Introduction
As the population ages and the treatment of Multiple Sclerosis (MS) advances, more individuals with MS will develop age-related neurodegenerative disorders, including Alzheimer’s disease (AD) [
10]. However, diagnosing AD in cognitively impaired MS patients is challenging and little is known about the coexistence of the two conditions [
9].
Cognitive dysfunction is common in MS, affecting 45–65% of patients [
14]. Neuropsychological symptoms include deficits in processing speed, executive function, episodic memory and visuospatial function. However, progressive dementia with prominent amnesia and classic cortical features has also been described [
19]. Grey matter involvement and cortical tissue loss in MS are increasingly recognised [
4] and correlate better with MS-related cognitive impairment than white matter lesion load [
2]. Deep grey matter and cortical atrophy appears to be tightly coupled to cognitive decline in late relapsing–remitting and progressive MS [
7], and hence, distinguishing this from coexisting Alzheimer’s disease using structural imaging alone can be problematic.
The introduction of two reliable biomarkers for amyloid pathology, cerebrospinal fluid amyloid β1-42/tau levels and amyloid PET Imaging (API), has transformed pre-mortem diagnosis in AD, particularly in patients with atypical presentations or co-morbidities known to impair cognition. Clinical API utilises fluorinated tracers (
18F-florbetapir,
18F-florbetaben or
18F-flutemetamol) that bind to amyloid beta in cerebral amyloid plaques, leading to increased cortical signal in AD. There is a growing research interest in using amyloid PET as a surrogate marker of MS demyelination–remyelination, and reductions in white matter tracer uptake have been demonstrated with demyelination in MS [
3]. However, this is independent of cortical β-amyloid deposition, and tracer uptake in the cortex in late MS has been found to be no different from age-matched controls [
21].
Two recent studies have examined the association between amyloid PET tracer binding and cognitive function in MS [
11,
21], and a prospective population-based study used amyloid PET to investigate beta-amyloid accumulation in ageing MS patients and matched controls [
20]. Yet, there are no reports of API to diagnose AD in patients with established MS and increasing cognitive impairment.
Here, three MS patients presenting with progressive cognitive impairment are described. Each had API because of a lack of diagnostic clarity with standard dementia investigations. It is highlighted how clinical diagnosis of AD might be aided by this approach.
Discussion
Cognitive impairment in MS may be related to mood, fatigue and sleep disturbance as well as strategic lesions [
2,
7]. Using clinical assessment and structural imaging, it is often difficult to differentiate degeneration related to MS progression from coexisting Alzheimer’s, with the underlying diagnosis only becoming clear following post-mortem examination [
18]. In such situations, API offers non-invasive detection of beta-amyloid plaques, enabling recognition of AD in the MS population and earlier introduction of appropriate management.
Here, three MS patients, all in their 70s, presenting with progressive cognitive impairment of unclear aetiology were described. Following MDT discussion, they underwent API because of a lack of diagnostic clarity from standard investigations. One patient had a negative amyloid PET scan, while two were diagnosed with AD based on positive scans. Both individuals diagnosed with AD were previously thought to have MS-related cognitive decline. API led to a change in diagnosis, as well as a change in management, including initiation of new medication and enrolment into clinical trials. Importantly, patients and their families could also be provided with information about the prognosis and appropriate support services available to them. This is in keeping with recent studies examining the wider utility of amyloid PET imaging [
5,
13]. When used in individuals who meet appropriate criteria [
8], API reduces the number of further investigations and significantly affects clinical management, in addition to increasing diagnostic certainty.
In MS, which is associated with cortical atrophy [
17], examination of structural imaging for typical AD atrophy patterns is challenging as the combination of MS- and AD-related cortical atrophy leads to a less well-defined pattern. This is illustrated by Cases 1 and 3, where both patients had a degree of asymmetrical hippocampal atrophy. This is a relatively typical finding in Alzheimer's disease and strongly associated with a positive amyloid PET [
1], but regional hippocampal atrophy has also been found in patients with MS [
16], with some reports also describing asymmetry [
15]. Thus, API may provide key information regarding the underlying cause of cognitive decline. CSF examination for amyloid β1-42 and Tau levels is a possible alternative approach but is invasive with more potential for adverse effects. Moreover, establishing CSF cut-off points is difficult, as evidenced by the wide variation in normal ranges used in different centres. Furthermore, there is evidence that atypical AD syndromes may have less clear-cut CSF profiles than are normally observed in typical AD [
12].
One potential issue when using API in MS is that the reduced tracer uptake that has been found in demyelination might result in a failure to detect clinically relevant amyloid plaque, generating false-negative results. A recent study found that cortical β-amyloid deposition measured with API was lower in ageing MS patients than the controls matched for age, sex and APOE ε4 status [
20]. While the authors concluded that MS could be protective of beta‐amyloid pathology, this finding may also reflect a loss of tracer binding due to demyelination, resulting in a falsely low estimation of cortical amyloid accumulation. Importantly, the research cohort imaged in this study mainly comprised cognitively unimpaired MS patients, in contrast to the case series described here, all of whom had dementia (and in whom ApoE status was not tested).
Another potential concern is that the proportion of cognitively normal individuals with clinically silent amyloid PET increases with age, and that any amyloid deposition may not be responsible for cognitive symptoms. However, these patients’ subsequent clinical course was in keeping with the diagnoses made with API.
Furthermore, although AD pathology seems to develop in MS in a similar incidence to that observed in normal ageing [
6], it may be that individuals with MS are more vulnerable to the effects of amyloid because of their pre-existing cortical atrophy, leading to a shorter asymptomatic phase of AD. Studies such as that by Zeydan and colleagues which use modalities that are currently available in the research setting, such Tau PET imaging, may shed further light on this. However, given the possible confounds associated with tracer binding, neuropathological studies are more likely to be definitive.
In clinical practice, implementation of API in appropriate MS patients is recommended through a multidisciplinary approach according to appropriate use criteria in order to aid diagnosis and management of patients with cognitive decline. As described here, it may provide diagnostic clarity and assist with therapeutic decisions, while reducing the overall burden of investigations.