Olfactory and Imaging Features in Atypical Alzheimer's Disease.

OBJECTIVES: Cognition and speech disorders are the most common symptoms of dementia in neurodegenerative disease. Here, we present a detailed clinical evaluation of a case of logopenic variant of primary progressive aphasia (lv-PPA), an atypical form of Alzheimer disease (AD), including cognitive testing over time, brain imaging, electrophysiology, and tests of olfactory function. CASE REPORT: We present the case of a 58-year-old man suffering from progressive language difficulties who was finally diagnosed with lv-PPA. Clinical data included neuropsychological examinations, electrophysiology tests, neuroimaging, biomarkers, olfactory tests, and olfactory functional magnetic resonance imaging (fMRI). RESULTS AND DISCUSSION: The patient suffered from language disorders, including stumbling speech and forgetting appropriate words and how to pronounce some words. This had started 2 years earlier, and he had begun to deteriorate in recent months. In addition to his speech disorder, scores on the Mini Mental State Examination and Montreal cognitive assessment indicated that his cognition was affected. Structural imaging revealed no obvious hippocampal atrophy (score of 1), and molecular imaging showed hypometabolism and amyloid deposits in the temporal parietal region. The patient also presented with olfactory impairment. Although his odour detection threshold was normal, his cognitive threshold for scent recognition was significantly increased. Olfactory fMRI showed that activation of the whole brain and primary olfactory cortex was rare.
CONCLUSION: This case provides evidence suggesting that lv-PPA is an atypical form of AD, with symptoms including speech disorders and impaired cognition. This patient with lv-PPA presented with olfactory impairment.

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. The neuropathological process involves the accumulation of amyloid beta plaques and tau tangles. Typical AD is characterized by episodic memory loss. In other subtypes, dysfunctions of language, visual-spatial skills or executive function commonly accompany memory loss. Most often, speech disorders are the initial motivation for potential dementia patients to present to the hospital. The logopenic variant of primary progressive aphasia (lv-PPA), a unique primary progressive aphasia (PPA) syndrome, is characterized by anomia, word-finding difficulties, and impaired sentence repetition [1, 2]. The neuropathology and biomarkers (molecular amyloid nuclear imaging) of lv-PPA frequently reveal AD, so it is defined as a variant of AD. Because there is no effective medication for lv-PPA, specific linguistic therapies are needed. Therefore, early diagnosis can improve patients’ quality of life.

Olfactory dysfunction was recently found to be associated with AD. AD causes neuropathological changes in entorhinal and trans-entorhinal areas that are critical to olfactory information processing. Olfactory deficits in AD include decreases in odour threshold sensitivity [3, 4], odour identification [5, 6], and olfactory event-related potentials [7]. In this case study, olfactory function was determined using the T&T olfactometer and olfactory functional magnetic resonance imaging (fMRI) was used to determine the threshold for odour sensitivity, odour identification and olfactory cortex function.

In this article, we present the case of a patient suffering from speech difficulties characteristic of lv-PPA. Data from cognitive testing, analyses of speech disorder, brain imaging, electrophysiology and olfactory function are carefully integrated to present a complete characterization of the development of cognitive defects in lv-PPA over time. We hope this will aid other clinicians in identifying lv-PPA and its progression.

Methods and results

Case report

The patient, a 58-year-old man, is righthanded, has a university degree, and has no history of stroke, nasosinusitis, chronic obstructive pulmonary disease, schizophrenia, depression or family dementia. He was admitted to our outpatient department for diagnosis of his language disorders, which had persisted for approximately 2 years. He and his wife complained that he was unable to express himself and stumbled trying to find appropriate words. Moreover, he found it difficult to pronounce some words. His language comprehension was relatively well preserved. He could identify the appropriate word when others suggested words he might be trying to remember. During the previous 2 years, he insisted on driving to work by himself. During the past few months, his symptoms had worsened enough to limit his verbal contact with others, and he experienced memory impairment, such as forgetting his things and his co-workers’ names, difficulty concentrating and with logic, and a poor temper.

Physical and neurological examinations identified no cardiac dysfunction, pulmonary disease, sensory deficiencies, muscular strength deficiencies or pyramidal symptoms, except the clumsy use of language. Laboratory examinations showed normal ranges of liver, kidney, and thyroid function, as well as normal levels of homocysteine, vitamin B12, and folic acid were in the normal range, and the levels of . Levels of low density lipoprotein cholesterol (3.03 mmol/L) and total cholesterol (6.08 mmol/L) were slightly higher than the normal range. The apolipoprotein genotype was ε3/ε3. Neuropsychological examinations included cognition, executive function, and neuropsychiatric tests. The Montreal cognitive assessment (15 points) and clock drawing test (2 points) revealed symptoms of dementia, including impaired memory, executive function and language. He had no positive symptoms in the neuropsychiatric tests, but did present with increased levels of anxiety and aggression.

