Communication in the Laboratory and Communication in the Clinic†

IT IS now 25 years since Frieda Fromm-Reichmann died—over 30 years since she published her only book, Principles of Intensive Psychotherapy. Most of those who now attend the presentations of the annual research award of the Academy or the annual lectures of the Washington School of Psychiatry, both of which are named in her honor, never saw her. It seem appropriate to ask whether she still speaks to us today, whether in any significant way she influenced the development of what is now common practice in our field.     

What's in the literature?

The neuromuscular literature over the past 3 months has been diverse, including useful information on the epidemiology of several disorders. Our understanding of the genetics of amyotrophic lateral sclerosis continues to grow, and in the process, it makes the distinction between familial and sporadic forms of the disorder increasingly murky. Some interesting articles about peripheral neuropathy provide insight into relationships with diabetes and with Parkinson disease and summarize the state of knowledge of the increasingly complex topic of hereditary neuropathies in children. Epidemiology and electrodiagnosis of lateral femoral cutaneous neuropathy is nicely discussed in 2 articles. Several muscle diseases, including Pompe disease, sporadic inclusion body myositis, and the congenital myopathies, receive attention in articles that provide very useful information for the clinician, and there is a treatment-oriented article on dystrophinopathies, which makes for excellent reading. There are also discussions of several uncommon disorders, including a mitochondrial myopathy, periodic paralysis, and congenital myasthenic syndromes, which are helpful in providing information to clinicians who may see such disorders only infrequently.     

Dancing in the dark?

Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-rofiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.     

Changes in the Expression of Genes of the Glutamate Transporter and Subunits of the NMDA and AMPA Receptors in the Rat Amygdala in the Lithium–Pilocarpine Model of Epilepsy

The molecular changes in the glutamatergic system of the rat amygdala were studied during the latent phase of the lithium–pilocarpine model of temporal lobe epilepsy in order to identify the potential involvement of these changes in epileptogenesis. The real-time PCR method was used to evaluate the mRNA expression of the NMDA and AMPA receptor subunits, as well as the excitatory amino acid transporter-2 (EAAT2) in the basolateral nucleus of the amygdala 7 days after the seizures caused by administration of pilocarpine. The results of the experiments were as follows: (1) an increase in the expression ratio of the GluN2a/GluN2b NMDA receptor subunits with an unchanged expression level of the GluN1 subunit; (2) increased expression of the GluA2 subunit of AMPA receptors with the invariance of GluA1, and (3) enhanced expression of the EAAT2. According to literature data, the expression of the same genes decreased in the hippocampus in the same model of epilepsy. Neurodegeneration was reported in both brain regions. The opposite changes in the expression of the glutamatergic system genes in the hippocampus and amygdala during the latent period of the lithium–pilocarpine model suggest the occurrence of factors that can both contribute to and hinder epileptogenesis.     

Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein

Increased intracellular levels of α-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how α-synuclein is degraded by neurons in vivo. To address this, our study uses α-synuclein transgenic mice, expressing human α-synuclein or α-synuclein-eGFP under the (h)PDGF-β promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for α-synuclein under normal conditions in vivo while with increased α-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS in α-synuclein transgenic mice and age dependence to the role of the UPS in α-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and α-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.     

Is the cerebellum involved in the visuo-locomotor associative learning?

The role played by cerebellar circuits in visuo-motor associative learning is still unclear. The aim of the present study was to analyse cerebellar involvement using a visuo-locomotor associative learning paradigm that did not require spatial competences. Hemicerebellectomized (HCbed) and Control rats were tested in a visual discrimination task. First, both groups of rats had to learn that a reward was associated with an object that had a specific colour and shape (Experiment 1). Then, the shape but not the colour of the rewarded object was modified to verify whether the animals were able to transfer the rule of rewarding or whether they had to acquire a new association (Experiment 2). In the first sessions of the Experiment 1, HCbed animals displayed a tendency toward peripheral circling and a delay of about three sessions in reaching the criterion of correct choices compared to Controls. This delay has to be correlated to the need to overcome the procedural impairment elicited by the HCb. Once the HCbed animals put efficient procedural abilities into action, they exhibited a similar increase in percentages of successes from the fourth session onward as Controls. The results of Experiment 2 confirm the intact associative abilities of HCbed animals, as demonstrated by their progressive increase in successful associative responses, which, at the end of the transfer phase, were not significantly different from those of the Control group. The present findings indicate that the presence of a cerebellar lesion delays but does not prevent visuo-locomotor associative learning and that stimulus generalisation is performed without difficulty even in the presence of a cerebellar lesion.     

