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Advances in the early diagnosis of Alzheimer’s Disease

Many challenges exist in a patient’s journey to their diagnosis of Alzheimer’s Disease (AD) and beyond. The pathological hallmarks of the disease may appear up to 20 years before a clinical diagnosis can be made.1 According to Philip Scheltens MD, PhD (VU University Medical Center, The Netherlands), an early diagnosis through improved guidelines, biomarkers and diagnostic tools can provide a greater window of opportunity to impact the disease and prevent cognitive decline.

The value of cognitive assessments in diagnosing Alzheimer’s Disease

A clinical diagnosis of dementia requires the identification of both cognitive and behavioral symptoms that interfere with daily functioning.2 Determination of cognitive impairment requires detailed history taking and objective cognitive assessment.

Although cognitive assessments can support the diagnosis of AD or rule out differential diagnoses, they alone are not diagnostic, explained John Harrison PhD (Kings College London, UK). However, these tools can provide an objective measure of an individual’s cognitive status, identify the nature and extent of cognitive deficits, and show changes in cognitive status over time. Indeed, perhaps the most efficient way of identifying people at risk of developing AD is tracking cognition longitudinally.

Perhaps the most efficient way of identifying people at risk of developing AD is tracking cognition longitudinally

Cognition is comprised of a number of domains, including episodic memory, executive functions, and working memory. Different levels of impairment are seen in different domains across neurodegenerative diseases.3 As neurodegenerative diseases progress, the number of cognitive domains affected increases and the more difficult it becomes to distinguish between AD and other underlying causes of dementia. It is important to recognize that although individual assessment tools may provide broad measures of deficits in particular cognitive domains, there are large overlaps in the test performance of patients with AD and other clinical syndromes, suggesting that cognitive assessment tools should be in combination.

Cognitive assessment tools should be in combination

There is a considerable battery of cognitive assessment tools to choose from, which when used together provide an understanding of the domains affected in an individual patient. A number are particularly suitable for use in primary care settings and can be administered within 10 minutes. These include, Delayed Recall, the Digit Symbol Substitution Test (DSST), the Controlled Oral Word Association Test (COWAT), the verbal fluency test, and the reaction time test. Several cognitive assessment tools are being adapted for use in digital formats to improve their accessibility via mobile and tablet devices.

The early stages of AD appear to involve deficits in several cognitive domains, including episodic memory, executive functioning and attention, however it is important that a broad range of cognitive skills are assessed in patients. Furthermore, serial progressive decline in cognition may prove the most valuable measure in identifying patients with early stage AD.

Serial progressive decline in cognition may prove the most valuable measure in identifying patients with early stage AD

Imaging biomarkers as differential diagnostic tools in neurodegenerative disease

Traditionally, structural magnetic resonance imaging (MRI) has been used as a method for excluding differential diagnoses explained Marwan Sabbagh MD (Cleveland Clinic Lou Ruvo Center for Brain Health, USA), but with new imaging techniques and biomarkers there is a move towards a diagnosis of inclusion.

Structural and functional MRI can identify general differences between dementias, although these changes are not always specific to a particular disease

T1-weighted coronal imaging allows progressive atrophy to be tracked over time. It is important to recognize that the volumetric data provided are not diagnostic, although the pattern of atrophy is helpful for differential diagnosis. Both structural and functional MRI can identify general differences between dementias, although these changes are not always specific to a particular disease.4 Visual rating scales can also be used to enhance the specificity and sensitivity with the goal to distinguish between dementias,5 with tools such as the Fazekas scale of white matter pathology being used increasingly.4 In addition to temporal lobe atrophy that is commonly seen in AD, the presence of microbleeds within the white matter also suggests the possibility of amyloid deposition.

Cerebrospinal fluid biomarkers amyloid-beta42 and phosphorylated tau can help with the diagnosis of AD given their specificity. Amyloid-positron-emission tomography (PET) correlates well with CSF amyloid and can detect cerebral amyloid-beta deposition very early – although it does not confirm a diagnosis of AD, negative amyloid PET excludes AD pathology. Tau-PET correlates strongly with Braak stage and a recent study has shown that the pattern of tau tangles can distinguish between pathologies of AD.6

The pattern of tau tangles can distinguish between pathologies of AD

Management implications of an early diagnosis of Alzheimer’s Disease

Early diagnosis is important both for patients and caregivers, with the majority of patients expressing a wish to be advised of a potential diagnosis of AD and to be involved in the development of an advanced care plan.7 But, explained Miia Kivipelto MD, PhD (Karolinska Institutet, Sweden), there is a need for the physician to balance this disclosure with the negative aspects such as emotional distress, uncertainty, and the current lack of effective treatments.

