Progressive supranuclear palsy (PSP): general pathology and visual signs and symptoms

Progressive supranuclear palsy (PSP) is a rare, degenerative disorder of the brain believed to affect between 1.39 and 6.6 individuals per 100,000 of the population. The disorder is likely to be more common than suggested by these data due to difficulties in diagnosis and especially in distinguishing PSP from other conditions with similar symptoms such as multiple system atrophy (MSA), corticobasal degeneration (CBD), and Parkinson’s disease (PD). PSP was first described in 1964 by Steele, Richardson and Olszewski and originally called Steele-Richardson-Olszewski syndrome. The disorder is the second commonest syndrome in which the patient exhibits ‘parkinsonism’, viz., a range of problems involving movement most typically manifest in PD itself but also seen in PSP, MSA and CBD. Although primarily a brain disorder, patients with PSP exhibit a range of visual clinical signs and symptoms that may be useful in differential diagnosis. Hence, the present article describes the general clinical and pathological features of PSP, its specific visual signs and symptoms, discusses the usefulness of these signs in differential diagnosis, and considers the various treatment options.

Principal components analysis of Alzheimer's disease based on neuropathological data: a study of 79 patients

A principal components analysis was carried out on neuropathological data collected from 79 cases of Alzheimer's disease (AD) diagnosed in a single centre. The purpose of the study was to determine whether on neuropathological criteria there was evidence for clearly defined subtypes of the disease. Two principal components (PC1 and PC2) were extracted from the data. PC1 was considerable more important than PC2 accounting for 72% of the total variance. When plotted in relation to the first two principal components the majority of cases (65/79) were distributed in a single cluster within which subgroupings were not clearly evident. In addition, there were a number of individual, mainly early-onset cases, which were neither related to each other nor to the main cluster. The distribution of each neuropathological feature was examined in relation to PC1 and 2, Disease onset, rhe degree of gross brain atrophy, neuronal loss and the devlopment of senile plaques (SP) and neurofibrillary tangles (NFT) were negatively correlated with PC1. The devlopment of SP and NFT and the degree of brain athersclerosis were positively correlated with PC2. These results suggested: 1) that there were different forms of AD but no clear division of the cases into subclasses could be made based on the neuropathological criteria used; the cases showing a more continuous distribution from one form to another, 2) that disease onset was an important variable and was associated with a greater development of pathological changes, 3) familial cases were not a distinct subclass of AD; the cases being widely distributed in relation to PC1 and PC2 and 4) that there may be two forms of late-onset AD whic grade into each other, one of which was associated with less SP and NFT development but with a greater degree of brain atherosclerosis.

Visual signs and symptoms of progressive supranuclear palsy

Progressive supranuclear palsy is a rare, degenerative brain disorder and the second most common syndrome in which the patient exhibits 'parkinsonism', that is, a variety of symptoms involving problems with movement. General symptoms include difficulties with gait and balance; the patient walking clumsily and often falling backwards. The syndrome can be difficult to diagnose and visual signs and symptoms can help to separate it from closely related movement disorders such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies and corticobasal degeneration. A combination of the presence of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm and apraxia of eyelid opening and closing may be useful visual signs in the identification of progressive supranuclear palsy. As primary eye-care practitioners, optometrists should be able to identify the visual problems of patients with this disorder and be expected to work with patients and their carers to manage their visual welfare.

Immunological studies in multiple low dose streptozotocin induced diabetes in mice

1. Multiple low doses of streptozotocin (MSZ) treatment successfully induced diabetes in male TO, MFI and HO lean mice. In contrast however, BALB/c mice failed to develop persistent hyperglycaemia. Single streptozotocin (SSZ) treatment also produced diabetes in TO mice. SSZ treatment however, produced severe weight loss and atrophy of the lymphoid organs. MSZ treatment on the other hand, was not cytotoxic towards lymphoid organs and, whilst there was no loss of body weight, growth rates were reduced in MSZ treated mice. 2. Following sheep red blood cell (SRBC) immunisation of MSZ-treated mice, haemagglutination titres, and numbers of antigen reactive cells and plaque forming cells were all significantly lower than control values. 3. In vitro proliferation of spleen cells in response to phytohaemagglutinin (PHA) and conconavalin A (ConA) was found to be significantly depressed in MSZ treated mice. However, T-lymphocyte responses were intact when the mice were not overtly hyperglycaemic. In contrast, however, T cell independent responses to lipopolysaccharide (LPS) were generally intact throughout the study period. 4. Cell mediated immunity, as assessed by measurements of delayed (Type IV) hypersensitivity, was also depressed in MSZ treated mice. This suppression could be reversed by insulin therapy. 5. Both natural killer cell activity and antibody dependent cell mediated cytotoxicity were found to be significantly increased in MSZ treated mice. 6. Histological examination of the pancreas showed the presence of insulitis, in MSZ treated mice, and cytotoxic effector cells against obese mice islet cells (as assessed by 51Cr release) and HIT-T15 cells (as assessed by insulin secretion) were found to be significantly increased. Furthermore, these effector cells were also found to show increased proliferation in the presence of homogenates prepared from HIT-T15 cells. Examination of the Sera from MSZ treated mice showed that islet cell surface antibodies were present.

