Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-β/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P = 0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include “presence of other neuropathological lesions likely to cause dementia”, an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of β/A4 plaques. The presence of β/A4 amyloid in the brain may influence PrP morphogenesis. Received: 18 November 1997 / Revised, accepted: 11 February 1998     

Raised CSF phospho-tau concentrations in variant Creutzfeldt-Jakob disease: diagnostic and pathological implications

OBJECTIVE: To investigate whether phosphorylated tau protein (tau-pT181) is increased in variant Creutzfeldt-Jakob disease (vCJD) and if the tau-pT181/tau protein ratio is useful for distinguishing between patients with and without CJD. METHODS: CSF tau protein and tau-pT181 were measured in 50 patients with sporadic CJD (sCJD), 51 patients with vCJD, 46 sCJD controls, and 37 vCJD controls, using Innotest hTau and Innotest P-Thr181, Innogenetics. RESULTS: Concentrations of CSF tau protein were increased in sCJD (5120 v 367 pg/ml in controls, p < 0.001) and vCJD (952 v 106 pg/ml, p < 0.001); tau-pT181 was also raised in sCJD (61 v 35 pg/ml in controls, p = 0.002) and vCJD (114 v 33 pg/ml, p < 0.001). Median concentrations of tau-pT181 were higher in vCJD than in sCJD (p < 0.001). The tau-pT181/tau protein ratio was lower than in controls in both sCJD (12 v 128 (p < 0.001)) and vCJD (119 v 279 (p < 0.001)). Mean tau-pT181/tau protein ratio was 10-fold higher in vCJD than in sCJD. Raised CSF tau protein had the highest efficiency for distinguishing sCJD and vCJD from controls. CONCLUSIONS: CSF tau-pT181 concentrations are raised in vCJD and are higher than in sCJD. Measurement of CSF tau-pT181/tau protein ratio does not improve the diagnostic efficiency of CSF tau protein alone for either vCJD or sCJD. The higher concentration of CSF tau-pT181 found in vCJD suggests that unexplained pathogenic factors influence the phosphorylation of tau protein in vCJD patients.     

Unilateral positive-negative myoclonus in Creutzfeldt-Jakob disease.

We report a patient with Creutzfeldt-Jakob disease who presented asymmetric myoclonus. Positive-negative myoclonus was seen only in the right extremities in association with periodic synchronous discharges (PSDs) on the electroencephalogram, although pure positive myoclonus was rarely seen in the left extremities, independently in PSDs. The duration of the silent period recorded in the right-hand muscle produced by transcranial magnetic stimulation was much longer than that in the left-hand muscle or that in normal subjects. Brain MRI diffusion-weighted images showed signal hyperintensities in the putamen and cerebral cortex, including the motor cortex, predominantly on the left side.     

Glucose metabolism in sporadic Creutzfeldt-Jakob disease: a statistical parametric mapping analysis of (18) F-FDG PET

Background and purpose: Reports describing functional neuroimaging techniques, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), in sporadic Creutzfeldt–Jakob disease (sCJD) have consistently suggested that these tools are sensitive for the identification of areas of hypoperfusion or hypometabolism, even in the early stages of sCJD. However, there are few reports on the use of [18F]fluoro‐2‐deoxy‐D‐glucose (FDG) PET in sCJD, and most of them are single case reports. Only two small cohort studies based on visual inspection or a region of interest method have been published to date. Using a statistical parametric mapping (SPM) analysis of ¹⁸F‐FDG PET, we investigated whether there are brain regions preferentially affected in sCJD. Methods: After controlling for age and gender, using SPM 2, we compared the glucose metabolism between (i) 11 patients with sCJD and 35 controls and (ii) the subset of five patients with the Heidenhain variant of sCJD and 35 controls. Results: The patients with sCJD showed decreased glucose metabolism in bilateral parietal, frontal and occipital cortices. The Heidenhain variant of sCJD showed glucose hypometabolism mainly in bilateral occipital areas. Conclusions: Glucose hypometabolism in sCJD was detected in extensive cortical regions; however, it was not found in the basal ganglia or thalamus, which are frequently reported to be affected on diffusion‐weighted images. The medial temporal area, which is possibly resistant to the prion deposits, was also less involved in sCJD.     

Serial EEG findings in sporadic and iatrogenic Creutzfeldt-Jakob disease.

