Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia

Abstract

Primary progressive aphasia is a neurodegenerative syndrome characterized by gradual dissolution of language but relative sparing of other cognitive domains, especially memory. It is associated with asymmetric atrophy in the language-dominant hemisphere (usually left), and differs from typical Alzheimer-type dementia where amnesia is the primary deficit. Various pathologies have been reported, including the tangles and plaques of Alzheimer's disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimer's disease typically emerge in memory-related structures such as entorhinal cortex and spread to language-related neocortex later in the disease. Furthermore, Alzheimer pathology is typically symmetric. How can a predominantly limbic and symmetric pathology cause the primary progressive aphasia phenotype, characterized by relative preservation of memory and asymmetric predilection for the language-dominant hemisphere? Initial investigations into the possibility that Alzheimer pathology displays an atypical distribution in primary progressive aphasia yielded inconclusive results. The current study was based on larger groups of patients with either primary progressive aphasia or a typical amnestic dementia. Alzheimer pathology was the principal diagnosis in all cases. The goal was to determine whether Alzheimer pathology had clinically-concordant, and hence different distributions in these two phenotypes. Stereological counts of tangles and plaques revealed greater leftward asymmetry for tangles in primary progressive aphasia but not in the amnestic Alzheimer-type dementia (P < 0.05). Five of seven aphasics had more leftward tangle asymmetry in all four neocortical regions analysed, whereas this pattern was not seen in any of the predominantly amnestic cases. One aphasic case displayed higher right-hemisphere tangle density despite greater left-hemisphere hypoperfusion and atrophy during life. Although there were more tangles in the memory-related entorhinal cortex than in language-related neocortical areas in both phenotypes (P < 0.0001), the ratio of neocortical-to-entorhinal tangles was significantly higher in the aphasic cases (P = 0.034). Additionally, overall numbers of tangles and plaques were greater in the aphasic than amnestic cases (P < 0.05), especially in neocortical areas. No significant hemispheric asymmetry was found in plaque distribution, reinforcing the conclusion that tangles have greater clinical concordance than plaques in the spectrum of Alzheimer pathologies. The presence of left-sided tangle predominance and higher neocortical-to-entorhinal tangle ratio in primary progressive aphasia establishes clinical concordance of Alzheimer pathology with the aphasic phenotype. The one case with reversed asymmetry, however, suggests that these concordant clinicopathological relationships are not universal and that individual primary progressive aphasia cases with Alzheimer pathology exist where distributions of plaques and tangles do not account for the observed phenotype.

Figure 1

Thioflavin-S staining of neurofibrillary tangles and amyloid plaques. Photomicrograph (×20) of thioflavin-S-stained sections showing examples of neurofibrillary tangles and amyloid plaques in the left inferior frontal gyrus versus the left entorhinal cortex in Case P7 (A and B), and in left versus right inferior frontal gyrus in Case P4 (C and D). Magnification bar in A is 20 μm, and applies to B–D. AP = amyloid plaque; ERC = entorhinal cortex; IFG = inferior frontal gyrus; NFT = neurofibrillary tangle.

Figure 2

Mean stereological counts of neurofibrillary tangles (NFTs) and amyloid plaques in neocortical areas in DAT/AD versus PPA/AD. Heights of the bars represent mean estimated counts of neurofibrillary tangles and amyloid plaques per cubic millimetre in left versus right hemisphere in DAT/AD and PPA/AD. (A) The asterisk represents significantly greater leftward asymmetry of neurofibrillary tangles in PPA/AD (*P < 0.05); no significant difference was detected in DAT/AD. (B) No significant differences were found between neocortical plaque density in the left versus right hemisphere in either PPA/AD or DAT/AD. LH = left hemisphere; RH = right hemisphere.

Figure 3

Concordance of atrophy with plaques and tangles in Case P7. (A) Cortical thickness map shows regional distribution of cortical thinning (i.e. atrophy) in Case P7 compared with 27 healthy controls. For each hemisphere, the top panels are lateral views, the bottom panels are medial views. Significance is displayed as a log(10) P-value; red and yellow areas designate peak atrophy sites. (B and C) Stereological counts of neurofibrillary tangles and amyloid plaques in Case P7. Heights of the bars represent quantitative estimated counts of Alzheimer’s disease pathological markers per cubic millimetre. CG = cingulate gyrus; ERC = entorhinal cortex; IFG = inferior frontal gyrus; IPL = inferior parietal lobule; LH = left hemisphere; NFTs = neurofibrillary tangles; MFG = middle frontal gyrus; PHG = parahippocampal gyrus; RH = right hemisphere; STG = superior temporal gyrus; TPJ = temporoparietal junction.

Figure 4

Neurofibrillary tangles (NFTs) in left/right neocortical regions. Ratios of neurofibrillary tangle density in individual left/right neocortical regions, as shown in Table 2, were transformed logarithmically (base 10) to illustrate relative distributional patterns of left-to-right neurofibrillary tangle pathology in DAT/AD and PPA/AD cases; the 0.0 mark represents no left/right asymmetry. Actual ratio values are indicated on the y-axis on right side. Dagger indicates left superior temporal gyrus and left inferior parietal lobule not available from Case P5. L = left; NFTs = neurofibrillary tangles; R = right.

Figure 5

Amyloid plaques in left/right neocortical regions. Ratios of amyloid plaque density in individual left/right neocortical regions, as shown in Table 2, were transformed logarithmically (base 10) to illustrate relative distributional patterns of left-to-right plaque pathology in DAT/AD and PPA/AD cases; the 0.0 mark represents no left/right asymmetry. Actual ratio values are indicated on the y-axis on right side. Dagger indicates left superior temporal gyrus and left inferior parietal lobule not available from Case P5.

Figure 6

Mean neurofibrillary tangles in neocortical/entorhinal regions. Ratios of average neurofibrillary tangle (NFT) density in neocortical regions versus entorhinal cortex, as shown in Table 2, were transformed logarithmically (base 10) to illustrate relative distributional patterns of neocortical-to-entorhinal neurofibrillary tangle pathology in DAT/AD and PPA/AD cases; the 0.0 mark represents unity of the neocortical/entorhinal ratio. Actual ratio values are indicated on the y-axis on right side. Case P7 is the only case to demonstrate a higher density of neurofibrillary tangles in each neocortical region compared with the entorhinal cortex. Note: right entorhinal cortex was not available in Cases D3, P1 and P3.