Alzheimer’s disease (AD) is the most common cause of YOD, followed by vascular dementia and frontotemporal dementia. The advancement of amyloid biomarkers has enabled the identification of amyloid pathologies in vivo across the AD spectrum
A 50-year-old male without any significant medical or psychiatric history presented to the memory clinic with progressive behavioural change and cognitive impairment over 18 months. His behavioural disturbance started with low mood, apathy, reduced appetite and fleeting suicidal thoughts. This gradually intensified to false beliefs that other people were out to harm his family. In addition, he had the constant thought that his father in-law was monitoring his movements. He also experienced auditory hallucinations telling him that he was “weak and useless”, and commanding him to “run away from home”.
Over time, he began to consider his wife as an imposter and he would always require a text message from her to prove that she was his wife. Only after confirming that the text message was sent from the same mobile number as belonging to his wife, would he be agreeable to speak to her.
At the same time, he became more forgetful and often repeated what he had said earlier. He was not able to cope at work and needed help to complete the tasks that he was previously familiar with. He also had difficulties managing his finances.
During physical examination, he was well-groomed and orientated. There were no focal neurological deficits, extrapyramidal signs or apraxia. However, he had anomia and difficulty in performing the Luria’s three-step test and go-no-go test. He scored 15/30 for the mini-mental state examination, 9/30 for the Montreal Cognitive Assessment and 10/18 for the frontal assessment battery.
Laboratory testing revealed normal thyroid hormone profile, vitamin B12, folate, negative syphilis and HIV screen. Genetic testing revealed homozygosity for APOE e4 alleles. His brain MRI showed predominant parietal and medial temporal atrophy (Figure 1), [18F]Fluorodeoxyglucose (FDG) PET scan showed frontal, parietal and posterior temporal hypometabolism and [18F]Flutemetamol PET scan was positive for amyloid deposition (Figure 2), which is consistent with the diagnosis of Alzheimer’s disease.
Here, we describe an atypical presentation of a patient with young onset dementia (YOD) due to Alzheimer’s disease (AD), who had prominent psychotic symptoms and Capgras syndrome. Capgras syndrome (CS) is a form of delusional misidentification syndrome characterised by a delusional belief that an identical or near-identical looking imposter has replaced the identity of a closely-related person. While CS was originally reported in schizophrenia and schizoaffective disorders, it is increasingly recognised in neurological conditions such as AD1.
Although the patient’s psychiatric symptoms at mid-life onset may be suggestive of late-onset schizophrenia, the presence of concurrent cognitive impairment typical of AD led to a detailed clinical evaluation using AD imaging biomarkers. Amyloid PET findings characteristic of AD led to a revision of the diagnosis to young onset dementia (YOD) due to AD.
This case discussion demonstrates the key role of AD neuroimaging biomarkers in the clinical evaluation of YOD patients with atypical presentation.
INCIDENCE OF YOUNG ONSET DEMENTIA IN SINGAPORE IS INCREASING
Dementia is a neurodegenerative disease that is characterised by a decline in at least one cognitive domain interfering with independence in everyday activities.
In 2018, dementia has affected 50 million people worldwide, and this number is expected to rise to 82 million by 2030 and 152 million by 20501. In Singapore, one in 10 people aged 60 and above may have dementia, which translates to almost 82,000 people in 2018 and the number is expected to exceed 100,000 in a few years’ time3.
While dementia typically affects older adults aged 65 years and above, this condition is increasingly diagnosed in younger individuals in recent years. In this regard, the term young-onset dementia (YOD) is used to describe patients with onset of dementia before 65 years of age4.
At the National Neuroscience Institute (NNI), the number of new patients with YOD (<65 years) has gradually increased from 180 in 2016 to 228 in 2018 and almost doubled from 2015. Hence, greater awareness of this condition among clinicians is paramount.
CLINICAL PRESENTATIONS OF YOUNG ONSET DEMENTIA DUE TO ALZHEIMER’S DISEASE
Alzheimer’s disease (AD) is the most common cause of YOD, followed by vascular dementia and frontotemporal dementia3.
1. In AD, amnestic syndrome is the most common presentation, including impairment in learning and recall of recently learned information5.
2. In addition, there should also be evidence of cognitive impairment in at least one other cognitive domain, such as executive dysfunction, visuospatial impairment, language difficulties or changes in personality and/or behaviour.
3. Importantly, about a third of the patients with YOD may have an atypical presentation such as executive, behavioural, language dysfunction and posterior cortical atrophy which makes the diagnosis of AD in YOD challenging. This has been shown in a study where pathologically proven YOD patients with atypical presentations were often misdiagnosed6.
NEUROPSYCHIATRIC SYMPTOMS - in Youth Onset Dementia due to Alzheimer’s Disease
Neuropsychiatric symptoms (NPS) such as delusions are frequently observed in Alzheimer’s disease (AD) and are associated with greater functional impairment, poorer quality of life and accelerated cognitive decline7.
Common delusions observed in AD patients include delusions of persecution, abandonment and the belief that deceased relatives such as parents are still alive.
