Clinical features

2 Review of the Literature

2.1 ALZHEIMER’S DISEASE

2.1.1 Epidemiology

Alzheimer’s disease is the most common cause of dementia accounting for approximately 70% of all cases (Reitz, Mayeux 2014, Querfurth, LaFerla 2010). In 2006, it was estimated that there were around 26.6 million patients with AD (Brookmeyer, Johnson et al. 2007), with the actual numbers being highest in countries with low and middle incomes. In relation to the size of the population, the prevalence is, however, higher in Northern America and Western Europe. As with dementia in general, the prevalence increases almost exponentially with age and is expected to double every 20 years (Reitz, Mayeux 2014, Mayeux, Stern 2012a, Ballard, Gauthier et al. 2011). It has been estimated that in 2050, there will be more than 100 million people affected by AD (Brookmeyer, Johnson et al. 2007).

Women are predominantly affected by AD; it has been claimed that women account for approximately two thirds of all AD cases (Launer, Andersen et al. 1999, Andersen, Launer et al. 1999).

2.1.2 Clinical features

The prodromal phase of the disease precedes the AD dementia syndrome; at this time, a certain degree of cognitive impairment can be detected together with AD-type pathological changes in either imaging or CSF (Pena-Casanova, Sanchez-Benavides et al. 2012). The first symptom is typically an impairment of episodic memory that is also the most characteristic feature of AD (Dubois, Feldman et al. 2014, Salmon, Bondi 2009) occurring in as many as 94%

of all patients (Dubois, Feldman et al. 2014). The actual AD typically progresses in three stages: from mild to moderate and eventually to severe dementia. In mild AD, in conjuction with memory disturbances also other areas of cognition, especially executive functions and language skills, become affected. In addition, agnosia and apraxia are common. The patients start to experience problems in more complex activities of daily living, such as financial tasks.

In the moderate stage of the disease, the impairment of cognition becomes more severe and challenges in daily living are more apparent. In addition to losing older memories, orientation with respect to time and space may be impaired, and there is an increased risk for wandering and becoming lost. The patient starts to require a greater level of care. In the final, severe, stage of the disease, cognition continues to worsen. The patients struggle with communication, and eventually lose their ability to respond to the environment and control movement, even swallowing (McKhann, Knopman et al. 2011, Dubois, Feldman et al. 2007, Weintraub, Wicklund et al. 2012, Bondi, Jak et al. 2008, Blennow, de Leon et al. 2006). In addition to cognitive impairments, neuropsychiatric symptoms are common in AD, affecting up to 90% of the patients at some point in their disease course (Robert, Verhey et al. 2005, Lyketsos, Carrillo et al. 2011). Some of these symptoms may be present already in the prodromal phase of the disease, and they have also been proven to increase the risk of developing AD as well as accelerating the progression from mild cognitive impairment (MCI) into dementia (Geda, Roberts et al. 2008). Apathy is the most common of the symptoms, and it typically persists throughout the disease course (Lyketsos, Lopez et al.

2002, Robert, Verhey et al. 2005, Devanand, Jacobs et al. 1997). Depression and alterations in sleep-wake rhythm are also frequently seen, and are present already in early stages of the disease. As the disease progresses, more severe neuropsychiatric symptoms appear. The patients may start to exhibit aggression as well as suffering delucions or hallucinations, even

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outright psychosis is possible (Lyketsos, Carrillo et al. 2011, Robert, Verhey et al. 2005).

However, it should be borne in mind that the disease progression regarding both symptoms and survival varies between individuals (Brookmeyer, Johnson et al. 2007, Frisoni, Rozzini et al. 1999, Lopez, Becker et al. 2003). The mean survival after the diagnosis has been estimated to be approximately six years, but it is dependent on the time at which the diagnosis is achieved, the subtype of the disease, and on the presence of possible comorbidities. If diagnosed early, the survival of the patient may be as long as 30 years.

(Brookmeyer, Johnson et al. 2007, Armstrong 2014, van de Vorst, Vaartjes et al. 2015).

Aspiration pneumonia is the most common cause of death in AD patients (van der Steen, Ooms et al. 2002).

In addition to typical amnestic AD, atypical variants have been observed. They are usually divided into posterior cortical atrophy (PCA), logopenic progressive aphasia (LPA) and a frontal variant of AD (Dubois, Feldman et al. 2014, Galton, Patterson et al. 2000, Wolk 2013).

These atypical presentations have been shown to be rather common, especially among younger AD subjects (Smits, Pijnenburg et al. 2012).

2.1.3 Diagnostics

Today, the certain diagnosis of AD can only be achieved by brain biopsy. Clinical diagnostics is based on clinical and neuropsychological evaluation, brain imaging, and laboratory findings typical of the disease or findings excluding other reasons behind the symptoms. The AD diagnostic criteria according to Dubois et al. (Dubois, Feldman et al. 2007) are depicted in Table 1.

A typical finding in neuropsychological testing is poor performance in tests measuring delayed recall. Furthermore, the benefit of cueing is reduced in AD patients (Dubois, Feldman et al. 2007). In order to be diagnostical for AD, the impairment of episodic memory has had to be seen early in the course of the symptoms and to have progressed for at least six months (Dubois, Feldman et al. 2007).

