Progressive Behavioral Changes Research Articles

THUR 103 Chorea associated with atrial myxoma

BackgroundChorea is a hyperkinetic movement disorder characterised by involuntary, unpredictable muscle contractions and is associated with a broad range of primary and secondary aetiologies.CaseA 73-year-old gentleman presented with a 12 month history of progressive behavioural change and involuntary movements. His family had become concerned about periods of erratic behaviour and confusion. He appeared agitated and restless. On examination he had choreiform movements predominantly affecting his upper limbs. An abnormal diastolic heart sound was detected on auscultation.MRI brain and CSF analysis were normal; ASO titre, paraneoplastic, anti-NMDAr antibodies and Huntington’s genetics were negative. A blood film was normal. Transoesophageal echocardiogram demonstrated a variegated mobile mass within the left atrium.An immune-mediated mechanism was suspected. Intravenous immunoglobulins and oral corticosteroids were trialled with initial major benefit but he relapsed several months later and did not respond to a further trial. The atrial mass was resected and histological analysis confirmed an atrial myxoma. The chorea and cognitive symptoms significantly improved after surgery and he remains well.DiscussionAtrial myxoma is the most common primary tumour of the heart and is rare with an incidence of 0.5/1,000,000 population/year. There has only been one other case in the paediatric literature.

Subacute sclerosing panencephalitis - current perspectives.

Subacute sclerosing panencephalitis is a progressive neurodegenerative disease. It usually occurs 7–10 years after measles infection. The clinical course is characterized by progressive cognitive decline and behavior changes followed by focal or generalized seizures as well as myoclonus, ataxia, visual disturbance, and later vegetative state, eventually leading to death. It is diagnosed on the basis of Dyken’s criteria. There is no known cure for subacute sclerosing panencephalitis to date, but it is preventable by ensuring that an effective vaccine program for measles is made compulsory for all children younger than 5 years in endemic countries.

Amyloid pathology enhances seeding and propagation of fibrillar endogenous non-mutant tau in vivo

Amyloid pathology enhances seeding and propagation of fibrillar endogenous non-mutant tau in vivo

18F-THK5351 PET Imaging in the Behavioral Variant of Frontotemporal Dementia.

Background and PurposeBehavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD.MethodsForty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients.ResultsIn the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem.ConclusionsThe distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.

SPORADIC CREUTZFELDT-JAKOB DISEASE: A CLINICAL APPROACH OF A SMALL CASE SERIES AND LITERATURE REVIEW

Introduction. Creutzfeldt-Jakob Disease (CJD) is a very rare neurodegenerative disease with no cure that always leads to death. It is the most frequent prion disease and has multiple recognized forms, from which the sporadic form (sCJD) is the most common. The defining histological characteristic of CJD is the accumulation of the abnormal prion protein (PrPSc) along with neuronal loss and spongiform vacuolation. Typical neurological signs found in sCJD are rapidly progressive dementia, myoclonus, visual disturbances, pyramidal signs, extrapyramidal signs, behavioral changes and akinetic mutism. Material and method. We performed a retrospective study over the 2007-2017 period that included five cases of patients diagnosed with probable sCJD from our department. Results. The most common findings in the patients’ MRI were cerebral atrophy and ventricular enlargement, but we also found typical MRI changes such as increased T2 and FLAIR signal intensity in the head of the caudate nucleus, putamen and cerebral cortex. Repeated electroencephalograms showed typical sCJD patterns like periodic sharp wave complexes, mostly with biphasic or triphasic aspect. A complex differential diagnosis and numerous routine investigations (CBC, biochemical analysis, autoimmune panel, HIV antibodies, VDRL, anti-Borrelia antibodies, anti-TPO antibodies, anti-neuronal antibodies, B12 vitamin) were performed, without indicating an alternative diagnosis. All the patients died several months after the onset of symptoms. Conclusions. Given the rarity of the disease and the broad differential diagnosis, CJD proves to be a diagnostic challenge. In the absence of an alternative diagnosis, the association of rapidly progressive dementia, myoclonus, visual and cerebellar signs are highly suggestive for sCJD.

