L Massey

Does corticobasal degeneration exist? A clinicopathological re-evaluation

The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies. We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls. Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity=26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years. On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimers disease and the remaining five had other non-tau pathologies. Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardsons syndrome, and we propose the term corticobasal degeneration-Richardsons syndrome for this subgroup. Cases of corticobasal degeneration-Richardsons syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology. In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%). Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.

Nonmotor symptoms as presenting complaints in Parkinson's disease: A clinicopathological study

Nonmotor symptoms (NMS) are increasingly recognized as a significant cause of morbidity in later stages of Parkinsons disease (PD). Prodromal NMS are also a well recognized component of the clinical picture in some patients but the prevalence of NMS as presenting complaints, and their impact on clinical management, in pathologically‐proven cases of PD is unknown. The presenting complaints of 433 cases of pathologically‐proven PD archived at the Queen Square Brain Bank for Neurological Diseases were identified from the clinical case notes. 91/433 (21%) of patients with PD presented with NMS of which the most frequent were pain (15%), urinary dysfunction (3.9%), anxiety, or depression (2.5%). Presenting with NMS is associated with a delayed diagnosis of PD (Mann‐Whitney U, P = 0.001). These patients were more likely to be misdiagnosed initially and were more likely to have been referred to orthopedeic surgeons or rheumatologists than neurologists (nonmotor group 5.5% vs. motor group 44.2%, χ2 P < 0.0001). NMS are commonly seen as presenting complaints in pathologically confirmed PD, and initial misdiagnosis may be associated with potentially inappropriate medical interventions. Presenting with NMS does not affect the motor response to medication, but is associated with shorter disease duration (χ2 P = 0.016).

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinsons disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohens kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The “hummingbird” and “morning glory” signs were highly specific for PSP, and “the middle cerebellar peduncle sign” and “hot cross bun” for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.

The midbrain to pons ratio A simple and specific MRI sign of progressive supranuclear palsy

Objectives: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP. Methods: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21). Results: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm. Conclusions: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

High resolution MR anatomy of the subthalamic nucleus: Imaging at 9.4 T with histological validation

Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.

Anatomy of the substantia nigra and subthalamic nucleus on MR imaging.

The substantia nigra and subthalamic nucleus are two key structures in the midbrain that are very important in movement disorders, particularly those associated with parkinsonism. Using conventional magnetic resonance (MR) imaging, the anatomic description of both these structures can be challenging. This article describes the importance of understanding the underlying anatomy and some of the changes associated with pathology in these structures. Advances in MR imaging are discussed, including high-field MR imaging, diffusion tensor imaging, inversion-recovery imaging, and susceptibility-weighted imaging, with particular reference to the substantia nigra and subthalamic nucleus. Understanding of MR imaging features of these nuclei needs to be firmly based on underlying knowledge of anatomy and pathology from postmortem studies, and more work is needed in this field.

Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant

Since the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardsons syndrome (PSP‐RS), several distinct clinical syndromes have been associated with PSP‐tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP‐CBS) was reported to have more tau load in the mid‐frontal and inferior‐parietal cortices than in PSP‐RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP‐CBS.

Parkinson’s disease with Onuf’s nucleus involvement mimicking multiple system atrophy

Urinary frequency, urgency and nocturia are common complaints in Parkinson’s disease (PD). The hypothesis most widely proposed to explain neurogenic bladder symptoms in PD is that cell loss in the substantia nigra may cause detrusor hyperactivity due to a loss in the D1 receptor-mediated tonic inhibition of the micturition reflex, although other causes including anti-parkinsonian medication cortical effects have been considered.1 We present the clinical and pathological findings of a patient with parkinsonism who presented with prominent dysautonomia and a poor response to dopaminergic medications and was considered to have possible multiple system atrophy parkinsonism (MSA-P). Pathological examination revealed that the patient had PD with α-synuclein pathology in the Onuf’s nucleus (ON). A 52-year-old male presented with a 12-month history of urinary frequency and urgency in 1999. Examination revealed no prostate enlargement. Urodynamic studies showed evidence of bladder instability and obstruction, with flexible cystoscopy not showing any abnormalities. Two years later, he started to slow down in his movements, shuffle and complain of stiffness. He had a stooped posture, a frozen facial appearance, reduced blinking and mild limb rigidity. Deep tendon reflexes were brisk, with equivocal plantar responses. Orthostatic hypotension was found with a …

Concomitant progressive supranuclear palsy and multiple system atrophy: More than a simple twist of fate?

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are both rare neurodegenerative diseases. In the Queen Square Brain Bank, from 2001 to 2008, we received 120 cases of pathologically confirmed PSP and 36 of MSA, and one had concomitant PSP and MSA pathology. The clinical symptoms in this case were compatible with PSP and did not predict the dual pathology. The growing number of collective case reports, including the one reported here, might suggest an increased prevalence of concomitant PSP and MSA than what would be expected by chance.

9.4 T MR microscopy of the substantia nigra with pathological validation in controls and disease

BACKGROUND The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinsons disease and progressive supranuclear palsy. METHODS 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinsons disease) and imaged using high field 9.4Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinsons disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinsons disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinsons disease whereas in progressive supranuclear palsy there was microarchitectural destruction.Background The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinsons disease and progressive supranuclear palsy. Methods 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinsons disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. Results The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinsons disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinsons disease and controls, but reduced in progressive supranuclear palsy. Conclusions We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinsons disease whereas in progressive supranuclear palsy there was microarchitectural destruction.