Misidentification delusions such as Capgras syndrome (CS) are also reported in AD patients8. This includes the belief that a family member is an imposter, and the home is not the patient’s own home. The prevalence of CS among AD patients seen in memory clinics ranges from 10.1% to 14.8%2,9. The mean age of onset of CS among AD patients ranges from 72 to 82 years and AD patients with misidentification delusions are associated with increased cognitive impairment and advanced dementia10.
In this case study, the presentation of prominent psychotic symptoms and CS at mid-life onset suggest the possibility of late-onset schizophrenia. However, unlike schizophrenia, delusions in AD are usually not bizarre and the first-rank symptoms of schizophrenia are not common. Furthermore, the patient has concurrent cognitive impairment such as amnesia and executive dysfunction which raises a differential diagnosis of AD. Hence, a further work up using AD imaging biomarkers is performed.
ROLE OF AD BIOMARKERS IN CLINICAL PRACTICE
Amyloid plaque is a core histopathological hallmark of AD and the amyloid cascade hypothesis suggests that AD begins with amyloid beta (Aß) deposition which results in neuronal dysfunction and neuronal cell death.
The advancement of amyloid biomarkers has enabled the identification of amyloid pathologies in vivo across the AD spectrum. The biomarkers of Aß deposition include low cerebrospinal (CSF) Aß42 and high uptake of amyloid PET tracers in the brain. There is a close correlation between in vivo amyloid biomarkers and brain amyloid plaques assessed in post-mortem studies.
Amyloid PET provides information regarding regional distribution and longitudinal changes of amyloid deposition in AD patients. However, 10–30% of cognitively normal people may have a positive amyloid PET scan11 and pathological amyloid deposition in the brain is also shown in non-demented individuals12. Hence, its clinical utility in medical practice requires careful consideration. Prior to ordering of an amyloid PET scan, the physician should consider the possibility of an incidental, age-related amyloid detection in a patient that may not be related to or relevant to the presenting symptoms.
A positive amyloid PET scan may also be seen in other neurodegenerative conditions such aas dementia with Lewy bodies (DLB). Hence, it is important to emphasise that a positive amyloid PET scan alone does not establish Jul - Sep 2019 the diagnosis of AD or distinguish AD from other neurodegenerative conditions such as DLB.
The Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT) to define a set of specific appropriate indications and inappropriate use criteria as a guidance for the ordering of amyloid PET13 (Table 1).
Table 1 Appropriate use criteria for anyloid PET
|(i) A cognitive complaint with objectively confirmed impairment|
|(ii) AD as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert|
|(iii) When knowledge of the presence or absence of amyloid pathology is expected to increase diagnostic certainty and alter management|
|(i) Patients with persistent or progressive unexplained mild cognitive impairment|
|(ii) Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation|
|(iii) Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)|
|(i) Patients with core clinical criteria for probable AD with typical age of onset|
|(ii) To determine dementia severity|
|(iii) Based solely on a positive family history of dementia or presence of apolipoprotein E (APOE) ε4|
|(iv) Patients with a cognitive complaint that is unconfirmed on clinical examination|
|(v) In lieu of genotyping for suspected autosomal mutation carriers|
|(vi) In asymptomatic individuals|
|(vii) Nonmedical use (e.g. legal, insurance coverage, or employment screening)|
K.A. Johnson et al. / Alzheimer’s & Dementia 9 (2013) e1 – e16
The preamble restricts the group of patients for whom amyloid imaging would be appropriate.
Firstly, the patient must be evaluated by a dementia expert so as to determine that a cognitive complaint is supported with objectively confirmed impairment. This can be assessed through a detailed mental status examination or a neuropsychological assessment.
Secondly, the cause of the cognitive impairment should remain uncertain after a comprehensive evaluation and AD may be a possible differential diagnosis.
Thirdly, the physician must conclude that a determination of amyloid status would increase the level of diagnostic certainty and alter the plan for patient management.
This case study highlights YOD due to AD as a differential diagnosis in young patients who present with prominent neuropsychiatric symptoms and cognitive impairment. The availability of AD imaging biomarkers such as amyloid and FDG PET has enabled the identification of in vivo AD pathophysiology and play an important role in the accurate diagnosis of AD. With the current advancement in the development of disease modifying drugs, early and accurate diagnosis will be essential. Furthermore, the ability to provide a definitive diagnosis and prognosis will enable patients and their families to plan for their future, including life, finances and advance directives.
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Dr Ng Kok Pin is a Consultant at the Department of Neurology, National Neuroscience Institute. After graduating from the Yong Loo Lin School of Medicine, National University of Singapore in 2006, he obtained his MRCP(UK) in 2011 and was accredited as a Neurologist by the Ministry of Health Singapore in 2015. In 2016, he obtained his Master of Clinical Investigation (NUS). Dr Ng subspecialises in dementia and his research interest is PET imaging in neurocognitive diseases. He completed his 1-year clinical research fellowship at the McGill University Research Centre for Studies in Aging, Montreal, Canada in 2017.
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