Auditory dysfunction in patients with Huntington’s disease

ObjectiveHuntington’s disease (HD) is an autosomal, dominantly inherited, neurodegenerative disease. The main clinical features are motor impairment, progressive cognitive deterioration and behavioral changes. The aim of our study was to find out whether patients with HD suffer from disorders of the auditory system. MethodsA group of 17 genetically verified patients (11 males, 6 females) with various stages of HD (examined by UHDRS – motor part and total functional capacity, MMSE for cognitive functions) underwent an audiological examination (high frequency pure tone audiometry, otoacoustic emissions, speech audiometry, speech audiometry in babble noise, auditory brainstem responses). Additionally, 5 patients underwent a more extensive audiological examination, focused on central auditory processing. The results were compared with a group of age-matched healthy volunteers. ResultsOur results show that HD patients have physiologic hearing thresholds, otoacoustic emissions and auditory brainstem responses; however, they display a significant decrease in speech understanding, especially under demanding conditions (speech in noise) compared to age-matched controls. Additional auditory tests also show deficits in sound source localization, based on temporal and intensity cues. We also observed a statistically significant correlation between the perception of speech in noise, and motoric and cognitive functions. However, a correlation between genetic predisposition (number of triplets) and function of inner ear was not found. ConclusionsWe conclude that HD negatively influences the function of the central part of the auditory system at cortical and subcortical levels, altering predominantly speech processing and sound source lateralization. SignificanceWe have thoroughly characterized auditory pathology in patients with HD that suggests involvement of central auditory and cognitive areas.

Positive impacts of early auditory training on cortical processing at an older age

Progressive negative behavioral changes in normal aging are paralleled by a complex series of physical and functional declines expressed in the cerebral cortex. In studies conducted in the auditory domain, these degrading physical and functional cortical changes have been shown to be broadly reversed by intensive progressive training that improves the spectral and temporal resolution of acoustic inputs and suppresses behavioral distractors. Here we found older rats that were intensively trained on an attentionally demanding modulation-rate recognition task in young adulthood substantially retained training-driven improvements in temporal rate discrimination abilities over a subsequent 18-mo epoch-that is, forward into their older age. In parallel, this young-adult auditory training enduringly enhanced temporal and spectral information processing in their primary auditory cortices (A1). Substantially greater numbers of parvalbumin- and somatostatin-labeled inhibitory neurons (closer to the numbers recorded in young vigorous adults) were recorded in the A1 and hippocampus in old trained versus untrained age-matched rats. These results show that a simple form of training in young adulthood in this rat model enduringly delays the otherwise expected deterioration of the physical status and functional operations of the auditory nervous system, with evident training impacts generalized to the hippocampus.

Variante comportamental da demência frontotemporal: relato de caso

Introduction: Frontotemporal dementia is characterized by changes in personality, behavior, and language. Atrophy of the frontal and temporal cortex is the main pathological finding. As this entity is under-diagnosed, it is important to raise awareness of the difficulties in diagnosis and management. Case Description: A 74 year-old man had progressive changes in appropriate social behavior from age 66. This included a lack of impulse control, inadequate food behaviors and rituals, and reduced production of speech. Some time after the onset of symptoms and consultation with different medical specialists, he was referred to a neurologist who made the diagnosis of frontotemporal dementia. Commentary: The family physician can play an important role by suspecting this condition, through longitudinal care and personal knowledge of the patient. Proper investigation and appropriate and timely guidance can help avoid unnecessary and potentially harmful treatments. The family physician can also manage associated comorbidity and support the family and other caregivers.

White matter predicts functional connectivity in premanifest Huntington's disease

ObjectivesThe distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's.MethodsUsing diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease.ResultsWe find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases.InterpretationOur findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD.

The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: A longitudinal case report

IntroductionMutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1-associated FTD is currently unclear. MethodsWe performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem. ResultsThe patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)–positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other TBK1 mutation cases. DiscussionTBK1-associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.

Perceived Stigma Negatively Affects Social Participation and Satisfaction Among Individuals With Huntington Disease

Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disease characterized by progressive physical, cognitive, and behavioral changes with profound functional decline, including social functioning. Negative perceptions, interactions, and rejection may contribute to perceived stigma in HD. We examined whether perceived stigma predicts satisfaction and participation in social activities in individuals with HD.

Schizophrenia associated sensory gating deficits develop after adolescent microglia activation

Maternal infection during pregnancy is a well-established risk factor for schizophrenia in the adult offspring. Consistently, prenatal Poly(I:C) treatment in mice has been validated to model behavioral and neurodevelopmental abnormalities associated with schizophrenia. By using the Poly(I:C) BALB/c mouse model, we investigated the functional profile of microglia by flow cytometry in relation to progressive behavioral changes from adolescence to adulthood.Prenatal Poly(I:C) treatment induced the expected sensory gating deficits (pre-pulse inhibition (PPI) of the acoustic startle response) in 100day-old adult offspring, but only in female not in male descendants. No PPI-deficits were present in 30day-old adolescent mice. Sensory gating deficits in adult females were preceded by a strong M1-type microglia polarization pattern during puberty as determined by flow cytometric analysis of multiple pro- and anti-inflammatory surface markers. Microglia activation in females did not persist until adulthood and was absent in behaviorally unaffected male descendants. Further, the specific activation pattern of microglia was not mirrored by a similar activation of peripheral immune cells. We conclude that prenatal Poly(I:C) treatment induces post pubertal deficits in sensory gating which are specifically preceded by a pro-inflammatory activation pattern of microglia during puberty.

