispheres and it is thought to be involved in motor and sensory integration as well as in higher cognitive function, including abstract reasoning, problem solving, ability to generalize, planning, social skills, attention, arousal, language comprehension and expression of syntax and pragmatics, emotion, memory (Paul et al. 2007). Recent investigations have employed a three-dimensional volumetric measurement of CC in ASD and frequently reported a reduction in the overall structure (Hardan et al. 2009; McAlonan et al. 2009; Duan et al. 2010; Anderson et al. 2011; Frazier et al. 2012), or in one or more components of this axonal pathway, including the anterior (Alexander et al. 2007; Keary et al. 2009; Thomas et al. 2011), the posterior sub-regions (Waiter et al. 2005) or some of the anterior and posterior regions contemporaneously (Vidal et al. 2006). The reductions in the CC volume is present over a wide age-range, since it is reported in ASD studies involving children (Vidal et al. 2006; Hardan et al. 2009; McAlonan et al. 2009; Frazier et al. 2012), adolescents (Waiter et al. 2004, 2005; Alexander et al. 2007) and adults (Keary et al. 2009; Ecker et al. 2010; Anderson et al. 2011; Thomas et al. 2011). On the other hand, the sparse literature on CC volume in low-functioning ASD (Riva et al. 2011) prevents us from drawing inferences about the influence of IQ on CC volume and calls for further investigation. Only a relatively few studies did not reveal significant CC volume differences between ASD patients and typically developing controls; in particular, this finding has been reported more often in voxel-based morphometry (Waiter et al. 2004; Bonilha et al. 2008; Ke et al. 2008; Ecker et al. 2010; Toal et al. 2010; Cheng et al. 2011; Mengotti et al. 2011; Calderoni et al. 2012) than in region of interest-based (Hong et al. 2011) analyses. Notably, to our knowledge, there have been no published studies reporting volumetric increase of CC (2012), whereas a cross-sectional approach failed to detect such relationship (Alexander et al. 2007). In addition, volume reduction in the CC has been found to correlate with core ASD features such social deficits, repetitive behaviours and sensory abnormalities (Frazier et al. 2012), as well as executive function and complex motor tasks deficits (Keary et al. 2009). Table 1.Studies investigating CC volumetry in patients with ASD compared with typically developing control subjects

Freed-amino acids in human cerebrospinal fluid of alzheimer disease,multiple sclerosis,and healthy control subjects

This is the first report of the presence of freeD-amino acids in lumbar and ventricular human cerebrospinal fluid (CSF) of individuals with Alzheimer disease (AD) compared with CSF of normal control subjects and with individuals affected by multiple sclerosis, as an unrelated neurologic disorder. Freed-amino acids are present at significantly higher levels in AD CSF than normal CSF, whereas in the CSF of patients affected by multiple sclerosis,d-amino acids occurs at the same level as in the normal controls. The totald-amino acid content in ventricular CSF was 1.48 times higher in the AD than controls (26.4 vs 17.9 nmol/mL,p=0.025). The totald-amino acid content was 1.43 times higher in AD lumbar CSF than controls (1.89 vs. 1.32 nmol/mL,p=0.001).d-Aspartate in particular was 2.74 times higher in AD ventricular CSF compared to normal ventricular CSF (3.34 vs 1.22 nmol/mL,p=0.029). In lumbar CSF,d-aspartate was 1.5 times higher in AD than controls (0.054 vs 0.036 nmol/mL,p=0.041). Previously we reported thatd-amino acids are elevated in AD brain proteins associated with neurofibrillary tangles compared to normal brain proteins (D'Aniello et al., 1992c; Fisher et al., 1992a,b). Thus, thed-amino acids present in CSF may originate from degradation of brain proteins.     

Psychiatric disorders in preclinical Huntington's disease

Background

Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.

Objectives

To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.

Methods

Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.

Results

Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.

Conclusions

Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,^1,2,3 irritability,^4,5,6 apathy^1,3,6 and psychosis.^4,7,8 Both major depression^1,2,4,9 and more subtle mood disturbances¹⁰ have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,^9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.^2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,^9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),² whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.^10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.^4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.^10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,^4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.^3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.¹⁶ The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset.     

