Pathology of neurodegenerative disease for the general neurologist.

Neurodegeneration refers to progressive dysfunction or loss of selectively vulnerable neurones from brain and spinal cord regions. Despite important advances in fluid and imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still relies on neuropathological examination. Not only has careful clinicopathological correlation shaped current clinical diagnostic criteria and informed our understanding of the natural history of neurodegenerative diseases, but it has also identified conditions with important public health implications, including variant Creutzfeldt-Jakob disease, iatrogenic amyloid-ß and chronic traumatic encephalopathy. Neuropathological examination may also point to previously unsuspected genetic diagnoses with potential implications for living relatives. Moreover, detailed neuropathological assessment is crucial for research studies that rely on curated postmortem tissue to investigate the molecular mechanisms responsible for neurodegeneration and for biomarker discovery and validation. This review aims to elucidate the hallmark pathological features of neurodegenerative diseases commonly seen in general neurology clinics, such as Alzheimer's disease and Parkinson's disease; rare but well-known diseases, including progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy and more recently described entities such as chronic traumatic encephalopathy and age-related tau astrogliopathy.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

Late Presentation of Chronic Traumatic Encephalopathy in a Former Association Football Player.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players. Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB). Methods: A retrospective review of the patient's primary care and hospital medical records was performed along with a comprehensive neuropathological examination. Results: This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A post-mortem examination revealed stage 4 CTE. Conclusions: While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts.

Single center analysis of patients with H1N1 vaccine-related narcolepsy and sporadic narcolepsy presenting over the same time period.

STUDY OBJECTIVES: We aimed to describe the clinical features of narcolepsy in patients referred to our sleep center between 2009 and 2016, and to compare these features across age groups and between sporadic vs AS03-adjuvanted H1N1 influenza vaccine-related patients. METHODS: This is a retrospective, consecutive study of adult and pediatric narcolepsy patients in the Republic of Ireland. All participants underwent structured assessments, including polysomnography and the Multiple Sleep Latency Test. Brain magnetic resonance imaging, hypocretin levels, and human leukocyte antigen typing were also carried out on the majority of patients. Patients were compared across age groups as well as etiology. RESULTS: The conditions of 40 (74%) patients were vaccine-related. The median age was 13.5 years and time from symptom onset to diagnosis was 112 weeks. Median time from vaccination to symptom onset was 26 weeks. In children, hypnogogic hallucinations and sleep paralysis were less frequent than in adults (17% vs 67%, P = .018 and 0% vs 75%, P < .0005). Sleep latency determined by the Multiple Sleep Latency Test was shorter in children than adults (median 1.75 vs 4 minutes, P = .011). Patients with vaccine-related and sporadic narcolepsies had typical clinical presentations. Vaccine-related patients had longer polysomnography latency (median 10.5 vs 5 minutes, P = .043), longer stage N2 sleep (209.6 ± 44.6 vs 182.3 ± 34.2 minutes, P = .042), and a trend toward longer total sleep times (P = .09). No differences were noted in relation to Multiple Sleep Latency Test, hypocretin, human leukocyte antigen typing, and magnetic resonance imaging. CONCLUSIONS: Results show that vaccine-related patients greatly outnumbered sporadic patients during the study period and suggest that sporadic and vaccine-related narcolepsy are clinically similar entities.

Five-year outcomes of patients attending a diabetic foot clinic in a tertiary referral centre.

BACKGROUND: Diabetic foot ulcers (DFU) are associated with an increased risk of lower limb amputation and death. Reported mortality rates for patients with DFU are as high as 50% after 5 years. AIMS: The aim of this retrospective study was to examine the 5-year clinical outcomes of patients with high-risk diabetic foot disease attending a specialist foot clinic in Beaumont Hospital between 2007 and 2010. METHODS: Clinical information was obtained from the CELLMA electronic patient record and laboratory results were extracted from the Beaumont Hospital information system. RESULTS: In total, data from 98 patients, who attended the foot clinic over the 4-year period, was collected. The 5-year mortality rate was 13.3% with an amputation rate of 28.6%. A significant proportion of patients (33.7%) had recurrent/new DFU after 5 years of follow-up. In this cohort, there was no association between poor glycaemic control, presence of co-existent cardiovascular disease or renal failure, and increased mortality or amputation. CONCLUSIONS: Diabetic foot disease is an important cause of morbidity and mortality in clinical practice. It remains to be seen whether implementation of the national model of foot care in 2011 will improve outcomes for patients with high-risk diabetic foot disease.

Insulin-Like Growth Factor 1: At the Crossroads of Brain Development and Aging.

Insulin-like growth factor 1 (IGF1) is a polypeptide hormone structurally similar to insulin. It is central to the somatotropic axis, acting downstream of growth hormone (GH). It activates both the mitogen-activated protein (MAP) kinase and PI3K signaling pathways, acting in almost every tissue in the body to promote tissue growth and maturation through upregulation of anabolic processes. Overall GH and IGF1 signaling falls with age, suggesting that it is this reduced IGF1 activity that leads to age-related changes in organisms. However, mutations that reduce IGF1-signaling activity can dramatically extend the lifespan of organisms. Therefore, the role of IGF1 in the overall aging process is unclear. This review article will focus on the role of IGF1 in brain development and aging. The evidence points towards a role for IGF1 in neurodevelopment both prenatally and in the early post-natal period, and in plasticity and remodeling throughout life. This review article will then discuss the hallmarks of aging and cognitive decline associated with falls in IGF1 levels towards the end of life. Finally, the role of IGF1 will be discussed within the context of both neuropsychiatric disorders caused by impaired development of the nervous system, and neurodegenerative disorders associated with aging. IGF1 and its derivatives are shown to improve the symptoms of certain neuropsychiatric disorders caused by deranged neurodevelopment and these effects have been correlated with changes in the underlying biology in both in vitro and in vivo studies. On the other hand, studies looking at IGF1 in neurodegenerative diseases have been conflicting, supporting both a role for increased and decreased IGF1 signaling in the underlying pathogenesis of these diseases.

Role of stigma and attitudes toward help-seeking from a general practitioner for mental health problems in a rural town.

OBJECTIVE: To examine the role of perceived stigma and attitudes to seeking care in predicting help-seeking from a general practitioner (GP) for mental health problems. METHOD: A cross-sectional survey in 2002 with self-report questionnaires assessing current levels of symptomatology, disability, attitudes towards mental illness, knowledge of prevalence and causes of mental illness, contact with mental illness and help-seeking behaviour and preferences and attitudes toward seeking professional psychological help. RESULTS: No significant relationship was found between symptom measures and measures of disability and help-seeking. Variables positively associated with general attitudes to seeking professional psychological help were: lower perceived stigma, and biological rather than person-based causal attributions for schizophrenia. Willingness to discuss mental health issues with a GP was predicted by the perceived helpfulness of the GP and by no other variable. CONCLUSIONS: Causal attributions and perceived stigma rather than participants' levels of symptomatology and disability influence attitudes to help-seeking for mental health issues. Efforts to improve attitudes to help-seeking should focus on reducing stigma and improving mental health literacy regarding the causes of disorders.