OBJECTIVE: To study temporal and spatial development of EEG patterns in sporadic and iatrogenic Creutzfeldt-Jakob disease patients. METHODS: Temporal and spatial development of EEG patterns in 4 patients with sporadic Creutzfeldt-Jakob disease and 2 patients with iatrogenic Creutzfeldt-Jakob disease due to implantation of contaminated brain depth electrodes were investigated. A total of 56 EEGs were analyzed, over time spans ranging from 1272 to 3 days prior to death. RESULTS: Frontal intermittent rhythmical delta activity (FIRDA) was seen at early timepoints in 4/6 patients and might represent an early EEG pattern that is associated, with human prion diseases. EEG patterns associated with CJD are sensitive to midazolam. Initial EEG changes were seen at the site of prion exposure in iatrogenic Creutzfeldt-Jakob disease patients, before they could be observed at distant sites, suggesting that prion disease was initiated at the site of prion exposure. CONCLUSIONS: Serial EEG recordings are a valuable tool not only in the early diagnosis of sporadic CJD, but also in the determination of prion exposure in iatrogenic Creutzfeldt-Jakob disease. SIGNIFICANCE: FIRDA occur at an early stage of CJD and are progressively replaced by the classical PSWC. The EEG patterns of CJD are sensitive to midazolam. The initial EEG changes in iatrogenic CJD are seen at the site of prion exposure.     

Demyelinating peripheral neuropathy in Creutzfeldt-Jakob disease.

We describe 2 patients of Jewish Libyan descent, who presented with a clinical syndrome compatible with Creutzfeldt-Jakob disease and who were found to have a mutation of codon 200 in the prion protein. The patients developed symptoms and signs of peripheral nerve involvement diagnosed by electrodiagnostic and histopathological studies as demyelinating neuropathy. This may be a rare manifestation of Creutzfeldt-Jakob disease.     

Coexistence of movement disorders and epilepsia partialis continua as the initial signs in probable Creutzfeldt-Jakob disease.

Movement disorders and epilepsy rarely occur in the early stage of Creutzfeldt-Jakob disease (CJD) but have not been reported concurrently. We report on a 47-year-old patient with probable CJD who presented with generalized chorea and focal dystonia with myoclonic jerks on the right hand. Myoclonic jerks progressed to epilepsia partialis continua within 5 days of admission to the hospital. The diagnosis of our patient was compatible with probable CJD on the basis of clinical course, electroencephalogram, and diffusion-weighted magnetic resonance imaging findings, and presence of 14-3-3 protein in cerebrospinal fluid. To our knowledge, this is the first report of a case developing both movement disorders and epilepsia partialis continua in the early stage of the disease.     

The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression

Cohen OS, Prohovnik I, Korczyn AD, Ephraty L, Nitsan Z, Tsabari R, Appel S, Rosenmann H, Kahana E, Chapman J. The Creutzfeldt–Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression.
Acta Neurol Scand: 2011: 124: 368–374.
© 2011 John Wiley & Sons A/S. Objectives – To develop a scale sensitive for the neurological manifestations of Creutzfeldt–Jakob disease (CJD). Methods – A 26‐item CJD neurological status scale (CJD‐NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first‐degree relatives of the patients and 14 elderly patients with Parkinson’s disease (PD). Results – The mean TSS (±SD) was significantly higher in patients with CJD (13.19 ± 5.63) compared with normal controls (0.41 ± 0.78) and PD patients (9.71 ± 3.05). The mean SIS was also significantly different between the CJD (5.19 ± 1.22) and PD (2.78 ± 1.18 P ≤ 0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS > 4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3–9 months revealed a time‐dependent increase in both the TSS and the SIS reflecting the scale’s ability to track disease progression. Conclusions – The CJD‐NS scale is sensitive to neurological signs and their progression in CJD patients.     

Striatal [123I] FP-CIT SPECT demonstrates dopaminergic deficit in a sporadic case of Creutzfeldt-Jakob disease

Background – The frequent occurrence of movement disorders such as myoclonus, parkinsonism and dystonia, strongly suggests an involvement of the dopaminergic system in sporadic Creutzfeldt‐Jakob disease (sCJD), but this issue has not been specifically addressed yet. Methods – We report a patient who after a sub‐acute focal clinical onset, developed the full clinical picture of probable sCJD. Given the early unilateral right extrapyramidal rigidity, the patient was assessed by single‐photon emission computed tomography of the dopamine transporter (DAT) using [123I] FP‐CIT. Results – DAT‐scan demonstrated reduced values of presynaptic receptorial trace in the putamen, particularly on the left side, consistent with functional putaminal dopaminergic presynaptic alteration. Conclusions – The present observation emphasizes the possible role of DAT imaging studies in the investigation of the pathogenesis of movement disorders in CJD.     