Neuro-Behçet's psychiatric symptoms

Neuro-Behçet (NB) results from inflammatory peri-vasculitis affecting the central nervous system. Non-specific neurological and psychiatric symptoms are rarely the first presentation and may difficult or delay diagnosis and treatment.We review, based on a case study and published literature, the psychiatric symptoms of NB when no clear evidence of neurologic disease activity is present.We present the case of a female patient, who was diagnosed NB at age 23 for recurrent meningo-encephalitis, that showed progressive behavioral changes, with increased impulsivity, disinhibition, hostility and self-neglect.Raised in a dysfunctional family, she ran away from home at 16, abandoned her studies, started abusing cannabinoids and showed an erratic life course.In 2015, because of increasing psychiatric symptoms, she was admitted to hospital and a complete neuropsychological evaluation showed that she had a significant decline from an above average premorbid cognitive function, specifically related to memory deficits. CT and MRI didn’t show typical signs of active disease. However, a SPECT scan showed hypo-perfusion of the frontal cortex compatible with the patient's symptoms.It is difficult to assess NB's activity as brain inflammation is only observed after structural changes are present. In this case the SPECT correlated well with psychiatric symptoms. The differential diagnosis includes organic pathology with psychiatric symptoms, psychiatric disease, personality disorders and substance abuse.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Profound Autonomic Instability Complicated by Multiple Episodes of Cardiac Asystole and Refractory Bradycardia in a Patient with Anti-NMDA Encephalitis.

Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is autoimmune encephalitis primarily affecting young adults and children. First described about a decade ago, it frequently manifests as a syndrome that includes progressive behavioral changes, psychosis, central hypoventilation, seizures, and autonomic instability. Although cardiac arrhythmias often accompany anti-NMDARE, the need for long-term electrophysiological support is rare. We describe the case of NMDARE whose ICU course was complicated by progressively worsening episodes of tachyarrhythmia-bradyarrhythmia and episodes of asystole from which she was successfully resuscitated. Her life-threatening episodes of autonomic instability were successfully controlled only after the placement of a permanent pacemaker during her ICU stay. She made a clinical recovery and was discharged to a skilled nursing facility after a protracted hospital course.

PHF-tau propagation in the presence of Amyloid ß pathology

PHF-tau propagation in the presence of Amyloid ß pathology

Subacute Sclerosing Panencephalitis With Atypical Clinical and MRI Findings

Subacute sclerosing panencephalitis (SSPE) is a progressive inflammatory disorder of the central nervous system and a slow virus infection caused by aberrant measles virus. Typical neurological manifestations include psychomotor impairment, progressive intellectual deterioration, myoclonic jerks and behavioral changes, with or without pyramidal symptoms. It usually affecting people aged 10 to 14 year. We report the case of an 17-year-old girl presenting with initial symptom of visual loss, seizures, a lack of SSPE specific EEG pattern, late onset and atypical fast progression of disease. The case highlights the importance of atypical clinical findings of SSPE at onset and also firstly disappearing, then appearing MRI findings at sequential images which can complicate the accurate diagnosis. High suspicion is needed because of its rareness.

Getting to NO Alzheimer's Disease: Neuroprotection versus Neurotoxicity Mediated by Nitric Oxide.

Alzheimer's disease (AD) is a neurodegenerative disorder involving the loss of neurons in the brain which leads to progressive memory loss and behavioral changes. To date, there are only limited medications for AD and no known cure. Nitric oxide (NO) has long been considered part of the neurotoxic insult caused by neuroinflammation in the Alzheimer's brain. However, focusing on early developments, prior to the appearance of cognitive symptoms, is changing that perception. This has highlighted a compensatory, neuroprotective role for NO that protects synapses by increasing neuronal excitability. A potential mechanism for augmentation of excitability by NO is via modulation of voltage-gated potassium channel activity (Kv7 and Kv2). Identification of the ionic mechanisms and signaling pathways that mediate this protection is an important next step for the field. Harnessing the protective role of NO and related signaling pathways could provide a therapeutic avenue that prevents synapse loss early in disease.