Patients and caregivers want to feel empowered in the diagnosis of AD

Patient-centered care through shared decision making between physicians, patients and caregivers in the diagnosis of AD is also important.8 A recent study from the ABIDE project, showed that both patients and caregivers want to feel empowered in the diagnosis of AD.9 However, although they felt involved in the decisions to perform diagnostic tests they did not feel involved in which tests were chosen. Patients and caregivers expressed a need for more information on what the results of diagnostic tests would mean for their day-to-day lives. This highlights the need for healthcare professionals to manage the expectations of patients and caregivers before initiating diagnostic testing.

If you want to read more detail information on The Ethics of Preclinical Diagnosis, go to Lundbeck Institute Campus

But once a diagnosis has been given, what next? The AAN has developed practice guidelines for physicians managing patients who present with memory complaints (https://www.aan.com/Guidelines/home/GetGuidelineContent/882), which includes recommendations on a number of non-pharmacological or lifestyle interventions, including regular exercise and cognitive interventions. Indeed, a number of studies are investigating the potential of multimodal interventions in AD.

The future may see the use of multimodal lifestyle interventions alongside disease-modifying therapies in the prevention and management of AD

The FINGER double-blind randomized study showed that in at-risk elderly people a 2-year multidomain intervention comprising diet, exercise, cognitive training, and vascular risk monitoring could improve many cognitive subdomains, compared with the provision of general health advice alone.10 The recent LipiDiDiet study looked at the efficacy of medical food in patients with prodromal AD. Although there were no significant differences in terms of overall cognition on the primary endpoint between patients receiving a multinutrient and those who did not, there were some differences in secondary measures of cognition and function.11 MIND-AD is an ongoing study looking at multimodal preventative strategies such as lifestyle interventions + medical food, in at-risk groups (http://www.mind-ad.eu/). The future may see the use of multimodal lifestyle interventions alongside disease-modifying therapies in the prevention and management of AD.

This expert science exchange was organised by Biogen.

Further reading at:

  1. https://progress.im/en/content/biomarkers-enable-early-diagnosis-and-intervention-and-monitor-progression
  2. https://progress.im/en/content/alzheimer%E2%80%99s-disease-ethics-early-diagnosis-and-practicalities-prevention-0

 

References
  1.  Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012; 367: 795-804.
  2. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7: 263-269.
  3.  Karantzoulis S, Galvin JE. Distinguishing Alzheimer's disease from other major forms of dementia. Expert Rev Neurother. 2011; 11: 1579-1591.
  4. Mortimer AM, Likeman M, Lewis TT. Neuroimaging in dementia: a practical guide. Pract Neurol. 2013; 13: 92-103.
  5.  Harper L, Fumagalli GG, Barkhof F, et al. MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases. Brain. 2016; 139: 1211-1225.
  6.  Ossenkoppele R, Schonhaut DR, Scholl M, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016; 139: 1551-1567.
  7.  Riva M, Caratozzolo S, Cerea E, et al. Diagnosis disclosure and advance care planning in Alzheimer disease: opinions of a sample of Italian citizens. Aging Clin Exp Res. 2014; 26: 427-434.
  8. van der Flier WM, Kunneman M, Bouwman FH, et al. Diagnostic dilemmas in Alzheimer's disease: Room for shared decision making. Alzheimers Dement (N Y). 2017; 3: 301-304.
  9.  Kunneman M, Pel-Littel R, Bouwman FH, et al. Patients' and caregivers' views on conversations and shared decision making in diagnostic testing for Alzheimer's disease: The ABIDE project. Alzheimers Dement (N Y). 2017; 3: 314-322.
  10. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015; 385: 2255-2263.
  11.   Soininen H, Solomon A, Visser PJ, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol. 2017; 16: 965-975.

 

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