Age and Ageing Advance Access originally published online on May 5, 2008
Age and Ageing 2008 37(4):467-469; doi:10.1093/ageing/afn094
Rapidly progressive Alzheimer's disease and elevated 14-3-3 proteins in cerebrospinal fluid
SIR—A 74-year-old Scottish male was admitted to a university hospital after being found on the floor of his home, following a 5-week history of vomiting, difficulty preparing meals, weight loss, loss of interest in hobbies, decreased mobility, impaired driving skills and myoclonus. His family and friends were adamant that his cognition and function were normal until 5 weeks earlier. His past medical history included hypertension, hypercholesterolaemia and Meniere's disease. He had no known family history of any disease. He emigrated to Australia over 40 years ago, but revisited the United Kingdom on several occasions. He lived alone, and until 7 years previously had consumed 150 g of alcohol per day. The duration of heavy alcohol consumption and the reasons for cessation were unknown.On review, he was disorientated to time and place and had poor concentration. He scored 18/30 in the Mini-Mental State Examination of Folstein, with deficits primarily in orientation, recall and visuo-spatial tasks. Physical examination found myoclonus but no other neurological signs. He had no stigmata of chronic liver disease. He was mildly dehydrated (urea 6.5 mmol/l [3.0–8.5], creatinine 134 µmol/l [60–120], 3.8 and 80, respectively, after rehydration). Routine investigations were otherwise normal and he was free of infection.
During his admission, multiple tonic clonic seizures were treated with carbamazepine. Serial electroencephalographs (EEGs) showed changes consistent with an encephalopathy but without epileptiform patterns. Though not fulfilling the objective diagnostic criteria for sporadic Creutzfeldt-Jakob disease proposed by Steinhoff [1], one of six EEGs showed periodic sharp wave complexes. All six EEGs showed increased delta wave activity. Two cerebral magnetic resonance imaging (MRI) scans 1 month apart showed moderate generalised atrophy, and scattered hyper-intense signals on FLAIR and T2 images. Cerebrospinal fluid collected 9 days after the last seizure was positive for 14-3-3 proteins. Other investigations for rapidly progressive dementia, including those for neoplastic disease (thoracic and abdominal CT, and tumour markers) and vasculitis (erythrocyte sedimentation rate [ESR], DNA-binding, antibodies to extractable nuclear antigens [ENA] and anti-neutrophil cytoplasmic antibodies [ANCA]) were negative. A positive antinuclear antibody (ANA) at a titre of 1:160 was considered to be non-specific [0002] and unrelated to his neurological disease. Despite treatment for a nosocomial urinary tract infection and seizures, his cognition and function continued to decline rapidly, and he was discharged to residential care. Sporadic Creutzfeldt-Jakob disease was thought to be the most likely explanation for his rapidly progressive mental deterioration and myoclonus.
He was readmitted to hospital 8 days later with vomiting associated with urinary tract infection and pneumonia. His myoclonus had worsened and was now easily provoked by startle. He was given antibiotics and standard supportive care, but continued to deteriorate rapidly, dying 28 days after re-presentation to hospital, and 4.5 months after the onset of his neurological illness. Post-mortem examination showed histological features of Alzheimer's disease (Braak neocortical stage 5–6) [3], with neuritic plaques and neurofibrillary tangles in the frontal, parietal and temporal lobes (Figure 1). An old microinfarct was seen in the right putamen. There were no features of spongiform encephalopathy, and prion protein immunohistochemistry was not undertaken.