Is the midbrain involved in the manifestation of gait disturbance in idiopathic normal-pressure hydrocephalus?

Gait disturbance is the most common symptom in idiopathic normal-pressure hydrocephalus (iNPH). However, its pathophysiology in iNPH has not been clarified. Some researchers have hypothesized that the mesencephalic locomotor region, which is a functionally defined area in the brainstem playing an important role in locomotion, is involved in the development of gait disturbance in iNPH. The purpose of the study was to investigate whether the midbrain is involved in the manifestation of gait disturbance in iNPH. Twenty-one iNPH patients who showed clinical improvements after shunt surgery were studied. Brain magnetic resonance imaging (MRI) was performed and clinical symptoms were assessed before and 1 year after surgery. Gait disturbance was assessed by the Timed Up and Go test and gait subcategory of the iNPH Grading Scale, a validated assessment tool for iNPH symptoms. Anteroposterior, left-to-right diameter and cross-sectional areas of the midbrain were measured at the inferior collicular level of axial images in MRI. The diameters and cross-sectional area of the midbrain at baseline did not show significant correlation with gait assessments at baseline (Spearman’s correlation). The midbrain measurement did not show significant difference between the baseline and postoperative values (paired t test), and its change rates did not show significant correlation with the change (rates) of the gait assessments. In this study there were no findings to suggest involvement of the midbrain in the manifestation of gait disturbance in iNPH. The hypothesis that the mesencephalic locomotor region is involved in the manifestation of gait disturbance in iNPH needs to be reconsidered.     

Can a cutaneous-muscular biopsy be helpful in the diagnosis of vasculitis in the stroke?

Vasculitis includes a heterogeneous group of multisystemic disorders characterized pathologically by inflammation of blood vessels. The diagnosis of vasculitis is difficult and more often than not, it is made indirectly after eliminating other causes of the stroke. Vasculitis is an infrequent disorder and a rare cause of the stroke. This is a case report of a 41-year-old man who had the first-ever stroke with vasculitis diagnosed histologically in a cutaneous-muscular biopsy from the place not changed by the disease. After corticosteroid therapy the hemiparesis disappeared. The patient has continued the treatment with immunosuppressive drugs.     

Is epilepsy in the elderly overlooked? An investigation in a home for the aged

The symptoms of epileptic seizures in old patients differ from those in younger patients. Therefore, these seizures may be misinterpreted as symptoms of other "typical" diseases in old people. In an old people's home, we assessed whether a standardized questionnaire is able to reveal undiagnosed epilepsy in the elderly. Reported sudden falls, loss of consciousness, and cramps were the criteria for further diagnostic procedures. We found epilepsy in 11 of 389 study participants. In four of them (1% of the total sample), the epilepsy was newly diagnosed; five more cases remained unclear. Therefore, the total number of epileptic patients might have been even higher. Most of the reported sudden falls and unconsciousness (89%) were due to internal medical or other neurological or orthopaedic causes. Once these have been excluded, the diagnosis of epilepsy should be considered. The results of our pilot study suggest that epilepsy in old people's homes is often unrecognised. Early diagnosis and treatment of epilepsy in the elderly is important to improve prognosis and social consequences for affected persons.     

Astrocytes dynamically regulate the blood-brain barrier in the healthy brain

<正>The blood-brain barrier (BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul E hrlich (Verkhratsky a nd Pivoriunas,2023)) that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.     

Kainate receptors in the CA2 region of the hippocampus

<正>The hippocampus is involved in important brain functions such as learning and memory,spatial navigation,fear processing,and social behavior(Dudek et al,2016).The most prominent areas of the hippocampus are typically denoted as the dentate gyrus and the three areas of the cornu ammonis(CA1,CA2,and CA3).Discovered by Lorente de Nó(1934),the CA2 region of the hippocampus is a relatively small area interposed between CA3 and CA1 that forms the nexus linking the input of the entorhinal corte...     

What is the role of the cerebellum in the pathophysiology of dystonia?

Journal of Neurology -     

Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb

The neuromodulatory transmitter serotonin(5-hydroxytryptamine,5-HT)is synthesized by neurons located in the brainstem,which project more or less densely to the entire central nervous system(Charnay and Leger,2010).Serotonin regulates a variety of physiological functions,including food intake,reward,reproduction,sleep-wake cycle,memory,cognition,emotion,and mood(Charnay and Leger,2010).