Magnetic resonance imaging (MRI), which was performed with a 3.0 T Siemens MR system using a standard head coil, included structural MRI and olfactory functional MRI. The structural MRI (Fig. 1) revealed demyelination of cerebral white matter (0–1 degree on the Fazekas scale) [8], and a hippocampal score of 1 using the medial temporal lobe atrophy score.

Figure 1

MRI image of this patient

Electrophysiology test

During the electrophysiology study, cognitive and motor cortical functions were evaluated using the P300 and transcranial magnetic stimulation (TMS). The P300 wave is a prominent event-related potential (ERP) that indicates changes in the cognitive cortex [9]. The P300 wave is the most commonly recorded potential and can be elicited using the oddball paradigm. In this method, the patient was instructed to focus on an infrequent target stimulus (2,000 Hz, 100 dB) embedded in a series of frequent background stimuli (1,000 Hz, 100 dB). The P300 latency was 374 ms at the Cz-A1 site and 368 ms at the Pz-A1 site, and the amplitudes were 4.1 μv and -0.77 μv at different sites, which indicates cognitive impairment. In addition to the cognitive cortex, TMS was conducted to assess the motor cortex function. The cortical motor-evoked potential of the abductor pollicis brevis (left) showed that the resting motor threshold (RMT) was 40%, the facilitated motor threshold (FMT) was 31%, and the cortical silent period (CSP) was 145.1 ms for the right cortex. On the other side, the thresholds were 47%, 31%, and 146.4 ms, respectively. These results indicate that excitability of the motor cortex was increased in this patient compared with age-matched controls in our hospital.

Positron Emission Tomography Imaging (PET)

To further clarify the diagnosis, PET images were acquired on a GE Discovery LS PET/CT scanner in the three-dimensional scanning mode. Ten minutes before intravenous administration of the radiotracer, the patient rested in supine position in a quiet, dimly lit room. The 11 C-labeled Pittsburgh compound B (11C-PIB) was injected into an antecubital vein at a mean dose of 370 MBq. PIB PET images were acquired during a 90-min dynamic PET scan. The same scanner was used for the 18F-fludeoxyglucose (FDG) study conducted 30 min after the 11C-PIB scan. The patient was intravenously injected with 250 MBq of 18F-FDG and underwent a 10 min static PET emission scan 60 min after the injection. Cortical-to-cerebellar grey matter ratios (standardized uptake value ratio) were generated for regions of interest. The analysis was performed by two experienced nuclear medicine physicians.

The FDG scan revealed bilateral temporal-parietal junction regions, bilateral precuneus regions, and right frontal lobe hypometabolism. Among these regions, the right temporalparietal junction hypometabolism was the most distinct (Fig. 2A). Moreover, the PIB scan revealed amyloid deposits in the temporal, parietal, and frontal regions (Fig. 2B), consistent with AD. Based on the patient’s clinical symptoms and examination results, we diagnosed him with lv-PPA [2].

Figure 2

A. The 18F-FDG PET of this patient, B. The 11C-PIB image of this patient

Olfactory function

Olfactory test

To determine olfactory function, the patient underwent testing with a standard Toyoda and Takagi’s perfumist’s strip (T&T olfactometry, Japan) [10, 11]. We tested the thresholds of five odorants using T&T olfactometry. The 8 degrees (-2, -1, 0, +1, +2, +3, +4, +5) of odorant on the T&T olfactometry represent a concentration series from 10-2 to 105, and zero represents the average detection threshold of normosmic subjects. Lack of response to the highest concentration was scored as 6. For this patient, the detection threshold was -1.2 (degree 1), and the cognitive threshold was 6.

Olfactory functional magnetic resonance imaging (fMRI)

Lavender oil is one of the most effective olfactory stimulants. It has minimal to no effect on the trigeminal system, and has been used in olfactory fMRI studies [12]. Lavender oil at concentrations of 0.10%, 0.33%, and 1.00% were used as stimuli. Olfactory stimuli were delivered through the tube of a custom-built olfactometer placed approximately 1 cm from the participant’s nose, with air flow at 8 L/min. Each odorant was presented in 6-second blocks separated by a 42-second interval of odourless air. Each concentration was repeated five times in succession, beginning with the weakest. Before fMRI, we explained the progression of the examination, instructed the subject to keep his head and body motionless, and to receive the odours without sniffing.

The olfactory fMRI showed that activation of the whole brain was rare, especially in the bilateral primary olfactory cortical (POC), which directly reflects the subject’s impaired olfactory function.

