Dementia

• Dementia is a major neurocognitive disorder characterised by an acquired cognitive decline across multiple domains, impacting social and occupational functionality. Dementia stands as an important public health issue, and Alzheimer's disease, a major contributor to this condition, currently affects more than 400,000 people in Australia and 55 million people worldwide, with prevalence set to increase due to an ageing population 1, 2. . 

• With increasing longevity, the number of people living with dementia continues to rise 3 and is projected to be 153 million by 2050 4.

  The age-specific incidence of dementia decreases in high-income countries and this emphasises the need to identify and implement prevention strategies 3.

• Emerging interventions have generated a renewed interest in the need for an early diagnosis before the onset of clinical symptoms to slow down or stop subsequent neuronal loss.

• In dementia, the role of modern imaging is in diagnosis, in exclusion of reversible organic causes of cognitive impairment, and in determination of subtype.

• Commonest causes:

• Alzheimer  Disease (AD)

• Frontotemporal Dementia (FTD)

• Vascular Dementia (VaD)

• Dementia with Lewy Bodies (DLB)

• Less common or rare causes, include:

• Normal Pressure Hydrocephalus

• Huntingdon’s disease

• Corticobasal degeneration

• Progressive supranuclear palsy

• Parkinson’s disease

• Extracranial or systemic causes, including:

• Chronic alcohol abuse

• HIV/AIDS

• Tertiary Syphilis

• Atherosclerosis

• Autoimmune encephalitis

• Prion disease

With increasing age most people with Dementia have several types of Dementia 3.

About 45% of all dementia cases may theoretically be prevented by eliminating 14 risk factors (ie, less education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity,diabetes, excessive alcohol consumption [ie, >21 UK units, equivalent to >12 US units], traumatic brain injury [TBI], air pollution, vision loss, high cholesterol and social isolation) 3.

• • The diagnostic process begins with a comprehensive assessment that encompasses a detailed review of the patient's clinical history and an evaluation of functional impairment, often augmented by insights from close associates.

  •  A mental status examination conducted by a clinician is essential to identify deficits across cognitive domains such as memory, language, attention, visuospatial cognition, executive function, and mood 6, 7.

  • There are several standardised cognitive tests for the diagnosis of dementia, description of which is beyond the scope of this article

  • For cases presenting atypical forms of dementia, additional diagnostic measures, including cerebrospinal fluid assays and genetic testing, may be warranted to refine diagnoses 

  • It is important to consider and exclude extracranial or systemic/metabolic causes of dementia, including 6:

  • Chronic alcohol abuse

  • HIV/AIDS

  • Tertiary Syphilis

  • Atherosclerosis

  • Thyroid disease

  • Vitamin B₁₂ deficiency

  • Clinical depression

• • The primary role of structural neuroimaging in AD has been to exclude significant structural intracranial abnormalities such as: 

  • space occupying lesions, e.g frontal tumour

  • subdural haematoma,

  • Previous brain trauma

  • Strokes

  • MRI and CT are standard approaches.

  • CT (non-IV contrast) is usually sufficient to exclude the above causes, 

  • However, with regard to diagnosis and characterisation of neurodegenerative causes of dementia, MRI is preferred over CT 6, 8 because, although CT can show typical patterns of cortical atrophy, MRI is superior in exclusion of other causes of dementia (such as multiple infarcts). 

  • For example, MRI can identify hippocampal and entorhinal cortex atrophy in Alzheimer’s disease, as well as infarcts and white matter lesions in vascular dementia (VaD). 

  • NICE guidance (2018; last assessed 2024) 7 states that structural brain imaging should be used to rule out reversible causes of cognitive decline and to assist with subtype diagnosis, unless diagnosis and subtype are already clear 7.

  • Initial CT or MRI may also support the diagnosis of AD. Although imaging may be normal early on in the disease, hippocampal atrophy with, as the disease progresses, increasing involvement of mesial temporal structures, the precuneus, cingulate gyri and parietal lobes may become apparent 6.

  • These structural changes are better observed by using volumetric imaging9.

  • The most common MRI tools used include T1-weighted sequences, which allow the identification and localization of areas of brain atrophy, and T2-weighted or fluid-attenuated inverted recovery (FLAIR) sequences to identify the presence and severity of cerebrovascular lesions 10.

  • In routine practice, the assessment of atrophy of specific areas of the brain is qualitative, but these structural changes are best observed using volumetric  imaging9.

  • semiquantitative and, recently available automated quantitative assessment on volumetric MRI using specialised software is recommended in specialised units 8, 9, 11, 12.

  • Therefore, the  MRI protocol for primary evaluation should include key sequences such as volumetric T1 (which will allow post hoc quantitative analysis even if the capability of the primary imaging site does not include analytic software) and Gradient Echo Sequences /Susceptibility Weighted Imaging to evaluate for haemorrhage.  In this way, as much relevant information is extracted as possible during the initial imaging.

  • However, while volumetric MRI enhances diagnostic accuracy by quantifying brain atrophy, its routine clinical use may be limited due to restricted availability, high costs, and the requirement for specialized expertise. Therefore, its use should be considered based on resource availability and the clinical necessity for a more precise diagnosis.

