Tamar Gefen

Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia

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 Alzheimers disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimers 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.

Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity

This human study is based on an established cohort of “SuperAgers,” 80+-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20–30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50- to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80+ year olds (n = 21) than in the healthy middle-aged group (n = 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n = 31) compared with cognitively average 80+ year olds and also to the much younger healthy 50–60 year olds (p < 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p < 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p < 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age.

Youthful memory capacity in old brains: Anatomic and genetic clues from the northwestern superaging project

The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ɛ4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.

Naming vs knowing faces in primary progressive aphasia A tale of 2 hemispheres

Objectives: This study examines the anatomical correlates of naming vs recognizing faces using a novel measure that utilizes culturally relevant and age-appropriate items, the Northwestern University Famous Faces (NUFFACE) Test, in primary progressive aphasia (PPA), a syndrome characterized by progressive language deficits and associated with cortical atrophy in areas important for word and object representations. Methods: NUFFACE Test performance of 27 controls (mean age 62.3 years) was compared with that of 30 patients with PPA (mean age 62 years). Associations between NUFFACE Test performance and cortical thickness measures were quantified within the PPA group. Results: Patients with PPA displayed significant impairment on the NUFFACE Test, demonstrating that it is a useful measure of famous-face identification for individuals with relatively young-onset dementias. Despite widespread distribution of atrophy in the PPA group, face naming impairments were correlated with atrophy of the left anterior temporal lobe while face recognition impairments were correlated with bitemporal atrophy. Conclusions: In addition to their clinical relevance for highlighting the distinction between face naming and recognition impairments in individuals with young-onset dementia, these findings add new insights into the dissociable clinico-anatomical substrates of lexical retrieval and object knowledge.

Longitudinal Neuropsychological Performance of Cognitive SuperAgers

To the Editor: If 80+ year-old healthy individuals are asked to memorize a list of words, the mean performance is expected to be substantially lower than the mean performance of healthy individuals who are 50–60 years old1. This effect has been repeatedly detected innumerous cross-sectional and longitudinal investigations (for a review see2) and is thought to reflect a fundamental age-related decline of memory capacity. Are all individuals prone to this aging effect? Are there some who are likely to have avoided it? If so, what are the factors that contribute to their resilience? These are the questions addressed by the Northwestern University SuperAging Study. The first step was to identify a subset of individuals at or above the age of 80 who are most likely to have avoided age-related involutional changes of memory. To this end, we recruited healthy seniors 80 years and older whose performance on the delayed recall portion of the Rey Auditory Verbal Learning Test (RAVLT Delay) was at or above the average normative values for individuals in the 56–66 year range1. We further required performance on non-memory tasks such as the 30-item Boston Naming Test (BNT-30), the Trail-Making Test Part B (TMT Part B), and Category Fluency (“Animals”) to be within or above one standard deviation of the average range for 80 year-olds according to published age-and-demographically-adjusted norms3–5. We designated these carefully selected individuals as “SuperAgers”. Initial investigations showed that SuperAgers have distinct genetic, anatomic, and histopathologic markers 6. In specific, they did not show the common pattern of age-related atrophy in the cerebral cortex, they had a lower frequency of the e4 allele of apolipoprotein E and their brains showed fewer markers of Alzheimer pathology6, 7. In this letter, we report preliminary longitudinal neuropsychological performance of 18 community-dwelling SuperAgers (mean age 82.2±2.4 years) at baseline and at 18-month follow-up. The purpose was to determine whether the performance parameters that qualified them as SuperAgers could be maintained during this relatively short interval. Paired t-tests were used to determine stability of longitudinal cognitive performance on a comprehensive neuropsychological battery of tests administered. On average, SuperAgers did not show significant decline on any neuropsychological measure of memory, attention, language, or executive function from baseline to 18-months (p>0.05 for each test, see Figure 1 for individual performance on each test), suggesting they maintained as a group stable cognitive performance in both memory and non-memory domains. Figure 1 Individual neuropsychological performance scores for all measures are shown at baseline and at 18-month follow-up. Raw scores were converted to scaled scores (ss; mean = 10; standard deviation = 3) based on normative values for individuals in their 50s ... While several studies of successful aging exist8, none have prospectively followed elderly individuals defined on the basis of the stringent criterion that we applied to SuperAgers, namely an episodic memory performance at a level that would be deemed “normal” for individuals 20–30 years younger. Two possibilities need to be considered. One is that SuperAgers were at a much higher level of performance when 50–60 years old and that the current scores are compatible with customary age-related declines. The second, and more interesting possibility, is that SuperAgers are resistant to age-related cognitive decline. Our findings provide initial support for the second possibility, suggesting that SuperAgers may represent a different and unusually benign trajectory of cognitive aging. Confirmation of this possibility will be based on showing stability over longer periods of time, and especially on the demonstration that rate of change in cognition is slower than what is seen in cognitively average individuals of the same age.