Follow-up

Data from follow-up examinations at 6 months and 1, 1.5, and 2 years are shown in Fig. 3. At the 6-month follow-up, the Mini Mental State Examination score decreased (Table 1), whereas scores for activity of daily living and neuropsychiatric Inventory (NPI) were increased. At the 1.5-year follow-up, his sense of orientation and memory had deteriorated, which induced a gradual downward trend in his cognitive function.

Figure 3

Line chart of each scale score

Table 1

Scores of sub-item of the MMSE scale

	orientation	memory	repetition	Attention and computation	recall	naming	reading	executive	writing	copying
First visit	10	3	0	1	3	2	1	2	1	0
6 Mon	10	3	0	0	3	2	1	2	1	0
12 Mon	10	3	0	0	3	2	1	1	0	0
18 Mon	7	3	0	0	2	2	1	2	1	0
24 Mon	8	3	0	0	2	2	1	2	1	0

Discussion

AD is one of the most common chronic diseases in the elderly, but there is currently no treatment that blocks the progression of AD. Moreover, patients whose initial symptoms are not memory impairment are often ignored or misdiagnosed. Atypical symptoms are present in at least 5% of AD patients over the age of 65 years and 1/3 of patients under the age of 65 [13, 14]. Lv-PPA is an atypical clinical variant of AD, which is characterized by anomia, word-finding difficulties, and impaired sentence repetition [2]. Imaging features include left temporal-parietal atrophy on MRI [1, 15] and hypometabolism on 18F-FDG PET [16]. Lv-PPA is not well understood, possibly because of the relatively small number of patients and a lack of comprehensive investigations. Therefore, we aimed to present a comprehensive description of brain imaging, electrophysiology, and olfactory function in a patient with lv-PPA. In our case, the patient initially presented with a speech disorder, characterized by difficulty in finding words and sentence-repeating. After 2 years of follow-up, his cognitive function, including orientation, delayed recall and ability to perform calculations deteriorated; all clinical symptoms consistent with AD. These results, combined with PET results, led to a diagnosis of lv-PPA [2].

Structural MRI revealed significant atrophy of the hippocampus, which might be a useful biomarker for distinguishing lv-PPA from typical AD and other degenerative diseases. Unlike typical AD, hippocampal regions are spared in lv-PPA [17], which is consistent with our results. In typical AD patients, PET shows some areas, including the frontal, temporal and parietal regions, with decreased metabolism, increased 11C-PIB uptake, and a decreased removal rate [18], which is similar to lv-PPA patients [16]. However, in lv-PPA patients, the degree of hypometabolism in the left parietal-temporal junction might be more severe, representing an anatomical signature of lv-PPA [19]. Conversely, our results showed more significant hypometabolism in the right parietal-temporal junction. This discrepancy might be attributed to lv-PPA endophenotypes with slightly different clinical profiles, disease severity and decline over time [20, 21]. The specific mechanisms underlying this difference should be studied in the future.

Our analysis of olfactory function included perception and recognition, as determined by detection and cognitive thresholds. Many previous studies found decreased recognition of olfactory stimuli in the elderly [22], and impairment may occur several years before the onset of AD symptoms [23, 24]. Some researchers have suggested that there is a relationship between olfactory recognition and cognition. It is noteworthy that our lv-PPA patient had a significantly impaired recognition of odours with no obvious impairment of detection threshold. The detection threshold reflects the function of peripheral olfactory structures, whereas the cognitive threshold mainly reflects the function of the olfactory centre [25]. Our patient’s limited olfactory dysfunction, difficulty recognizing odours, was related to the olfactory centre, which is consistent with a previous study [26]. The olfactory centre includes the anterior olfactory nucleus, piriform cortex, entorhinal cortex, and amygdala among other areas, all of which can atrophy and accumulate neurofibrillary tangles and amyloid deposits [27, 28].

By monitoring blood oxygen levels, fMRI allows noninvasive monitoring of brain function, and olfactory fMRI indicates the activity of the olfactory cortex. Olfactory fMRI of typical AD patients shows decreased activation of the POC compared with normal controls [12]. In our lv-PPA case, activation of the whole brain and the POC was rare, which is similar to the findings of our previous study. These results indicate dysfunction of the olfactory cortex [24, 29]. Because this lv-PPA patient presented with olfactory dysfunction, the assessment of olfaction might be helpful for the early diagnosis of lv-PPA.

Conclusion

In conclusion, the results of our molecular imaging studies indicate that lv-PPA is an atypical subtype of AD. Symptoms include speech disorders and cognitive impairment. Patients with lv-PPA may present with olfactory impairment.