• The primary role of structural neuroimaging in AD has been to exclude significant structural intracranial abnormalities such as:

• space occupying lesions, e.g frontal tumour

• subdural haematoma,

• Previous brain trauma

• Strokes

• MRI and CT are standard approaches.

• CT (non-IV contrast) is usually sufficient to exclude the above causes,

• However, with regard to diagnosis and characterisation of neurodegenerative causes of dementia, MRI is preferred over CT 6, 8 because, although CT can show typical patterns of cortical atrophy, MRI is superior in exclusion of other causes of dementia (such as multiple infarcts). 

• The primary role of structural neuroimaging in AD has been to exclude significant structural intracranial abnormalities such as: 

• space occupying lesions, e.g frontal tumour

• subdural haematoma,

• Previous brain trauma

• Strokes

• MRI and CT are standard approaches.

• CT (non-IV contrast) is usually sufficient to exclude the above causes, 

• Most of the advanced imaging techniques described have only limited availability in specialist or research centres in the developed world.

• If a diagnosis of a neurodegenerative cause of dementia is made on clinical criteria and standard CT or MRI, further imaging is usually only indicated if it is likely to alter management

• Advanced imaging techniques are only  indicated (if available):

• If the diagnosis of the cause or type of dementia is in doubt AND/OR

• The result is likely to change management of the patient

• That is, further tests should only be considered if it would help to diagnose a dementia subtype and knowing more about the subtype would change management 7

• Advanced imaging such as amyloid positron emission tomography (PET) should not be routinely used to make a diagnosis 7

• Advanced imaging techniques such as volumetric MRI and amyloid PET are employed selectively based on specific clinical scenarios to enhance diagnostic precision 13-15

• Typical findings of AD on CT/MRI include 10, 11, 16:

• In the classic amnestic AD syndrome, early atrophy is seen in the entorhinal cortex, in especially the mesial and lateral temporal lobes, the hippocampus and precuneus. 

• Hippocampal atrophy is linked to APOE ε4 polymorphism and the amnestic pattern of late-onset Alzheimer’s disease (LOAD) but may not be a primary feature of early-onset disease (EOAD),

• EOAD tends to have more early posterior cortical involvement. 

• Many LOAD atrophy patients also often have prominent posterior involvement 

• AD causes 60-80% of dementias

• Risk factors include (not a comprehensive list):

• Commoner with increasing age

• F>M

• Family history increases likelihood with, in some families, a genetic predisposition characterised as apolipoprotein E (ApoE) ε4 (epsilon 4) allele carrier status 17

• Chronic inflammatory conditions

• Other social factors (eg smoking, physical activity)

• Clinical Features

• In most cases of AD, a diagnosis is made based on clinical symptoms 18.

• Typical clinical features include:

• Progressive impairment of memory and cognition and the ability to carry out activities of daily living. Neuropsychiatric symptoms are also common 

• Progressive memory deficiency, often over several years, starting with short -term memory loss, leading to deterioration of attentional and executive process episodic memory deficits 19, 20.

• Clinical variants and atypical presentations of AD also occur. 20, 21

• Testing for AD

• Cognitive testing in a non-specialist environment should include one of the recognised and validated brief cognitive instruments 7.

• In a specialist centre  one of the standard validated criteria  is used, such as NINCDS-ADRA criteria 7, 20,

• If the diagnosis of AD remains uncertain but still suspected, either of the following may be considered:

• FDG-PET (fluorodeoxyglucose-positron emission tomography-CT), or perfusion SPECT (single-photon emission CT) if FDG-PET is unavailable

• examining cerebrospinal fluid for:

• either total tau or total tau and phosphorylated-tau 181 and

• either amyloid beta 1–42 or amyloid beta 1–42 and amyloid beta 1–40.7

•   If a diagnosis cannot be made after one of these tests, consider using the other one

• Appropriate Use Criteria (AUC) for amyloid PET PET/CT were recently published by the Society of Nuclear Medicine Imaging and Molecular Imaging (2024) 22

• Patients presenting with MCI or dementia <65 years old and in whom AD is suspected

• Patients presenting with MCI or dementia syndrome that is often consistent with AD pathology (amnesic presentation) with onset at 65 years or older

• Patients presenting with MCI or dementia consistent with AD but with atypical features

• Patients presenting with MCI or dementia with equivocal or inconclusive results on CSF biomarkers

• to inform the prognosis of patients with MCI due to suspected AD pathology

• to determine eligibility for treatment with amyloid-targeting therapy

• to monitor response to amyloid-targeting therapy

• A number of CSF biomarkers may aid in diagnosis of AD. These include beta-amyloid, total tau, and hyperphosphorylated tau 23

• Pathology

• AD is defined as a biological process that begins with the appearance of AD neuropathology change (ADNPC) while people are still asymptomatic. At this initial stage AD is initially evident in vivo with the presence of disease specific Core biomarkers 24. Neuropathological changes seen in Dementia do not inevitably lead to dementia 3.

