Alzheimer dementia

Alzheimer disease is a common neurodegenerative disease, responsible for 60-80% of all dementias, and imposing a significant burden on developed nations. It is the result of accumulation and deposition of cerebral amyloid-β (Aβ) and is the most common cerebral amyloid deposition disease.

Epidemiology

Alzheimer disease is the most common cause of dementia, responsible for 60-80% of all dementias . The prevalence is strongly linked to age, with >1% of 60-64-year-old patients being diagnosed with the condition, compared to 20-40% of those over 85-90 years of age .

Risk factors

Risk factors include :

• advanced age
• female gender
• apolipoprotein E (ApoE) ε4 (epsilon 4) allele carrier status
• current smoking
• family history of dementia
• mutations of amyloid precursor protein
• Down syndrome
• chronic inflammation e.g. psoriatic arthritis

In addition to the genetic and environmental factors above, the age of presentation is also influenced by socioeconomic factors :

• formal education
• income
• occupational status
• social network and family support

Individuals with premorbid higher function/supports are able to compensate for early disease changes to a greater degree and thus present later. Consequently, when well-supported patients eventually present, they tend to have more marked morphological changes on imaging .

Clinical presentation

Traditionally, Alzheimer disease has been clinically characterized predominantly by memory deficits, at least in initial stages. It has become increasingly evident that in addition to the typical presentation, a number of atypical clinical patterns exist, which are nonetheless pathologically Alzheimer disease.

Classical/typical Alzheimer disease

The typical patient with Alzheimer disease will present initially with antegrade episodic memory deficits . Over time (often years), the disease progresses, with eventual involvement of attentional and executive processes, semantic memory, praxis, and visuoperceptual abilities . Neuropsychiatric symptoms are also common and eventually affect almost all patients. These include apathy, depression, anxiety, aggression/agitation, and psychosis (delusions and hallucinations) .

Atypical/variant Alzheimer disease

These entities, often recognized clinically well before they were identified to be pathologically identical to Alzheimer disease, are characterized by slowly progressive focal cortical atrophy, with symptoms and signs matched to the affected area . Examples include:

• posterior cortical atrophy
• frontal variant of Alzheimer disease
• minority of cases with predominant semantic dementia

Diagnosis

Clinical diagnosis is made by identifying a progressive decline in memory both with clinical examinations and neuropsychologic tests and has been historically based on the NINCDS-ADRA criteria, which divides patients according to the certainty of the diagnosis into :

Although using longitudinal clinical criteria is highly sensitive in diagnosing a dementia of any type (>90%), they are relatively inaccurate (<70%) in diagnosing Alzheimer disease specifically .

Importantly, the NINCDS-ADRA criteria only include imaging and laboratory examination or blood and CSF in excluding other causes.

The only definitive diagnostic test is brain biopsy which in practice is rarely obtained. As such, the combination of clinical features and neuroimaging are usually considered sufficient, although, especially with the recognition of variants, this approach undoubtedly misdiagnoses a significant number of cases.

A number of CSF biomarkers are being used which may further aid in diagnosis. These include beta-amyloid, total tau, and hyperphosphorylated tau .

Pathology

Alzheimer disease is characterized by the accumulation within the brain of cerebral amyloid-β (Aβ or Abeta) forming neuritic plaques, neurofibrillary tangles and eventually progressive loss of neurons .

Cerebral amyloid-β particularly deposits in association areas of the neocortex, the posterior cingulate and precuneus, as well as the limbic cortex, although the reason for this distribution has not been elucidated .

The underlying reason for the accumulation of senile (neuritic) plaques and neurofibrillary tangles remains poorly understood, as does the reason for non-uniform distribution in the cortex.

There is, however, increasing evidence to suggest that chronic inflammation is at least partially responsible. Such inflammation can lead to prolonged parenchymal activation of microglial cells which in turn results in the release of inflammatory mediators with subsequent neuronal damage and amyloid-induced neurodegeneration .

Radiographic features

Although CT is able to demonstrate the characteristic patterns of cortical atrophy, MRI is more sensitive to these changes and better able to exclude other causes of dementia (e.g. multi-infarct dementia) and as such is the favored modality. In addition to structural imaging, molecular imaging with PET is increasingly of value in the diagnosis of Alzheimer disease.

