Usman Saeed

Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts

Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson’s disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson’s disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson’s disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a ‘window’ into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson’s disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well-established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors), and cerebral perfusion, 5) positron emission tomography for gauging nigrostriatal functions, glucose metabolism, amyloid and tau molecular imaging, as well as neuroinflammation, 6) myocardial scintigraphy for dysautonomia, and 7) transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity. Imaging biomarkers, using the ‘multimodal approach’, may aid in making early, accurate and objective diagnostic decisions, highlight neuroanatomical and pathophysiological mechanisms, as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials.

Giant cell arteritis or tension-type headache?: A differential diagnostic dilemma

Giant cell arteritis (GCA) or Temporal arteritis (TA) is an autoimmune disease and the most common type of vasculitis in the elderly. It causes inflammation of the medium and large arteries in the upper part of the body. GCA is an under-recognized cause of  head aches in the elderly, especially when it presents itself with atypical features, resulting in delayed or incorrect diagnosis. Since GCA is a treatable condition, an accurate diagnosis is crucial to prevent the most serious complication of CGA, permanent vision loss. The diagnosis can be further complicated as GCA may present with features of other painful neurological conditions. The present case is an 81-year-old woman diagnosed with GCA, who initially presented with features similar to tension-type headache. Due to overlapping features of these conditions, the diagnosis of GCA was delayed, resulting in irreversible vision loss. Although previous research highlights diagnostic dilemmas featuring GCA and other disease states, this case is exclusive in describing a unique dilemma where tension-type headache mimics GCA.

Role of environmental factors in Cryptococcal meningitis in immunocompetent individuals

Cryptococcal Meningitis (CM) is caused by members of the yeast species, Cryptococcus neoformans. Although C.neoformans can cause infection in any part of the body, the fungus prefers to invade regions of the lungs and CNS [1]. The infection is thought to be acquired through the respiratory tract, and reaches the meninges through the blood circulation [1]. Symptoms of CM include headaches, malaise, fever, and changing psycho-mental stability. CM is most commonly recognized as an opportunistic infection in immunocompromised individuals, especially those suffering from HIV/AIDS, liver cirrhosis or sarcoidosis [2]. Hence, CM risk is usually overlooked or totally ignored during the differential diagnosis of immunocompetent individuals who present meningitis like symptoms. Recent reports have indicated rising prevalence of CM in individuals who are believed to be immunocompetent, resulting in delayed or misdiagnosis of such patients [3]. Other factors are emerging to be important determinants when diagnosing a patient with meningitis like symptoms. Such factors include environmental factors originally believed to be important in Africa or in tropical environments. Environmental factors (as they relate to CM) can be defined as any factor originating from the environment that results in immunodeficiency, either by a significant decrease in white blood cells count or by interfering with normal immunological response of the body.

APOE-ε4 associates with hippocampal volume, learning, and memory across the spectrum of Alzheimer's disease and dementia with Lewy bodies

Although the apolipoprotein E ε4‐allele (APOE‐ε4) is a susceptibility factor for Alzheimers disease (AD) and dementia with Lewy bodies (DLB), its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored.

Alkaptonuria, more than just a mere disease.

Alkaptonuria (AKU) is considered a rare autosomal recessive condition that results in an accumulation of homogentisic acid in body tissues and causes long-term clinical, neurological and psychological complications. We present a comprehensive evaluation of an atypical 46-year-old Caucasian male who developed all clinical diagnostic symptoms of AKU (ochronotic pigmentations, dark urine and clinical arthritis of major joints including spine) by 25 years of age, well before the typical age mentioned in many reviews. First signs of ochronotic ear pigmentations unexpectedly started appearing as early as 12 years of age. A long “disease-free” period typical in classical AKU patient was also absent. This case report highlights the importance of considering psychological issues in AKU patients. The patient showed symptoms of dysthymia reporting social isolation, diminished interest in pleasurable activities, feeling of worthlessness and irritability as major psychological issues. Early ochronotic pigmentation, advanced spinal myelopathy and arthropathy of major joints suggests aggressive course of the disease. Our patient underwent bilateral shoulder replacement due to AKU-induced arthropathy resulting in restoration of some range of motions. AKU is not fully understood and we recommend treating it as a multidimensional disease with simultaneous physiological, neurological and psychological effects. Early diagnosis, understanding of disease prognosis and emphasis on psychological health is needed to improve the quality of life of AKU patients.

Unraveling PINK1 regulation: Ubiquitination of its mature form and insights for Parkinson's disease

PINK1 (PTEN-induced putative kinase-1) is a serinethreonine protein kinase involved in quality control mechanisms of mitochondria. Upon mitochondrial damage, PINK1 works in concert with Parkin ligase to induce mitophagy and protect the cell from mitochondrial toxicity. Dysfunctional PINK1 protein can compromise this important housekeeping mechanism, establishing the conditions for neurodegeneration. Indeed, recessively-inherited mutations in PINK1 are associated with young-onset Parkinson’s disease (PD). Given the contribution of PINK1 mutations and dysregulated mitophagy to the etiology of PD, understanding how fully functional PINK1 protein is regulated to maintain mitochondrial quality control can provide important insights into the mechanisms of neurodegeneration. Research has shown that under basal conditions, fulllength PINK1 (63 kDa) is imported into the mitochondria, where it is cleaved by mitochondrial processing peptidase into an intermediate form (60 kDa) and then by presenilinassociated rhomboid-like protein into the mature form (52 kDa). Despite constitutive expression of PINK1, the levels of these 3 PINK1 species are unexpectedly low, suggesting rapid turnover. Accordingly, PINK1 was found to be ubiquitinated (“marked”) for subsequent proteasomal degradation, although which of the 3 PINK1 species was altered remained unknown. Liu and colleagues studied this question and provided several important insights. They first confirmed PINK1 to be an outer mitochondrial membrane protein, which is often ubiquitinated in healthy mitochondria. They then showed that mature 52-kDa PINK1 is the prime target for polyubiquitination, and thus its levels are kept low in normal conditions via proteasomal degradation. What made the mature form more susceptible to polyubiquitination than the other PINK1 species? One conserved lysine residue (K137) was found to be important in mediating ubiquitination of the mature form. Although K137 is also present in full-length PINK1, it remained unubiquitinated. Using computational analysis, the authors proposed that preferential ubiquitination of mature PINK1 at K137 was because of conformational changes induced by proteolytic cleavage of the full-length form that disrupted the membrane-spanning domain, as well as because of ensuing membrane-protein rearrangements. These conformational changes exposed the K137 site for ubiquitination in mature, but not full-length PINK1. Research is under way to further understand the pathogenic mechanisms, including involvement of the proteasomal degradation machinery, in the etiology of PD. Unraveling the housekeeping processes that ensure proper mitochondrial function and neuronal survival will be vital to our understanding of PD disease-related mechanisms.