Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study.

BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET have a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17.

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder.

Clinical utility of amyloid PET imaging with (18)F-florbetapir: a retrospective study of 100 patients.

BACKGROUND AND OBJECTIVE: Amyloid-positron emission tomography (PET) imaging (API) detects amyloid-beta pathology early in the course of Alzheimer's disease (AD) with high sensitivity and specificity. (18)F-florbetapir (Amyvid) is an amyloid-binding PET ligand with a half-life suitable for clinical use outside of the research setting. How API affects patient investigation and management in the 'real-world' arena is unknown. To address this, we retrospectively documented the effect of API in patients in the memory clinic. METHODS: We reviewed the presenting clinical features, the pre-API and post-API investigations, diagnosis and outcomes for the first 100 patients who had API as part of their routine work-up at the Imperial Memory Centre, a tertiary referral clinic in the UK National Health Service. RESULTS: API was primarily used to investigate patients with atypical clinical features (56 cases) or those that were young at onset (42 cases). MRI features of AD did not always predict positive API (67%), and 6 of 23 patients with MRIs reported as normal were amyloid-PET positive. There were significantly more cases categorised as non-AD dementia post-API (from 11 to 23). Patients investigated when API was initially available had fewer overall investigations and all patients had significantly fewer investigations in total post-API. CONCLUSIONS: API has a clear impact on the investigation of young-onset or complex dementia while reducing the overall burden of investigations. It was most useful in younger patients, atypical presentations or individuals with multiple possible causes of cognitive impairment.

Dantrolene an unusual option for detrusor overactivity: observations of a patient with cerebral palsy.

We report a case of a 49-year-old female with cerebral palsy with spastic tri-plegia and lumbar spondyolisthesis diagnosed to have overactive neurogenic bladder, which improved on treatment with Dantrolene along with antimuscarinics. She was initially treated with antimuscarinics both transdermal and oral simultaneously and later received intravesical OnaBotulinum toxinA. Following lumbar spine fixation for spondylolisthesis, her bowel and bladder function deteriorated and she was commenced on Dantrolene for her spasticity, along with being on Oxybutinin and Mirabegron. This significantly improved her symptoms. Overactive bladder symptoms are a common manifestation in cases of CP. In refractory cases where antimuscarinics and intravesical botulinum toxin therapy have failed, a combination of Dantrolene with antimuscarinics and/or beta 3 receptor agonists may prove to be beneficial. While on therapy, regular monitoring of liver functions is required to promptly diagnose and treat hepatotoxicity.

Acute transverse myelitis as a rare manifestation of Campylobacter diarrhoea with concomitant disruption of the blood brain barrier.

We describe a case of acute transverse myelitis following Campylobacter diarrhoea in an adult. The patient presented with diplegia due to a longitudinal spinal cord lesion. The CSF demonstrated an aseptic meningitis. Oligoclonal bands and C. jejuni-specific IgG were detected in serum and cerebrospinal fluid at the beginning of the neurological illness. The patient was treated with antimicrobial therapy and steroids. A near full recovery was made and there were no relapses. C. jejuni is strongly implicated in the aetiology of acute motor axonal neuropathy and Miller Fisher syndrome through molecular mimicry of neuronal gangliosides. These gangliosides are expressed throughout the nervous system yet C. jejuni related central nervous system disease is exceedingly rare. We conclude that disruption of the blood-brain barrier was the key event in the pathogenesis of immune mediated post-infectious myelitis in our patient.

Familial cerebral cavernomas due to a KRIT1 mutation presenting with epilepsy.

The authors present the case of a 25-year-old individual who presented acutely following a generalised tonic-clonic seizure. Brain MRI of the individual demonstrated the classical appearance of multiple cerebral cavernous haemangiomas (cavernomas). There was an autosomal dominant family history. Genetic testing identified a truncating mutation in the KRIT1 gene in the individual and confirmed the diagnosis of familial cerebral cavernomas as the cause of epilepsy in the family.

Visual loss secondary to eosinophilic mucin rhinosinusitis in a woman: a case report.

INTRODUCTION: Eosinophilic mucin rhinosinusitis is an inflammatory pathological condition of the nose and paranasal sinuses. It is rare, occurs in immunocompetent patients and is characterised by peripheral eosinophilia and extensive bilateral sinus disease. To the best of our knowledge, visual loss with this condition has not been previously reported. CASE PRESENTATION: We present the case of a 26-year-old Asian woman with a background history of chronic sinusitis who presented with acute left-sided visual loss. Imaging showed significant opacification in the frontal, ethmoidal and sphenoidal sinuses as well as evidence of a unilateral optic neuritis. Histological analysis of sinus mucin revealed dense eosinophilic infiltrate and, despite medical and surgical intervention, vision was not restored in her left eye. CONCLUSION: We introduce visual loss as a complication of eosinophilic mucin rhinosinusitis. This adds further evidence to previous reports in the literature that optic neuropathy in sinusitis can occur secondary to non-compressive mechanisms. We also describe a rare finding: the vision in this patient did not improve following steroid therapy, antifungal therapy or surgical intervention. There are very few such cases described in the literature. We conclude that chronic sinusitis is an indolent inflammatory process which can cause visual loss and we reiterate the importance of recognizing and considering sinusitis as a cause of visual loss in patients in order that prompt medical and surgical treatment of the underlying disease can be initiated.

Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause?

BACKGROUND: To date there have been four instances of infection transmitted through blood transfusions derived from individuals who later developed variant Creutzfeldt-Jakob disease (vCJD). The identification of further transmission of vCJD through this route would have important implications for risk assessment and public health. STUDY DESIGN AND METHODS: Through the UK Transfusion Medicine Epidemiology Review (TMER) the fate of blood donations from individuals who develop vCJD is traced and recipients of labile components are identified. The details of recipients are cross-checked with the register of vCJD cases held at the National CJD Surveillance Unit (NCJDSU) to identify any linkage between donors and recipients. In the reverse study, when individuals with vCJD are found to have a history of blood transfusion the donors of the transfused blood components are traced and their details cross-checked with the vCJD register to identify any missed or unrecognized linkage between donors and recipients. CASE REPORT: A case of vCJD has been identified with a history of blood transfusion in infancy. The donors who provided the components transfused cannot be identified, but a blood donor known to have donated blood to another individual who subsequently developed vCJD could have been a donor to the index case. RESULTS: The at-risk donor is alive 20 years after the relevant donation and continued to donate for some years, until identified as at risk, with 27 other blood components issued for use in patients, none of whom are known to have developed vCJD. CONCLUSION: Circumstantial evidence has raised the possibility that the case in this report represents a further instance of transfusion transmission of vCJD. However, detailed investigation indicates that the pattern of events may have occurred by chance and disease in this individual may have been caused by transmission of bovine spongiform encephalopathy infection, as is the presumed cause in other primary cases of vCJD.

Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial.

BACKGROUND: The propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases. METHODS: Patients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585. FINDINGS: 107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrollment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related. INTERPRETATION: Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.

Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study.

[11C](R)PK11195-PET is a marker of activated microglia while [11C]PIB-PET detects raised amyloid load. Here we studied in vivo the distributions of amyloid load and microglial activation in Alzheimer's disease (AD) and their relationship with cognitive status. Thirteen AD subjects had [11C](R)PK11195-PET and [11C]PIB-PET scans. Ten healthy controls had [11C](R)PK11195-PET and 14 controls had [11C]PIB-PET scans. Region-of-interest analysis of [11C](R)PK11195-PET detected significant 20-35% increases in microglial activation in frontal, temporal, parietal, occipital and cingulate cortices (p<0.05) of the AD subjects. [11C]PIB-PET revealed significant two-fold increases in amyloid load in these same cortical areas (p<0.0001) and SPM (statistical parametric mapping) analysis confirmed the localisation of these increases to association areas. MMSE scores in AD subjects correlated with levels of cortical microglial activation but not with amyloid load. The inverse correlation between MMSE and microglial activation is compatible with a role of microglia in neuronal damage.

Impaired allocentric spatial memory underlying topographical disorientation.

The cognitive processes supporting spatial navigation are considered in the context of a patient (CF) with possible very early Alzheimer's disease who presents with topographical disorientation. Her verbal memory and her recognition memory for unknown buildings, landmarks and outdoor scenes was intact, although she showed an impairment in face processing. By contrast, her navigational ability, quantitatively assessed within a small virtual reality (VR) town, was significantly impaired. Interestingly, she showed a selective impairment in a VR object-location memory test whenever her viewpoint was shifted between presentation and test, but not when tested from the same viewpoint. We suggest that a specific impairment in locating objects relative to the environment rather than relative to the perceived viewpoint (i.e. allocentric rather than egocentric spatial memory) underlies her topographical disorientation. We discuss the likely neural bases of this deficit in the light of related studies in humans and animals, focusing on the hippocampus and related areas. The specificity of our test indicates a new way of assessing topographical disorientation, with possible application to the assessment of progressive dementias such as Alzheimer's disease.

Alzheimer's patients engage an alternative network during a memory task.

We conducted an event-related functional magnetic resonance imaging experiment to better understand the potentially compensatory alternative brain networks activated by a clinically relevant face-name association task in Alzheimer's disease (AD) patients and matched control subjects. We recruited 17 healthy subjects and 12 AD patients at an early stage of the disease. They underwent functional magnetic resonance imaging scanning in four sessions. Each of the sessions combined a "study" phase and a "test" phase. Face/name pairs were presented in each study phase, and subjects were asked to associate faces with names. In the test phase, a recognition task, faces seen in the study phase were presented each with four different names. The task required selection of appropriate previously associated names from the study phase. Responses were recorded for post hoc classification into those successfully or unsuccessfully encoded. There were significant differences between the groups in accuracy and reaction time. Comparison of correctly versus incorrectly encoded and recognized pairs in the two groups indicated bilateral hippocampal hypoactivation both when encoding and recognizing in the AD group. Moreover, patients showed bilateral hyperactivation of parts of the parietal and frontal lobes. We discuss whether hyperactivation of a frontoparietal network reflects compensatory strategies for failing associative memory in AD patients.

Three clinical problems: weird thyroid function tests, difficult gout, and dementia.

Speakers at the course were given vignettes describing one or more clinical scenarios on which to base their talks, selected because they represent common but challenging problems likely to be encountered by any physician practising in general internal medicine. Three of the subjects covered--weird thyroid function tests, difficult gout, and dementia--are presented here.