Brain anatomy of autism spectrum disorders II. Focus on amygdala

This brief review encompasses the key findings of structural Magnetic Resonance Imaging (sMRI) research on amygdala volume in autism spectrum disorders (ASD). We also highlight the possible correlation between the autistic behavioural phenotype and amygdala alteration.Key words: Amygdala, Autism Spectrum Disorders (ASD), Structural Magnetic Resonance Imaging (sMRI), Volumes

The lack of reliable, specific brain biomarkers for autism spectrum disorders (ASD) results in a diagnosis based on behavioural criteria (Muratori et al. 2011). However, recent structural magnetic resonance imaging (sMRI) studies provide new insights into the neuroanatomical substrate of ASD, suggesting the involvement of the corpus callosum and the fronto-parieto-temporal regions (Mengotti et al. 2011; Bellani et al. 2013). Among these latter, the amygdala is a relatively small subcortical brain region located in the anteromedial temporal lobe and included in the limbic system. It contains at least 13 distinct nuclei, among which four major nuclei (the lateral, basal, accessory basal and central nuclei) with unique patterns of connectivity with other brain regions. In particular, the central nucleus, a phylogenically primitive part, communicates mostly with brainstem and olfactory centres, while the basolateral nuclei are strongly connected to the neocortex. Besides its primary role of monitoring the environment for potential danger and modulating levels of vigilance, the amygdala plays a seminal contribution to social behaviour. Specifically, it is implicated in several cognitive functions, including social cognition, recognition of emotions, attribution of emotional valence to stimuli and regulation of the personal space. These findings have led researchers to postulate the ‘amygdala theory of autism’ since the amygdala may be primarily involved in the socio-emotional impairment peculiar of ASD subjects (Baron-Cohen et al. 2000).However, the presence of amygdala structural abnormalities in ASD is unclear since previous research has produced conflicting results. Indeed, increased, decreased and preserved volumes have been shown in studies using manual tracing to define the amygdala morphology (8, 1 and 4 studies, respectively; see 2008). Specifically, ASD toddlers and children frequently show significantly increased bilateral amygdala volumes relative to age-matched controls (Mosconi et al. 2009; Schumann et al. 2009; Kim et al. 2010; Nordahl et al. 2012), whereas older adolescents and adults either reduced (Nacewicz et al. 2006), or preserved size (Corbett et al. 2009; Dziobek et al. 2006; Nacewicz et al. 2006; Palmen et al. 2006). Despite the age of the subject population seems to be a critical factor, some heterogeneity in the rate of amygdala growth within the ASD population of the same age-range has been detected. Accordingly, a recent longitudinal study pointed to three ASD subgroups in the amygdala developmental time course between two and four years of age, i.e. (1) rapid growth, (2) slow growth, and (3) growth trajectories consistent with those of typically developing children (Nordahl et al. 2012). The behavioural correlates of different amygdala growth patterns, unfortunately, are not reported in this study. In contrast, very few papers performed a separate analysis by sex, showing more pronounced amygdala enlargement in female children with ASD (Schumann et al. 2009) compared with age- and gender-matched typically developing controls. These preliminary findings suggest a potential different pattern of amygdala development in ASD in accordance to gender. Table 1.Summary of studies published between 2006–2012 investigating amygdala volumetry in patients with ASD compared with control subjects*

Induction of gene expression of amyloid precursor protein (APP) in activated human lymphoblastoid cells and lymphocytes

To understand the possible role of amyloid precursor protein (APP) in human lymphocytes, and the regulation of APP gene expression in this cell type, we determined levels of cellular APP protein and of mRNA in human T-cell-derived Jurkat cells that were treated with lectin, phorbol ester, and calcium ionophore. We also related these levels to cell aggregation and adhesion. Cell-cell aggregation and cell-plastic adhesion were observed over a 24-h period after incubating cells for 2 h with phytohemagglutinin or phorbol myristate acetate. Cells treated with a calcium ionophore showed no aggregation or adhesion. Western blots indicated no obvious alteration in the level of cellular APP with different treatments. Northern blots showed a significant transient increase of APP mRNA after incubation with the calcium ionophore, whereas phorbol ester treatment showed a slight increase of APP mRNA. We analyzed the level of APP mRNA in human peripheral T cells which had been separated from peripheral lymphocytes. The level increased transiently by up to threefold after treatment with calcium ionophore plus phorbol esters. These data suggest that cell-cell aggregation and cell-matrix adhesion by human lymphocytes are not associated with an increased level of cellular APP protein or of mRNA.