Primary Progressive Aphasia Pathology May Help Differentiate Dementia Subtypes

The researchers found that the PPA-FTLD group had normal scores on all conditions—scores that were indistinguishable from those of healthy elderly control subjects.

Alzheimer’s pathology but not pathology associated with tau-related frontotemporal lobar degeneration (FTLD) may interfere with effortless learning and retrieval of verbal information in patients with primary progressive aphasia (PPA), according to a retrospective analysis conducted by researchers affiliated with the Northwestern Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine in Chicago.1 The findings open up new avenues of research into aphasia and the interactions between limbic and language networks, according to the study authors. The findings also seem to validate the assessment tool used in the study, the ThreeWords Three Shapes (3W3S) test, to identify dementia subtypes in patients with PPA.

The primary aim of the study was to detect subtle memory differences in PPA, which is generally caused by certain forms of FTLD (eg, tau- or TAR-based) or Alzheimer disease. Episodic memory is initially spared in PPA syndrome, but the neuropathology and functions related to subtle learning and memory in PPA have not been characterized until now, according to the study authors.

The researchers compared 3W3S test performance in 7 patients who had a primary clinical diagnosis of PPA and autopsy-confirmed Alzheimer’s disease, 6 patients with a primary clinical diagnosis of PPA and an autopsy-confirmed tau variant of FTLD, and 6 patients who had a clinical diagnosis of amnestic dementia and autopsy-confirmed Alzheimer’s disease. The study subjects, whose average age at symptom on set was 64 years, had been enrollees in Alzheimer Disease Center programs, sponsored by the National Institute on Aging. Average age at which these patients were administered the 3W3S test was 68 years.

The 3W3S test measures verbal and nonverbal memory and generally relies on visual rather than language-based cues. “These features distinguish the 3W3S test from many standard memory tests, which rely heavily on the use of language and therefore may yield the erroneous impression of episodic memory deficits in cases of aphasia,” the authors remarked in their paper. John R. Hodges, MBBS, of the University of New South Wales School of Medical Sciences in Sydney, New South Wales, Australia, also expressed enthusiasm for the authors’ utilization of the 3W3S in an editorial2 that accompanied the study. He remarked that the study demonstrates that 3W3S may be a simple, inexpensive and much more accessible clinical tool for differentiating dementia subtypes antemortem than ligand-based amyloid positron emission tomographic imaging.

The 3W3S test assesses learning and memory across 5 conditions: copying (of geometric designs and words), incidental recall (effortless learning), acquisition (effortful learning), delayed recall, and recognition. Each condition involves a word and shape score that is rated on a scale of 0 to 15 points in which 15 indicates an error-free performance.

Degree of Memory and Learning Deficits Tied to Dementia Subtype

The researchers found that the PPA-FTLD group had normal scores on all conditions—scores that were indistinguishable from those of healthy elderly control subjects documented in an earlier, related study.3 On the other hand, patients with Alzheimer’s disease exhibited deficits in verbal effortless learning and verbal delayed retrieval. Among the patients with Alzheimer’s disease, greater debility was seen among patients with amnestic dementia than PPA. The average number of errors made in effortless learning was 14.2±2.0 versus 9.9 ±4.6. For verbal delayed retrieval, patients with amnestic dementia made 12.0±4.4 errors whereas patients with PPA made 6.1±5.9 errors. Also, whereas deficits in nonverbal effortless learning and verbal retention were not seen in patients with Alzheimer’s disease and PPA, they were in patients with amnestic dementia (P < .005).

The researchers conceded that their study is limited by the small sample size but that it paves the way for new avenues of aphasia and dementia research. They also declared that the findings “provide support for the 3W3S test as a practical and informative test of episodic memory in patients with dementia” and encouraged readers to avail themselves of the materials to conduct the test, available for free through the Northwestern Cognitive Neurology and Alzheimer Disease Center.


  1. Kielb S; Cook A, Wieneke C, et al. Neuropathologic associations of learning and memory in primary progressive aphasia. JAMA Neurol. May 16, 2016. [E-pub ahead of print]
  2. Hodges JR. Pathological diagnosis during life in patients with primary progressive aphasia: Seeking the holy grail. JAMA Neurol. May 16, 2016. [E-pub ahead of print]
  3. Weintraub S, Rogalski E, Shaw E, et al. Verbal and nonverbal memory in primary progressive aphasia: the ThreeWords-Three Shapes Test. Behav Neurol. 2013;26(1-2):67-76.