Manifestation of neuronal ceroid lipofuscinosis in Australian Merino sheep: Observations on altered behaviour and growth

Neuronal ceroid lipofuscinoses (NCL) is an inherited neurodegenerative disorder in children. Presently there is no effective treatment and the disorder is lethal. NCL occur in a variety of non-human species including sheep, which are recognised as valuable large animal models for NCL. This experiment investigated the progressive postural, behavioural and liveweight changes in NCL-affected lambs, to establish practical, non-invasive biomarkers of disease progression for future preclinical trials in a CLN6 Merino sheep model. A flock of eight lambs at pasture was studied, with the observer blind to the disorder status. Three genotypes were compared: homozygous affected (NCL; n=4), clinically normal heterozygous (Carrier; n=2) and homozygous normal (non-carrier control (Normal); n=2). Direct observation during daylight and continuous accelerometer measurements over 72h were used to quantify lamb posture and behaviour in 11 sessions between 26 and 60 weeks of age, conducted at 3-5 week intervals. There was a Genotype (G)×Age (A) interaction (P=0.001) for liveweight of the lambs in the experiment, with NCL, Carrier and Normal lambs gaining 11.8, 16.5 and 23.4kg, respectively, between 26 and 60 weeks of age. G×A interactions were also found for walking behaviour (means for NCL, Carrier and Normal genotype groups at 26 and 60 weeks, were 1.7 and 7.9%, 3.3 and 3.1%, and 2.5 and 1.9% of observations, P=0.008) and a composite variable of key behaviours identified in the principal components analysis (P<0.001), with mean values for NCL lambs increasing three-fold compared to non-affected lambs as age increased. Similarly, NCL lambs became less responsive to visual and auditory stimuli as they aged. Mean responsiveness scores (out of 3) to visual stimuli for the NCL, Carrier and Normal genotypes at 26 and 60 weeks of age were 2.7 and 1.4, 2.8 and 2.9, and 3.0 and 3.0, respectively (G×A, P<0.001). Changes in response to auditory stimuli were similar to visual stimuli. NCL lambs took more (P=0.015) steps per 24h than Carrier and Normal genotype lambs, but there was no G×A interaction. At 26 and 60 weeks of age, respectively, NCL lambs took 2724 and 4121 steps per 24h, compared to Carrier (1708 and 3105 steps) and Normal genotype lambs (2109 and 3506 steps). NCL lambs also performed less (P=0.018) grazing behaviour than Carrier and Normal genotype lambs (66.5, 72.3 and 72.5% of observations for NCL, Carrier and Normal lambs, respectively). A number of behavioural changes identified in the experiment could form the basis for a protocol for monitoring and evaluation of disease progression.

Mystery Case: Lafora periodic acid–Schiff inclusion bodies

A 16-year-old boy presented with a 5-year history of progressive cognitive decline and behavioral change followed by generalized tonic-clonic and myoclonic seizures refractory to many anticonvulsants (valproic acid, phenobarbital, clonazepam, and topiramate) and cerebellar ataxia a year later. The son of consanguineous parents, he had a family history of 2 cousins who both had epilepsy and died at the ages of 15 and 25 years. Laboratory screening tests, including lactic acid, fundus examination, brain neuroimaging, and CSF, were normal. Skin biopsy (figure) revealed periodic acid–Schiff-positive intracellular polyglucosan inclusion bodies in myoepithelial and sweat gland duct cells. These findings are typical of Lafora disease, a fatal autosomal recessive disorder caused by mutations in one of 2 known genes, both located at chromosome 6: EPM2A , which encodes the protein laforin, and EPM2B , which encodes the protein malin. Differential diagnosis must be made with other causes of progressive myoclonic epilepsies, most commonly Unverricht-Lundborg disease (Baltic myoclonus), myoclonus epilepsy and ragged-red fibers syndrome, neuronal ceroid lipofuscinosis, and type 1 sialidosis. There is no treatment, and therapy is mainly supportive and symptomatic.1,2

Frontotemporal Dementia: Identification and Management

Dementia is a disease primarily affecting older adults in their ability to carry out daily activities. Frontotemporal dementia (FTD), a leading cause of early-onset dementia, can present in the fourth and fifth decade by progressive changes in personality, affect, and behavior. The atypical presentation of FTD may resemble a midlife crisis, depression, schizophrenia, or a traumatic brain injury among its causes. The etiology of FTD is unknown, although genetic links have been suggested, thus treatment focuses on behavioral and symptom management. Early diagnosis of FTD is needed to better support the emotional and financial burdens of family and caregivers.