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Discussion
The 14-3-3 proteins are a family of regulatory molecules expressed in all eukaryotic cells, but which are found in large quantities in cerebral tissue, predominantly within the cytoplasm of neurones [4]. By binding to, and modulating the function of a wide array of cellular proteins, the 14-3-3 proteins participate in many biological processes, including mitogenic signal transduction, cell cycle control and apoptotic cell death [5]. Whilst the detection of 14-3-3 proteins in cerebrospinal fluid has been shown to assist in the diagnosis of Creutzfeldt-Jakob disease (sensitivity 94% and specificity 84% for a clinical diagnosis) [6], the presence of 14-3-3 proteins in cerebrospinal fluid also occurs in many other diseases that cause acute or sub-acute neuronal damage, including Alzheimer's disease, stroke, cerebral vasculitis, infectious and paraneoplastic encephalitis, anoxic and metabolic encephalopathy and Creutzfeldt-Jakob disease [4, 7, 8].
Very few tests predict the progression and severity of neurodegenerative diseases. Though levels may vary with the stage of the illness and the sub-type, limited evidence in Creutzfeldt-Jakob disease suggests that the presence of 14-3-3 proteins in the cerebrospinal fluid indicates more rapid disease progression [9]. Such evidence in Alzheimer's disease has been scant. Patients with rapidly progressive Alzheimer's disease and positive cerebrospinal 14-3-3 proteins have been reported, though rarely. Reinwald [10] described a patient with rapidly progressive dementia, cerebellar symptoms, visual disturbances and akinetic mutism, who died in a nursing home 40 days after the first symptoms had been noticed. Huang [4] described another patient who died within 12 months of disease onset. Few other authors report an association between the presence of 14-3-3 proteins, or their concentration in the cerebrospinal fluid, with rapid illness progression. Whilst available treatments for early Alzheimer's disease are few and offer only limited symptomatic benefits, many disease-modifying treatments are in early stages of development [11]. Multimodal therapies, targeting í-amyloid, tau, inflammation and cognitive symptoms, may prove to be more efficacious than monotherapy. However, as these are more likely to cause adverse effects, they may not be acceptable to many patients during the earliest stages of the disease. On the other hand, the availability of an early predictor for rapid disease progression may mean those positive would be willing to accept aggressive treatments and concomitant side-effects.
This case demonstrates that Alzheimer's disease can progress extremely rapidly, with seizures and myoclonus as early manifestations. The presence of 14-3-3 proteins in the cerebrospinal fluid may suggest rapid disease progression. However, other neurological diseases associated with extensive neurological damage and 14-3-3 proteins in the cerebrospinal fluid should always be considered, and excluded with a detailed history and physical examination, together with appropriate investigations and imaging.
- In some cases of Alzheimer's disease, the progression of dementia can be extremely rapid.
- The presence of 14-3-3 proteins in the cerebrospinal fluid occurs in many diseases that cause acute or sub-acute neurological damage.
- Further research is needed on the association between rapidly progressive dementias and positive 14-3-3 proteins.
None
Liverpool Hospital—Geriatric Medicine, Locked Mailbag 7103, Liverpool BC, Sydney, New South Wales 1871, Australia
* To whom correspondence should be addressed E-mail: david.basic{at}swsahs.nsw.gov.au
References
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- Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum (1997) 40:1601–11.[Web of Science][Medline]
- Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (1991) 82:239–59.[CrossRef][Medline]
- Huang N, Marie SK, Livramento JA, et al. 14-3-3 protein in the CSF of patients with rapidly progressive dementia. Neurology (2003) 61:354–7.
[Abstract/Free Full Text] - Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol (2000) 40:617–47.[CrossRef][Web of Science][Medline]
- Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology (2000) 55:811–5.
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[Abstract/Free Full Text] - Castellani RJ, Colucci M, Xie Z, et al. Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease. Neurology (2004) 63:436–42.
[Abstract/Free Full Text] - Reinwald S, Westner IM, Niedermaier N. Rapidly progressive Alzheimer's disease mimicking Creutzfeldt-Jakob disease. J Neurol (2004) 251:1020–2.[Web of Science][Medline]
- Golde TE. Disease modifying therapy for AD. J Neurochem (2006) 99:689–707.[CrossRef][Web of Science][Medline]
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