In structural neuroimaging (magnetic resonance imaging (MRI) and computed tomography (CT)), the most pronounced brain atrophy is located in the medial temporal structures (entorhinal cortex, hippocampus, parahippocampal gyrus) already during the early stages of the disease but global brain atrophy may also be seen (Dubois, Feldman et al.

2007). In addition to structural brain imaging, functional imaging such as fluorodeoxyglucose positron emission computed tomography (FDG-PET) may be used. In those procedures, bilateral hypoperfusion and hypometabolism are detected in the temporal and parietal cortices (Hoffman, Welsh-Bohmer et al. 2000, Dubois, Feldman et al. 2007). In addition, amyloid-PET may be useful. For example, it has been proven that the radiotracer Pittsburgh compound B (PiB) binds highly selectively to Aβ deposits in the brain (Ikonomovic, Klunk et al. 2008), which enables the evaluation of the amyloid burden with PET imaging. The meta-analysis conducted by Ossenkoppele et al. (Ossenkoppele, Jansen et al. 2015) found that the prevalence of amyloid in a PET scan decreased with age in AD subjects, whereas the prevalence increased with age in most non-AD dementia subjects.

Hence, amyloid PET has been postulated as being helpful in the differential diagnostics of dementias, especially in the early stages of the diseases (Ossenkoppele, Jansen et al. 2015).

Certain CSF biomarkers specific for AD have also been identified. They reflect the pathological changes in the brain in an opposite manner, leading to reduced levels of Aβ1-42 and, on the contrary, increased levels of tau and p-tau in the CSF (Mattsson, Blennow et al. 2009, Tapiola, Alafuzoff et al. 2009a). The pathological changes in the brain begin already 20-30 years prior to the appearance clinical symptoms (Blennow, Dubois et al. 2014, Price, Morris 1999b), as do the changes in the levels of these biomarkers in the CSF (Figure 1) (Jack, Knopman et al. 2013). Hence, the CSF biomarkers make possible a very early diagnosis of AD. The biomarkers will be discussed further in chapter 2.7.

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Figure 1. Model of dynamic biomarkers of the pathological cascade of Alzheimer’s disease pathology. Modified from Jack et al. 2013.

In addition to fulfilling the core diagnostic criteria and supportive features, other possible reasons, such as depression, which could account for the memory deficit, must be excluded (Dubois, Feldman et al. 2007). Despite continuous revision, the clinical criteria for diagnosing AD are still considered as imperfect (Beach, Monsell et al. 2012).

Table 1. The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease (NINCDS-ADRDA) diagnostic criteria of AD according to Dubois et al. 2007.

Probable AD: A plus one or more supportive features B, C, D or E Core diagnostic criteria

A. Presence of an early and significant episodic memory impairment that includes the following features:

1. Gradual and progressive change in memory function reported by patients or informants over more than 6 months

2. Objective evidence of significantly impaired episodic memory on testing: this generally consists of recall deficit that does not improve significantly or does not normalize with cueing or recognition testing and after effective encoding of information has been previously controlled

3. The episodic memory impairment can be isolated or associated with other cognitive changes at the onset of AD or as AD advances

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Table 1. Continues.

Supportive features

B. Presence of medial temporal lobe atrophy

 Volume loss of hippocampi, entorhinal cortex, amygdala evidenced on MRI with qualitative ratings using visual scoring (referred to well characterized population with age norms) or quantitative volumetry of regions of interest (referenced to well characterized population with age norms)

C. Abnormal cerebrospinal fluid biomarker

 Low amyloid β1-42 concentration, increased total tau concentration, or increased phospho-tau concentration, or combinations of the three

 Other well validated markers to be discovered in the future D. Specific pattern on functional neuroimaging with PET

 Reduced glucose metabolism in bilateral temporal parietal regions

 Other well validated ligands, including those that foreseeably will emerge such as Pittsburgh compound B or FDDNP

E. Proven AD autosomal dominant mutation within the immediate family Exclusion criteria

History

 Sudden onset

 Early occurrence of the following symptoms: gait disturbances, seizures, behavioural changes Clinical features

 Focal neurological features including hemiparesis, sensory loss, visual field deficits

 Early extrapyramidal signs

Other medical disorders severe enough to account for memory and related symptoms

 Non-AD dementia

 Major depression

 Cerebrovascular disease

 Toxic and metabolic abnormalities, all of which may require specific investigations

 MRI FLAIR or T2 signal abnormalities in the medial temporal lobe that are consistent with infectious vascular insults

Criteria for definite AD

AD is considered definite if the following are present:

 Both clinical and histopathological (brain biopsy or autopsy) evidence of the disease, as required by the NIA-Reagan criteria for the post-mortem diagnosis of AD; criteria must both be present

 Both clinical and genetic evidence (mutation on chromosome 1, 14 or 21) of AD; criteria must both be present

There is extensive mixed neuropathology between AD and other dementing diseases (Ewers, Mattsson et al. 2015) and, furthermore, it has been shown that as many as every third of cognitively healthy elderly person displays an AD-type pathology in their brain (Hulette, Welsh-Bohmer et al. 1998, Knopman, Parisi et al. 2003a). In addition, AD-type pathological changes can be found in the brain of most subjects with DLB (Schneider, Arvanitakis et al.

2007). Similarly, up to 70% of AD cases have been reported to display Lewy body pathology in their brain (Walker, McAleese et al. 2015).

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2.1.4. Pathophysiology