Ethical aspects of this study were reviewed and approved by the Hospital Human Research Ethics Committee. This study was performed after obtaining informed consent from all participants and was performed in accordance with the Declaration of Helsinki. The study participants were recruited from the Cognitive Dysfunction Clinics associated with Ashikaga Red Cross Hospital and Edogawa Hospital, during the period from June 2015 to Nov 2020. Patients with the initial stages (0.5 Clinical dementia rating 14) of posterior cortical atrophy were included. Patients with > 1 on clinical dementia rating were excluded because the aim of this study was to examine whether the tapping span test is a potential diagnostic tool for posterior cortical atrophy in its initial stages. Among 13 patients who met both the clinical and imaging-supported diagnostic criteria for posterior cortical atrophy 2, eight individuals who were in the initial stages, that is, with a clinical dementia rating of 0.5 14, were recruited. Members of a control group were also recruited, that is, age- and severity-matched individuals with amnesic Alzheimer’s disease (n = 9) from the same clinics, all of whom developed their symptoms at <70 years of age to be matched in age for those with posterior cortical atrophy and also received their first medical examination while they were in the initial stages (0.5 clinical dementia rating). All patients were evaluated by neuropsychiatrists (MF and TT), each of whom had more than 15 years of experience in neuropsychology and clinical practice for degenerative disorders at the time of the study. Regarding clinical diagnosis for the eight individuals with posterior cortical atrophy, six patients had early-onset Alzheimer’s disease, one patient had corticobasal syndrome, and the remaining one had Creutzfeldt-Jacob disease. Regarding the initial symptoms, seven patients had visuospatial dysfunction as their initial symptoms, e.g., difficulties with connecting cables, following lines of text while reading, rearranging equipment, organizing a room, or causing a traffic accident, and the remaining one patient had agraphia. At the time of the neuropsychological assessments, none of the eight individuals had paresis, sensory disturbance, homonymous hemianopsia, or cortical blindness.
Demographics and basic neuropsychological assessments
The demographic factors investigated were age, gender, level of education, and the number of years post-onset. Basic cognitive function was evaluated using the Japanese version of the MMSE 15,16 and the Hasegawa Dementia Rating Scale-Revised (HDS-R) 17. The HDS-R is most frequently used to evaluate the basic cognitive function of patients with dementia in Japan and, similar to the MMSE, includes items that assess orientation, memory, repetition, and calculation as well as backward digit span and category fluency. The maximum number of possible points attainable for the HDS-R is 30, which is also the case for the MMSE. However, there are some differences between the two tests. The HDS-R puts more emphasis on memory function than the MMSE: 11 of 30 points account for memory function in the HDS-R, whereas 3 of 30 points account for this in the MMSE. The passing cut-off point for the HDS-R is 20/21, whereas that for the MMSE is 23/24 15-17.
Visuospatial function was evaluated using the Japanese version of the Trail Making Test A (TMT-A) 18-20. In the TMT-A test, participants are instructed to connect a set of 25 numbers written on paper in numerical order by a drawn line. Performance on this test was expected to be severely impaired for patients with posterior cortical atrophy owing to their visuospatial dysfunction 18. The time limit for the TMT-A was set at 300 sec. If the subject had not completed the test in this time, the trial was terminated, and a value of 300 sec was used for statistical analysis. For patients with posterior cortical atrophy, visuospatial and linguistic functions were compared using perceptual organization and verbal comprehension scores in the Japanese version of the Wechsler Adult Intelligence Scale – third edition, which reflect visuospatial function and linguistic function, respectively 21,22. The lowest computable score for the perceptual organization was 50. If the subject’s scale had not reached this score, a value of 50 was used for statistical analysis.
Tapping span test
The Tapping Span subtest from the Clinical Assessment for Attention 23 was administered. The Clinical Assessment for Attention is a validated, reliable, and standardized test that has been widely used to assess attention function in Japan for more than a decade. The configuration of the Tapping Span subtest is the same as that of Spatial Span Tapping Test in the Wechsler Memory Scale 12 with a slight difference in positions of probes on the cardboard. This Tapping Span subtest consists of a piece of cardboard with nine spatially distributed probes, each consisting of a square that is 2 cm wide. Two conditions were included in this subtest, i.e., Tapping Span Forward and Tapping Span Backward. The examiner taps sequences of probes of increasing length that have to be repeated in the same (forward) or reverse (backward) order by tapping them. Both conditions have two trials for each length of tapping sequence. If a participant is able to repeat either of the two trials for a tapping sequence of a certain length, he or she is regarded as having passed for that length, e.g., a tapping sequence of three probes. These methods for tapping span tests are also used in Corsi Block-Tapping Task 24. Regarding method of scoring, the maximum length of the tapping sequence that an individual can repeat is presented as the result of the tapping span test, which differs from that of Spatial Span Tapping Test in Wechsler Memory Scale 12, the result of which is the number of total correct answers in the individual span test. The reason why we employed the Tapping Span subtest from the Clinical Assessment for Attention is that it is simpler and less complicated in clinical settings to use the maximum length of the tapping sequence than the number of total correct answers for the result of the tapping span test.
