The featured paper is ‘Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly’ by Aizenstein and colleagues which is freely available here.
The authors begin by looking at ‘amyloid burden’ in the elderly estimating that Amyloid deposition was present in over 50% people over the age of 65 although the criteria for Amyloid deposition were not stated. This paper looks at the Pittsburgh Compound B which binds to amyloid-Beta (ABeta) deposits and examines the relationship with cognition in the elderly. Furthermore the authors hypothesise that correlating neuropsychological function in different brain regions should be impaired if there is a significant Amyloid burden in those areas. The authors look briefly at the literature in this regards and note that much of the results are dependent upon post-mortem examination and although neuropsychological measures were available the sampled populations were necessarily biased towards those with more severe illness. The authors also identify some studies looking at PIB retention and cognitive impairment with equivocal results. They state a number of aims including identification of prevalence of amyloid deposition in clinically unimpaired elderly people as well as the relationship between PiB retention and cognition.
There were three groups of subjects within the study – one group being recruited from adverts, one from a prior study on cognition in aging (however this means that the details of recruitment are described elsewhere) and the third through the University of Pittsburgh Alzheimer Disease Research Center. There were a number of exclusion criteria for this study. For instance, participants should not have experienced major psychiatric or neurological illness during their lifetime and thus the participants are not necessarily representative of the general population. For diagnostic purposes, a battery of neuropsychological tests were administered including the MMSE, immediate and delayed recall, letter and cognitive fluency and NINDS-ADRDA/DSM-IV criteria were used to identify dementia. A number of other tests were used to assess cognition including the Wechsler Test of Adult Reading, a task constructed to assess processing speed, working memory tasks including the N-back and inhibition tasks including the Hayling test.
The PiB testing was performed within 4 months of cognitive testing and utilised an ECAT HR+ scanner. PiB was injected i.v and PET scanning performed over 90 minutes. A coregistered MRI was used to look at Regions of Interest but the authors state that the technique is described in another paper. The uptake of PiB in different regions was measured in relation to the uptake in the Cerebellum (although the reason for choosing the cerebellum was not stated). They next looked at regions which typically show amyloid deposition and excluded outliers based on comparison with ’62 clinically unimpaired’ control subjects. However according to the introduction to this paper there is an equivocal relationship between cognitive impairment and PiB uptake in a number of studies which can be used as an argument against this approach. By using this approach however, they obtained a more homogenous group of subjects with regards to the PiB uptake in regions of interest relative to the Cerebellum and who were considered to be ‘unlikely to be amyloid-positive’. They used voxelwise comparisons for the 1.5T MR images and normalised to the Montreal Neurological Institute template. An arithemetic mean was used for the voxels in the PiB images to arrive at an approximation to the concentration of binding sites relative to the cerebellum and transformations were applied to the data (smoothing and scaling). This data was then applied to the first two groups described in the methodology section above.
There were 43 subjects, mean age 74 years with a mean of 15 years of education and mean MMSE score of 28.4. Using a scatterplot they were able to identify a clear distinction between AD subjects and controls. Threshold were stipulated for Amyloid Positive and Negative subjects and using these cut-offs they identified 21% of the 43 elderly subjects as Amyloid positive. A younger group with a small number (n=8) were all Amyloid negative although given the small number of subjects this finding needs further replication. On examination of the patterns of PiB retention, both those with AD and the cognitively unimpaired group who were amyloid positive showed a uptake in the frontal, ACG, PRC and temporoparietal regions.
The authors concluded that AD and non-AD subjects could be distinguished by visual inspection of the PiB images. They also identifeda dichotomous pattern in the MCI group with 30-40% being PiB negative and the remainder having an AD like pattern of uptake. They conclude that ‘amyloid deposition can be detected at an asymptomatic stage’.
This is an encouraging study that shows the utility of PiB uptake but uses a sample population who are relatively healthy for their age. Similarly larger studies would be expected to produce more robust findings. There were a number of points in which the methodlogy was described more fully elsewhere and thus the paper does not stand entirely on its own and the interested reader must go further afield to clairfy the methodology. Nevertheless it will be interesting to see larger replication studies and this method will compliment other approaches to investigating AD and MCI.
STT 3 (Replication needed, policy, diagnosis)
Steps To Treatment (STT)
STT = Steps To Treatment. An estimate of the number of steps between the results and translation into practice i.e. treatment. This is an opinion. A policy statement would have a value of 1 as this a guide for practice whereas a speculative model would get a much higher score as there are more steps between statement of the model and treatment (which would involve testing the model, informing treatment approaches and trialling these approaches for instance).
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