Search

Objective:To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard.Methods:Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria.Results:Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging.Conclusions:This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement.Classification of evidence:This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.

Objective: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia. Methods: Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N -acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia. Results: Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (β-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia. Conclusions: Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

Objective: To investigate whether an increasing load of β-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). Methods: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer β-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using α-synuclein immunostaining for Lewy body identification. β-Amyloid immunostaining was used for quantifying β-amyloid deposits. The Consortium to Establish a Registry for Alzheimer9s Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. Results: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution ( p p = 0.035), but not with the number of β-amyloid plaque deposits. Conclusions: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while β-amyloid load has no effect.

Professor Abe raises the important issue of the involvement of Lewy body disease in the substantia nigra (SN) when making the diagnosis of dementia with Lewy bodies (DLB). It has long been known that, even later on in their illness, about 25% of patients with DLB do not show features of parkinsonism. This is recognized in the consensus criteria for DLB, which do not require parkinsonism for diagnosis. Patients with DLB can have normal dopaminergic imaging because, as with our 3 patients who also had no parkinsonism,1 there is no significant involvement of the SN by Lewy body disease.

Hippocampal sclerosis (HS) is defined as severe gliosis and neuronal loss in the CA1 region of the hippocampus and in the subiculum, with a wide range of severity and distribution.1,2 Its prevalence in autopsy series of demented elderly individuals ranged from 0.4 to 26%2,3 and was 7.4% in an autopsy cohort of prospectively evaluated demented elderly subjects,4 whereas it is extremely rare in nondemented patients considered the “oldest old.” In a recent series of 528 consecutive autopsies from the University of California at Los Angeles, 34 subjects (6.4%) with and without dementia—9.9% of demented and 3% of nondemented ones—showed HS. It was observed in Alzheimer disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD), and Creutzfeldt–Jakob disease.5 Age at death was greater in demented subjects with than in those without HS (81.8 ± 12.5 vs …