Creutzfeldt-Jakob disease in a patient with a cadaveric dural graft

We report a 26-year-old woman with Creutzfeldt-Jakob disease (CJD) who had received cadaveric dural material 33 months before the onset of neurologic symptoms. This is the fourth case in which a dural graft was the putative source of the CJD agent. All four cases had the grafting before changes in the sterilization procedure adopted in 1987 to inactivate the CJD agent.     

Elevation of neuron-specific enolase in serum and cerebrospinal fluid of early stage Creutzfeldt-Jakob disease

OBJECTIVE: To investigate the levels of neuron-specific enolase (NSE) in serum and cerebrospinal fluid (CSF) of patients with early stage Creutzfeldt-Jakob disease (CJD). METHODS: The levels of NSE in serum and CSF were examined in 6 cases with CJD patients. The levels of NSE in CSF were measured in 8 age matched control patients with other neurological diseases and the levels of serum NSE were also measured in another 8 age matched control patients with other neurological diseases. The groups of 8 age matched control patients consisted of 1 same patient and 7 different patients in the 2 control groups both for serum and CSF. RESULTS: The level of serum NSE in CJD (17.3 +/- 7.0 ng/ml, mean +/- SD) was significantly higher than that of controls (6.5 +/- 1.6) (P < 0.02) as was the case in CSF (79.3 +/- 53.3 ng/ml) vs (9.6 +/- 2.9) (P < 0.03). CONCLUSION: Although mean NSE levels of CJD were higher in CSF than in the serum, there still is a case with higher serum NSE level than CSF. These results suggest that the mechanism of elevation of serum NSE may not be a simple leakage from CSF, and that the measurement of serum NSE level may be useful for diagnosis of early stage CJD.     

Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes

B. A. Faucheux, E. Morain, V. Diouron, J.‐P. Brandel, D. Salomon, V. Sazdovitch, N. Privat, J.‐L. Laplanche, J.‐J. Hauw and S. Haïk (2011) Neuropathology and Applied Neurobiology 37, 500–512 Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrP^Sc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrP^Sc deposits common to the various molecular subtypes Aims: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease‐related prion protein (PrP^Sc) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP^Sc deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt–Jakob disease (sCJD; n = 100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP^Sc molecular types. Methods: The numerical density of neurones was estimated with a computer‐assisted image analysis system and the accumulation of PrP^Sc deposits was scored. Results: The scores of PrP^Sc immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts – the higher the score the higher the neuronal loss – in all sCJD subtypes. Large 5‐ to 50‐µm‐wide deposits (focal type) were found in sCJD‐MV2 and sCJD‐VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5‐ to 50‐µm‐wide deposits observed in sCJD‐MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD‐VV2 subtype. Conclusions: These results support a putative pathogenic role for small PrP^Sc deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP^Sc type‐2 large deposits is consistent with a possible ‘protective’ role of aggregated deposits in both sCJD‐MV2 and sCJD‐VV2 subtypes.     

The association of neuroleptic sensitivity in Lewy body disease with a false positive clinical diagnosis of Creutzfeldt-Jakob disease

BACKGROUND: Dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) share clinical features like cognitive decline, motor disturbances en psychiatric symptoms. Overlapping symptoms may cause physicians to mistake DLB for CJD. METHODS: Clinical data of 12 patients with autopsy-confirmed DLB who had been clinically suspected to suffer from CJD were analysed to investigate possible clinical features which led to misdiagnosis. RESULTS: There was an association in time between administering neuroleptics and rapid clinical deterioration in 8 out of 9 patients. CONCLUSION: It is suggested that the neuroleptic sensitivity in LBD fuelled the misdiagnosis of CJD in the presented series. Diagnostic confusion between CJD and DLB may have important clinical consequences and may lead to treatment restrictions.     

Iatrogenic Creutzfeldt—Jakob disease in three growth hormone recipients: a neuropathological study

Since 1985, several cases of Creutzfeldt–Jakob disease, occurring after a treatment by human cadaveric hormone have been reported. Three new iatrogenic cases observed in French patients (two children and one young adult) are described here. Neuropathological study displayed the classical aspects of previously reported sporadic cases of Creutzfeldt–Jakob disease in adults, including severe cortical spongiform change with numerous vacuoles within neuronal dendrites, diffuse astrogliosis and neuronal loss. In addition, the iatrogenic cases described here included two more unusual points: (i) they were homozygotic for the PrP gene on codon 129 and therefore a genetic predisposition could be suspected; (ii) numerous kuru plaques were scattered in the cerebral cortex, the subcortical white matter and in the cerebellar cortex. They were decorated with a PrP monoclonal antibody, but not with a βA₄ antibody. This last point underlines the similarities between iatrogenic Creutzfeldt–Jakob disease and kuru.     