Braak staging on imaging shows the sequential involvement of various structures as follows :

• Stage I and II : earliest involvement of entorhinal cortex.
• Stage III and IV: involves limbic system and hippocampus.
• Stage V and VI: involves cortex (precuneus in particular) with temporal lobes 

MRI

The primary role of MRI (and CT for that matter) in the diagnosis of Alzheimer disease is the assessment of volume change in characteristic locations which can yield a diagnostic accuracy of up to 87% . Unfortunately, such volume loss is not apparent early in the course of the disease .

The diagnosis should be made on the basis of two features:

Mesial temporal lobe atrophy can be assessed directly or indirectly. Direct assessment is of hippocampal or parahippocampal volume loss while indirect assessment relies on an enlargement of the parahippocampal fissures. The former is more sensitive and specific but ideally, requires actual volumetric calculations rather than 'eyeballing' the scan . These measures have been combined in the medial temporal atrophy score which has been shown to be predictive of progression from mild cognitive impairment (MCI) to dementia .

Additionally, and particularly relevant to posterior cortical atrophy or early-onset Alzheimer disease, is the presence of parietal atrophy. This is often best seen on the interhemispheric surface of the parietal lobe  (see neurodegenerative MRI brain: an approach) by examining the posterior cingulate sulcal and parieto-occipital sulcal size and degree of atrophy of the precuneus and cortical surface of the parietal lobe. This has also been combined into a scoring system (see posterior atrophy score of parietal atrophy a.k.a. Koedam score).

Brain volume measurements, assessed with segmentation, demonstrate that patients with Alzheimer disease have accelerated rates of brain volume loss, typically around twice normal (1% vs ~0.5% per year) . This is even more marked in the hippocampi, with affected individuals exhibiting three times the volume loss per year (~4.5% vs ~1.5% per year) .

Nuclear medicine

SPECT and PET are able to detect regional hypoperfusion/hypometabolism in a biparietal and bitemporal distribution.

FDG PET

F-18 fluorodeoxyglucose (FDG) PET typically shows bilateral temporoparietal, precuneus and posterior cingulate hypometabolism which is usually symmetric. Uptake may be asymmetric in the early stages. The anterior cingulate, visual cortex (provided the eyes were kept open during uptake time), basal ganglia, thalami, occipital lobes and cerebellum are usually spared. Classically, even late in the disease, the sensorimotor cortices are relatively spared .  Frontal lobes may be involved in late stage .

Amyloid PET

C-11 Pittsburgh compound B, as well as newer compounds such as F-18 florbetapir (trade name Amyvid), F-18 flutemetamol (trade name Vizamyl), and F-18 florbetaben (trade name NeuraCeq), are PET tracers that bind preferentially to beta-amyloid fibrils and thus may be able to improve the specificity of antemortem diagnosis , although there is considerable overlap with normal controls .

With increased cerebral amyloid-β (Aβ) deposition, increased activity is demonstrated in the cortex . It is particularly useful in excluding Alzheimer disease as the cause of dementia, as a negative amyloid PET scan renders the diagnosis unlikely .

Tau PET

Newer PET agents that bind tau proteins in neurofibrillary tangles are being investigated (e.g. 18F-flortaucipir) which result in increased activity in the expected locations of deposition in Alzheimer disease (hippocampus, entorhinal cortex and temporal and parietal cortex) . These agents are, however, not specific to Alzheimer disease and will also deposit in other tauopathies (e.g. chronic traumatic encephalopathy and progressive supranuclear palsy) .

Treatment and prognosis

There is no cure for this disease; some drugs have been developed trying to improve symptoms or, at least, temporarily slow down their progression.

• cholinesterase inhibitors e.g. donepezil
• partial NMDA receptor antagonists
• medications for behavioral symptoms
  • antidepressants
  • anxiolytics
  • antiparkinsonian (movement symptoms)
  • anticonvulsants/sedatives (behavioral)

Differential diagnosis

In cases where bilateral mesial temporal lobe volume loss is present on imaging in an elderly amnestic patient, the main differential is limbic-predominant age-related TDP-43 encephalopathy (LATE) . Not only is this entity increasingly recognized as a significant cause of dementia of Alzheimer's type despite being pathologically distinct, but it can also co-exist with Alzheimer's disease . At present, there is no definitive way of establishing the diagnosis other than retrospectively at autopsy. A number of features may suggest the diagnosis :

• rostrocaudal involvement of the amygdala and hippocampus (amygdala involved first followed by hippocampal head and anterior body)
• profound and asymmetric amygdala and hippocampal volume loss with relatively little involvement of other parts of the brain. 
• negative amyloid-PET