Adam Martersteck

A novel frontal pathway underlies verbal fluency in primary progressive aphasia

The frontal aslant tract is a direct pathway connecting Brocas region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.

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.

Asymmetry of cortical decline in subtypes of primary progressive aphasia

Objective: The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials. Methods: Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes. Whole-brain vertex-wise and ROI imaging analysis were conducted using the FreeSurfer longitudinal pipeline. Results: Clinical deficits and cortical atrophy patterns showed distinct patterns of change among the subtypes over 2 years. Results confirmed that progression for each of the 3 subtypes showed left greater than right hemisphere asymmetry. An ROI analysis also revealed that progression was greater within, rather than outside, the language network. Conclusions: Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA.

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.

Aphasic variant of Alzheimer disease Clinical, anatomic, and genetic features

Objective: To identify features of primary progressive aphasia (PPA) associated with Alzheimer disease (AD) neuropathology. A related objective was to determine whether logopenic PPA is a clinical marker for AD. Methods: A total of 139 prospectively enrolled participants with a root diagnosis of PPA constituted the reference set. Those with autopsy or biomarker evidence of AD, and who had been evaluated at mild disease stages (Aphasia Quotient ≥85), were included (n = 19). All had quantitative language testing and APOE genotyping. Fifteen had MRI morphometry. Results: Impaired word-finding was the universal presenting complaint in the aphasic AD group. PPA clinical subtype was logopenic (n = 13) and agrammatic (n = 6). Fluency, repetition, naming, and grammaticality ranged from preserved to severely impaired. All had relative preservation of word comprehension. Eight of the 15 aphasic participants with AD showed no appreciable cortical atrophy at the individual level on MRI. As a group, atrophy was asymmetrically concentrated in the left perisylvian cortex. APOE ε4 frequency was not elevated. Conclusions: There is a close, but not obligatory, association between logopenic PPA and AD. No language measure, with the possible exception of word comprehension, can confirm or exclude AD in PPA. Biomarkers are therefore essential for diagnosis. Asymmetry of cortical atrophy and normal APOE ε4 prevalence constitute deviations from typical AD. These and additional neuropathologic features suggest that AD has biological subtypes, one of which causes PPA. Better appreciation of this fact should promote the inclusion of individuals with PPA and positive AD biomarkers into relevant clinical trials.

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.

Frontotemporal networks and behavioral symptoms in primary progressive aphasia

Objective: To determine if behavioral symptoms in patients with primary progressive aphasia (PPA) were associated with degeneration of a ventral frontotemporal network. Methods: We used diffusion tensor imaging tractography to quantify abnormalities of the uncinate fasciculus that connects the anterior temporal lobe and the ventrolateral frontal cortex. Two additional ventral tracts were studied: the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus. We also measured cortical thickness of anterior temporal and orbitofrontal regions interconnected by these tracts. Thirty-three patients with PPA and 26 healthy controls were recruited. Results: In keeping with the PPA diagnosis, behavioral symptoms were distinctly less prominent than the language deficits. Although all 3 tracts had structural pathology as determined by tractography, significant correlations with scores on the Frontal Behavioral Inventory were found only for the uncinate fasciculus. Cortical atrophy of the orbitofrontal and anterior temporal lobe cortex was also correlated with these scores. Conclusions: Our findings indicate that damage to a frontotemporal network mediated by the uncinate fasciculus may underlie the emergence of behavioral symptoms in patients with PPA.

Is in vivo amyloid distribution asymmetric in primary progressive aphasia

We aimed to determine whether 18F‐florbetapir amyloid positron emission tomography imaging shows a clinically concordant, left‐hemisphere–dominant pattern of deposition in primary progressive aphasia (PPA). Elevated cortical amyloid (Aβ+) was found in 19 of 32 PPA patients. Hemispheric laterality of amyloid burden was compared between Aβ+ PPA and an Aβ+ amnestic dementia groups (n = 22). The parietal region showed significantly greater left lateralized amyloid uptake in the PPA group than the amnestic group (p < 0.007), consistent with the left lateralized pattern of neurodegeneration in PPA. These results suggest that the cortical distribution of amyloid may have a greater clinical concordance than previously reported. ANN NEUROL 2016;79:496–501

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials

Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures.

Caudate volume change in primary progressive aphasia with motor speech symptoms

magnetic resonance imaging (fMRI) to assess the PFC-involved neural connections. Results:As expected, we found greater IIVRT in the MCI group compared to HCs. In the MCI group, IIVRT was positively correlated with the degree of connectivity in the fronto-basal ganglia circuit, and negatively correlated with the ECN in the right hemisphere. Conversely, IIVRT was negatively correlated with connectivity in fronto-basal ganglia circuit, and had no correlation with the ECN in the HC group. Conclusions: The altered relationship between IIVRT and two PFC-involved neural connections in MCI may indicate an early marker of the neurodegenerative process, though further work determining the causal link is needed.