The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of familial amyotrophic lateral sclerosis with FUS mutation, NIFID, basophilic inclusion body disease, and atypical FTLD with ubiquitin-immunoreactive inclusions (aFTLD-U). To further characterize FUS proteinopathy in NIFID, and to determine whether the pathology revealed by FUS immunohistochemistry (IHC) is more extensive than a-internexin, we have undertaken a quantitative assessment of ten clinically and neuropathologically well-characterized cases using FUS IHC. The densities of NCI were greatest in the dentate gyrus (DG) and in sectors CA1/2 of the hippocampus. Anti-FUS antibodies also labeled glial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN). Vacuolation was extensive across upper and lower cortical layers. Significantly greater densities of abnormally enlarged neurons and glial cell nuclei were present in the lower compared with the upper cortical laminae. FUS IHC revealed significantly greater numbers of NCI in all brain regions especially the DG. Our data suggest: (1) significant densities of FUS-immunoreactive NCI in NIFID especially in the DG and CA1/2; (2) infrequent FUS-immunoreactive GI, NII, and DN; (3) widely distributed vacuolation across the cortex, and (4) significantly more NCI revealed by FUS than a-internexin IHC.

Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate filament inclusion disease (NIFID)

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico-cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or a-internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or ???, and (3) the spatial patterns of the FUS-immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID.

Metabolic and morphological alterations induced by proteolysis-inducing factor from Walker tumour-bearing rats in C2C12 myotubes

BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model. © 2008 Yano et al; licensee BioMed Central Ltd.

Is twelve years old an acceptable age at which to begin Diabetic Retinopathy Screening?

Introduction: The English National Screening Programme for diabetic retinopathy (ENSPDR) states that “all people with diabetes aged 12 years and over should be offered screening” Purpose: The audit aims to assess whether the current guideline is suitable and whether diabetes duration should be taken into account when deciding at what age to start screening patients. Method: Retrospective analysis of 143 randomly selected patients aged twelve years or younger who have attended diabetic retinopathy (DR) screening in the Birmingham and Black Country Screening Programme. Results: 98% had Type 1 diabetes and mean visual acuity (VA) was 6/5 (6/4-6/36). 73 were under 12 with 7 the youngest age and 70 were aged 12. Both groups had mean diabetes duration of 5 years (1month-11years). For those under 12, 7/73 (9.6%) had background DR, of these mean diabetes duration was 7 years (6-8) and the youngest aged 8. In those aged 12, 5/70 (7.1%) had background DR; of these mean diabetes duration was 8 years (6-11). In total 12 (8.4%) patients aged 12 years or under developed DR. No patients had retinopathy worse than background changes. One patient was referred to ophthalmology for VAs of 6/12, 6/18 and was diagnosed with optic atrophy so returned to annual screening. Conclusion: The results suggest that the current guideline on when to begin screening should be readdressed as more patients under twelve developed DR than those aged 12. Diabetes duration may help when deciding what age to start screening adolescent patients as DR was not seen in those with disease duration.

Downregulation of muscle protein degradation in sepsis by eicosapentaenoic acid (EPA)

Eicosapentaenoic acid (EPA) has been shown to attenuate muscle atrophy in cancer, starvation and hyperthermia by downregulating the increased expression of the ubiquitin-proteasome proteolytic pathway leading to a reduction in protein degradation. In the current study EPA (0.5 g/kg) administered to septic mice completely attenuated the increased protein degradation in skeletal muscle by preventing the increase in both gene expression and protein concentration of the alpha- and beta-subunits of the 20S proteasome, as well as functional activity of the proteasome, as measured by the 'chymotrypsin-like' enzyme activity. These results suggest that muscle protein catabolism in sepsis is mediated by the same intracellular signalling pathways as found in other catabolic conditions.

Visual signs and symptoms of dementia with Lewy bodies

Dementia with Lewy bodies ('Lewy body dementia' or 'diffuse Lewy body disease') (DLB) is the second most common form of dementia to affect elderly people, after Alzheimer's disease. A combination of the clinical symptoms of Alzheimer's disease and Parkinson's disease is present in DLB and the disorder is classified as a 'parkinsonian syndrome', a group of diseases which also includes Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. Characteristics of DLB are fluctuating cognitive ability with pronounced variations in attention and alertness, recurrent visual hallucinations and spontaneous motor features, including akinesia, rigidity and tremor. In addition, DLB patients may exhibit visual signs and symptoms, including defects in eye movement, pupillary function and complex visual functions. Visual symptoms may aid the differential diagnoses of parkinsonian syndromes. Hence, the presence of visual hallucinations supports a diagnosis of Parkinson's disease or DLB rather than progressive supranuclear palsy. DLB and Parkinson's disease may exhibit similar impairments on a variety of saccadic and visual perception tasks (visual discrimination, space-motion and object-form recognition). Nevertheless, deficits in orientation, trail-making and reading the names of colours are often significantly greater in DLB than in Parkinson's disease. As primary eye-care practitioners, optometrists should be able to work with patients with DLB and their carers to manage their visual welfare.

Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease:a comparative study of eight disorders

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer's disease, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the 'fused in sarcoma' (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders. © 2012 Springer-Verlag.

Mechanism of induction of muscle protein loss by hyperglycaemia

Treatment of murine myotubes with high glucose concentrations (10 and 25 mM) stimulated protein degradation through the ubiquitin–proteasome pathway, and also caused activation (autophosphorylation) of PKR (double-stranded-RNA-dependent protein kinase) and eIF2a (eukaryotic initiation factor 2a). Phosphorylation of PKR and eIF2a was also seen in the gastrocnemius muscle of diabetic ob/ob mice. High glucose levels also inhibited protein synthesis. The effect of glucose on protein synthesis and degradation was not seen in myotubes transfected with a catalytically inactive variant (PKR?6). High glucose also induced an increased activity of both caspase-3 and -8, which led to activation of PKR, since this was completely attenuated by the specific caspase inhibitors. Activation of PKR also led to activation of p38MAPK (mitogen activated protein kinase), leading to ROS (reactive oxygen species) formation, since this was attenuated by the specific p38MAPK inhibitor SB203580. ROS formation was important in protein degradation, since it was completely attenuated by the antioxidant butylated hydroxytoluene. These results suggest that high glucose induces muscle atrophy through the caspase-3/-8 induced activation of PKR, leading to phosphorylation of eIF2a and depression of protein synthesis, together with PKR-mediated ROS production, through p38MAPK and increased protein degradation.

Oculo-visual dysfunction in Parkinson's disease

This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.

Visual hallucinations in the Parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes,viz., Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD) can be difficult. Visual hallucinations, however, are a chronic complication of some parkinsonian disorders and their presence may be a useful aid to diagnosis. The visual hallucinations in parkinsonism are often recurrent, well-formed, and detailed and occur in a significant proportion of cases of DLB and PD but are less common in PSP, MSA, and CBD. Hallucinations in PD often occur later in the disease and are complex, with flickering lights, and illusionary misconceptions often preceding the most common manifestation, viz., stereotypical colourful images. Hallucinations in DLB, however, are often present earlier in the disease and are similar to those in the 'misidentification syndromes', 'visual agnosias', and in 'delerium' but differ from those produced by hallucinogenic drugs such as LSD. Most typically in DLB, the hallucinations involve people or animals invading the patient's home but may also include inanimate objects and the appearance of writing on walls or ceilings. Visual hallucinations may involve a number of brain mechanisms including a change in the balance of neurotransmitter activity between the cholinergic and monoaminergic systems and may be a specific consequence of Lewy body (LB) pathology in brain stem nuclei. Ocular and retinal pathology may also contribute to hallucinations by reducing occipital stimulation. Hence, in patients with unclassifiable or with indeterminate parkinsonian symptoms, the presence of visual hallucinations should be regarded as a 'red flag' symptom indicating underlying Lewy body pathology and therefore, supporting a diagnosis of PD or DLB rather than PSP, MSA, or CBD. The presence of early visual hallucinations would support a diagnosis of DLB rather than PD. © 2013 Nova Science Publishers, Inc. All rights reserved.

Eye movement problems and differential diagnosis of the parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes, viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) can be difficult. Eye movement problems, however, are a chronic complication of many of these disorders and may be a useful aid to diagnosis. Hence, the presence in PSP of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm, and apraxia of eyelid opening and closing is useful in separating PD from PSP. Moreover, atypical features of PSP include slowing of upward saccades, moderate slowing of downward saccades, the presence of a full range of voluntary vertical eye movements, a curved trajectory of oblique saccades, and absence of square-wave jerks. Downgaze palsy is probably the most useful diagnostic clinical symptom of PSP. By contrast, DLB patients are specifically impaired in both reflexive and saccadic execution and in the performance of more complex saccadic eye movement tasks. Problems in convergence in DLB are also followed by akinesia and rigidity. Abnormal ocular fixation may occur in a significant proportion of MSA patients along with excessive square-wave jerks, a mild supranuclear gaze palsy, a gaze-evoked nystagmus, a positioning down-beat nystagmus, mild-moderate saccadic hypometria, impaired smooth pursuit movements, and reduced vestibulo-ocular reflex (VOR) suppression. There may be considerable overlap between the eye movement problems characteristic of the various parkinsonian disorders, but taken together with other signs and symptoms, can be a useful aid in differential diagnosis, especially in the separation of PD and PSP.