Digit Span test
To assess phonological working memory along with visuospatial working memory, the Digit Span Forward and Digit Span Backward tests from the Clinical Assessment for Attention 23 were evaluated, the methods of which were quite similar to those used in the Wechsler Memory Scale 12. In the forward condition, sequences of digits of increasing length have to be repeated verbally in the same order in which they were previously read aloud by the examiner. In the backward condition, the digit sequences have to be repeated in reverse order. In this task, both conditions have two trials for each length of digit sequences, e.g., 3-5-2 and 9-4-7 for sequences of three digits in the forward digit span test. If a participant is able to repeat either of the two trials for a digit sequence of a certain length, he or she is regarded as having passed for that length. The maximum length of a digit sequence that the individual repeats is considered the result of the digit span test. This scoring method is also different from that of Spatial Span Tapping Test in Wechsler Memory Scale 12, the result of which is the number of total correct answers in the individual span test. The reason why we employed these subtests from the Clinical Assessment for Attention for digit span test is the same as the one for the tapping span test.
To compare the results of these two kinds of span tests, the subtraction of digit span from tapping span data was carried out for all participants.
Visuospatial working memory test
The tapping span score has been considered to reflect visuospatial working function 24. However, caution should be exercised when interpreting a tapping span score in terms of the visuospatial working memory when this test is applied to individuals with visuospatial dysfunction. An individual with severe visuospatial dysfunction is frequently considered to have Bálint syndrome, which includes psychic paralysis of gaze, optic ataxia, and dorsal simultanagnosia (an inability to perceive several items in a visual scene at the same time 25,26. Optic ataxia, which indicates a difficulty in accurately reaching for an object under visual guidance despite having the normal limb strength required to do so, interferes with tapping span measurements because an individual with optic ataxia is unable to reach a probe with his or her hand even if they observe it visually. Considering the potential presence of optic ataxia, a test that requires no upper limb movement is preferable when assessing visuospatial working memory. In addition, psychic paralysis of gaze, an inability to voluntarily shift one's gaze to an object of interest despite unrestricted ocular movement, also negatively influences the results of a visuospatial working memory task. This occurs because an individual who has psychic paralysis of gaze is unable to visually perceive the probes in the tapping span test in the first place. Thus, to assess the relationship between the tapping span test and visuospatial working memory, a more elaborate paradigm is needed. To this end, a delayed visuospatial matching task and a shape-from-moving-dots task were used to assess visuospatial working memory, neither of which involves upper-limb movement. Moreover, before we could investigate visuospatial working memory, it was necessary to assess how these individuals inputted visuospatial information. As is often the case with severe visuospatial dysfunction with psychic paralysis of gaze and/or severe dorsal simultanagnosia, individuals are sometimes unable to perceive even one or two objects at a time.
We therefore first assessed if the participants could perceive several objects at a time and correctly judge the positional relationships of those objects, that is, their very basic visuospatial function. Detailed explanations of these tasks are provided elsewhere 27. In short, the judgment of positional relationships of two probes and three probes was used to assess the presence of either psychic paralysis of gaze and/or severe dorsal simultanagnosia. Each participant was asked to judge whether the position of a red probe was above or below that of a blue one for the condition with two probes and whether the position of a yellow probe was above, aligned with, or below with respect to the other two probes for the condition with three probes. There was a total of 30 trials for each of the two conditions.
Visuospatial working memory was then measured by two task types: a delayed visuospatial matching task for visuospatial short-term memory and a shape-from-moving-dots task for more active visuospatial working memory. Detailed descriptions of these tasks are provided elsewhere 27. The delayed visuospatial matching tasks that we used were much simpler than those used previously, given the severe visuospatial dysfunction of patients with posterior cortical atrophy, and consisted of two levels, that is, visuospatial working memory for one location and two locations, both of which included 30 trials. After a study phase, participants were asked whether the locations of the probes were in the same place or not in the response phase. For example, for the condition with one location, a blue probe (a circle of 2.5 cm in diameter) was displayed for 2 sec in the study phase. Then, the blue circle was removed and there was a 1-sec delay; a new blue circle was then shown for the response phase, during which the participant was instructed to say “same” when the circles were in the same place and “different” when they were not. For the condition with two locations, a blue probe was presented for 2 sec for the study phase, followed immediately by a second blue probe for 2 sec. After presentation of the first and second probes, there was a 1-sec delay, after which the participant was shown another blue probe (response phase) and the participant was then asked to state “same” if the location of the third probe was the same as one of the two probes or “different” if it was different from that of both probes. Probes were displayed on the vertical meridian on a computer screen, which circumvented the potential impact of unilateral neglect by the subjects. There was a total of 30 trials for each of the two conditions.
In the shape-from-moving-dots task, participants were asked to name the shape generated by consecutively moving dots, which were displayed one at a time for 1 sec each, which requires the participants to integrate them across space and time to generate a simple geometric object or a capital letter from the English alphabet. This task included a total of 10 trials.
The performance of individuals in the posterior cortical atrophy group were compared with those in the amnesic group. Excel 2010 with add-on Statcel 3 (OMS Ltd., Tokyo) was used for all statistical analyses. Significance was set at p < 0.05 (two tailed). Considering the small number of participants, variables were nonparametric and were compared between the two groups using the Mann-Whitney U-test. Gender distribution was compared between the two groups using Fisher's exact test. To investigate the relationship between the tapping span tests and visuospatial function/working memory tests, Pearson’s correlation coefficient was used. For this analysis, data from the posterior cortical atrophy group and amnesic group were combined, resulting in a total of 17 patients.