Variations in Acetylcholinesterase Activity within Human Cortical Pyramidal Neurons Across Age and Cognitive Trajectories

We described an extensive network of cortical pyramidal neurons in the human brain with abundant acetylcholinesterase (AChE) activity. Emergence of these neurons during childhood/adolescence, attainment of highest density in early adulthood, and virtual absence in other species led us to hypothesize involvement of AChE within these neurons in higher cortical functions. The current study quantified the density and staining intensity of these neurons using histochemical procedures. Few faintly stained AChE-positive cortical pyramidal neurons were observed in children/adolescents. These neurons attained their highest density and staining intensity in young adulthood. Compared with the young adult group, brains of cognitively normal elderly displayed no significant change in numerical density but a significant decrease in staining intensity of AChE-positive cortical pyramidal neurons. Brains of elderly above age 80 with unusually preserved memory performance (SuperAgers) showed significantly lower staining intensity and density of these neurons when compared with same-age peers. Conceivably, low levels of AChE activity could enhance the impact of acetylcholine on pyramidal neurons to counterbalance other involutional factors that mediate the decline of memory capacity during average aging. We cannot yet tell if elderly with superior memory capacity have constitutively low neuronal AChE levels or if this feature reflects adaptive neuroplasticity.

Cognitive trajectories and spectrum of neuropathology in SuperAgers: The first 10 cases

On average, memory capacity is significantly higher in populations of 50–60 year olds than in populations of 80 year olds. We define SuperAgers as individuals 80 or older whose episodic memory capacity is at least as good as that of cognitively average individuals in their 50s and 60s. SuperAgers therefore have memory capacity that is superior for age. Previous work showed that SuperAgers have greater cortical volumes and greater resistance to age‐related cortical atrophy than “cognitively average” individuals of the same age. Here we report on the cognitive, personality, and neuropathologic characteristics of the first 10 autopsy cases in the Northwestern SuperAging Program. During the follow‐up period, seven SuperAgers maintained episodic memory performance within or above the average range for 50–65 year‐old norms and all 10 SuperAgers maintained episodic memory scores within normal limits for their own age. Extraversion scores tended to be high on the NEO‐PI‐R measure of personality. The 10 autopsy specimens showed variable findings within the spectrum of Alzheimer pathology. The hippocampus and entorhinal cortex contained neurofibrillary degeneration mostly in the Braak II–III stages. However, even these limbic areas contained many healthy appearing neurons and the neocortex was generally free of neurofibrillary degeneration. In contrast, neocortical areas in at least five of the cases contained moderate to high densities of neuritic plaques. These findings need to be placed in context by comparing them to the neuropathology of cognitively average individuals of the same age. Future research on SuperAgers is likely to offer insights into factors that either prevent the emergence of involutional changes in the brain or that makes cognitive function more resistant to their consequences.

Cerebrospinal fluid markers detect Alzheimer's disease in nonamnestic dementia

The accuracy of cerebrospinal fluid (CSF) biomarkers for detecting Alzheimers disease (AD) pathology has not been fully validated in autopsied nonamnestic dementias.

Asymmetric TDP pathology in primary progressive aphasia with right hemisphere language dominance

Objective To quantitatively examine the regional densities and hemispheric distribution of the 43-kDa transactive response DNA-binding protein (TDP-43) inclusions, neurons, and activated microglia in a left-handed patient with right hemisphere language dominance and logopenic-variant primary progressive aphasia (PPA). Methods Phosphorylated TDP-43 inclusions, neurons, and activated microglia were visualized with immunohistochemical and histologic methods. Markers were quantified bilaterally with unbiased stereology in language- and memory-related cortical regions. Results Clinical MRI indicated cortical atrophy in the right hemisphere, mostly in the temporal lobe. Significantly higher densities of TDP-43 inclusions were present in right language-related temporal regions compared to the left or to other right hemisphere regions. The memory-related entorhinal cortex (ERC) and language regions without significant atrophy showed no asymmetry. Activated microglia displayed extensive asymmetry (R > L). A substantial density of neurons remained in all areas and showed no hemispheric asymmetry. However, perikaryal size was significantly smaller in the right hemisphere across all regions except the ERC. To demonstrate the specificity of this finding, sizes of residual neurons were measured in a right-handed case with PPA and were found to be smaller in the language-dominant left hemisphere. Conclusions The distribution of TDP-43 inclusions and microglial activation in right temporal language regions showed concordance with anatomic distribution of cortical atrophy and clinical presentation. The results revealed no direct relationship between density of TDP-43 inclusions and activated microglia. Reduced size of the remaining neurons is likely to contribute to cortical atrophy detected by MRI. These findings support the conclusion that there is no obligatory relationship between logopenic PPA and Alzheimer pathology.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia

Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimers disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD‐TDP pathology.