The coexistence of Alzheimer's disease and Creutzfeldt-Jakob disease in a patient with dementia of long duration

Summary We report here a 75-year-old-male with a slowly progressive dementia of 5-year duration along with a rapid exacerbation of symptoms in the terminal 3 months. Neuropathological examinations revealed findings consistent with conspicuous Alzheimer's disease and mild Creutzfeldt-Jakob disease (CJD). The plaque amyloid was exclusively composed of -protein. The immunohistochemistry of prion protein using hydrolytic autoclaving pretreatment showed diffuse gray matter stainings in the sections of both the cerebral and cerebellar cortices. This method was thus considered useful in confirming the diagnosis of CJD for this case.     

Mirror movements and involuntary homolateral limb synkinesis in a patient with probable Creutzfeldt–Jakob disease

We report a 63-year-old man, who was diagnosed with probable Creutzfeldt–Jakob disease, manifested by rapid progressive cognitive decline, gait disturbance, right focal hand dystonia, myoclonus, mirror movements, and involuntary homolateral limb synkinesis during alternating limb movements. Although the exact pathophysiology for contralateral and homolateral limb synkinesis is not known, dysfunction of the secondary motor areas and dorsal premotor cortex by spongiform degeneration of gray matter may cause these abnormalities.     

Leptomeningeal melanoma and Creutzfeldt–Jakob disease in a patient with chronic lymphocytic leukaemia

A 78-year-old woman with known chronic lymphocytic leukaemia (CLL) was admitted to a psychiatric unit because of rapidly declining cognitive function. Clinical examination also revealed cerebellar signs and she later became akinetic and mute. She deteriorated and died of bronchopneumonia. The histology from the post-mortem confirmed the presence of CLL in the lymph nodes and she was also found to have diffuse leptomeningeal melanoma. In addition, there was extensive prion protein deposition in the cerebral cortex, but without significant spongiosis. The astrocytosis that was present appeared superficial only. Furthermore, prion protein appeared to be co-expressed with betaA4 in the form of plaques. The patient therefore had evidence of sporadic Creutzfeldt-Jakob disease (CJD) in addition to meningeal melanoma and CLL. This case further illustrates the importance of employing prion protein immunohistochemistry in suspected cases of CJD, especially where the histology is atypical.     

Electron microsocopy of brain amyloid plaques from a patient with new variant Creutzfeldt-Jakob disease

Cerebral cortex biopsy from a patient with new variant Creutzfeldt-Jakob disease (nvCJD) has been examined at the electron microscope level. Spongiform changes corresponded mostly to distended neurites scattered in the neuropil or surrounding amyloid plaques. These latter exhibited heterogeneous submicroscopic morphology including variable amount of loosely interwoven amyloid fibrils admixed in a cellular-rich environment constituted essentially by abnormal neuronal processes. By immunoelectron microscopy, fibrils and some membrane structures reacted with anti-prion protein (PrP) antibodies. One striking aspect was the presence of many small dystrophic neurites without paired helical filaments. Moreover, amyloid fibrils showed unexpected intimate association with abnormal membranes, suggesting a relationship between PrP fibrillogenesis and membrane alteration. These ultrastructural findings provide an additional criterion to distinguish nvCJD- from sporadic CJD-type plaques and reinforce the hypothesis that nvCJD brain is infected by a distinctive strain of the transmissible agent encephalopathy. Received: 7 June 1999 / Accepted: 21 September 1999     

Neurosurgery in a patient with Creutzfeldt-Jakob disease after pituitary derived growth hormone therapy in childhood.

The case of a young man who had previously received pituitary derived growth hormone for treatment of radiation induced growth hormone deficiency is reported. He underwent neurosurgery for presumed recurrence of a posterior fossa tumour but was subsequently shown to have Creutzfeldt-Jakob disease, confirmed on necropsy. The risk of transmission of Creutzfeldt-Jakob disease by neurosurgical instruments is discussed. Since the occurrence of this case the Department of Health have issued guidelines concerning neurosurgery and ophthalmic surgery in patients who have previously received treatment with pituitary derived growth hormone and may therefore be at risk of developing Creutzfeldt-Jakob disease. Surgical instruments used on such patients should under no circumstances be reused, and should be destroyed after use.