• The “amyloid cascade” hypothesis suggests that the first step in the pathogenesis of AD is that amyloid-β (Aβ) aggregates and accumulates in plaques within the brain, triggering the formation of neurofibrillary (tau) tangles (NFT) throughout the brain 6. In AD there is accumulation within the brain of cerebral amyloid-β (Aβ or Abeta) forming neuritic plaques, neurofibrillary tangles and eventually progressive loss of neurones 23, 25. Amyloid-β particularly deposits in the posterior cingulate and precuneus, as well as the limbic cortex 25.

• NFT pathology is the strongest correlate of atrophy on MRI 26.

• Diagnosis

• The gold standard for a diagnosis of Alzheimer’s dementia is confirmation of the typical neuropathological findings in people with symptomatic cognitive impairment.

• In Alzheimer’s disease, the diagnosis primarily relies on clinical criteria, with biomarker evidence increasing the certainty of the diagnosis. These biomarkers include brain amyloid-beta protein deposition, evident from PET amyloid imaging and low cerebrospinal fluid Aβ42 levels, and markers of neuronal degeneration or injury such as elevated CSF tau.

• Typical findings of FTD on CT/MRI 27

• Brain imaging typically demonstrates atrophy of the frontal or temporal lobes and may be visible on MRI early in the disease course.

• FTD is a heterogenous group of neurodegenerative diseases that affect the frontal and temporal lobes

• FTD is the third commonest degenerative dementia after AD and Lewy Body Dementia

• Clinical presentation and pathology of the various forms of FTD are very variable

• FTD should be suspected in patients with atypical features for AD and who lack the biomarkers for AD

• FTD syndromes can feature extrapyramidal and parkinsonian motor symptoms with behavioural and cognitive impairments.

• CT and MRI are first-line imaging tools used to exclude space-occupying lesions and assess for characteristic brain atrophy patterns.

• Patients with FTD may be largely divided into those with primarily behavioural symptoms (behavioural variant FTD) and those with primarily language impairments (primary progressive aphasia)

• The main variants of FTD are:

• Behavioural variant FTD

• Nonfluent Variant and Semantic Variant FTD

• Semantic Variant of Primary Progressive Aphasia

• In FTD, brain imaging typically demonstrates atrophy of the frontal or temporal lobes and may be visible on MRI early in the disease course.

• Typical findings of Vascular Dementia (VaD) on MRI may include:

• areas of atrophy on T1 -weighted sequences

• white matter changes on T2 and FLAIR images 

• Iron/blood products on GRE, Susceptibility Weighted imaging 

• Evidence of acute stroke on Diffusion weighted imaging 

• If MRI is not available, CT can be used to identify cerebral infarcts and assess the severity of white matter changes

• The term “vascular cognitive impairment” includes  several forms of vascular pathology that may result in cognitive decline but do not meet the criteria for dementia in that they do not interfere with the activities of daily living 28.

• “Major vascular cognitive impairment” (vascular dementia; VaD) requires deficits in at least one cognitive domain and severe disruption activities of daily living that are independent of stroke- related motor or sensory impairment 28.

• Major vascular cognitive impairment includes the following subtypes: 1 poststroke dementia (cognitive decline within 6 months of stroke); 2subcortical ischemic vascular dementia; 3 multi-infarct dementia; and 4 dementias due to mixed pathologies, such as AD +VaD 28, 29.

• Elderly patients frequently exhibit a mixed picture of AD plus VaD.  Mixed dementia complicates diagnosis and treatment, as patients may present with symptoms of both neurodegeneration (AD) and vascular pathology (VaD). The clinical course of mixed dementia may be more variable than pure AD or VaD, with a combination of progressive memory loss, executive dysfunction, and vascular-related cognitive fluctuations. 

• In addition, Cerebral Amyloid Angiopathy (CAA) is a cerebrovascular disorder characterized by amyloid-beta deposition in the walls of small-to-medium-sized cerebral arteries, leading to an increased risk of hemorrhages, microbleeds, and cognitive decline. It is an important differential for vascular dementia and frequently coexists with Alzheimer’s disease pathology. Patients with CAA often present with progressive cognitive decline (as would be seen in Alzheimer dementia), episodic transient focal neurologic episodes ( “amyloid spells”) and sudden-onset focal neurologic deficits secondary to cortical lobar intracerebral hemorrhages (ICH)29 .

•    CAA is an important cause of cognitive impairment and spontaneous intracerebral hemorrhage in the elderly 29

•    As the initial imaging in suspected VaD, MRI is the  preferred modality because of its increased sensitivity to small vessel ischemic disease, compared to CT 29.

• MRI sequences should include 29:

• T1 -weighted sequences to show areas of atrophy

• T2 and FLAIR images to show white matter changes

• GRE, Susceptibility Weighted imaging (for example) to show iron/blood products 

• Diffusion weighted imaging to assess for acute stroke

• If MRI is not available, CT can be used to identify cerebral infarcts and assess the severity of white matter changes. Although FDG PET is not typically a first-line imaging test for VaD, it can reveal multiple focal cortical and subcortical metabolic defects, providing a pattern distinct from AD .

• FDG-PET can help differentiate mixed dementia from isolated AD by revealing patterns of metabolic dysfunction characteristic of VaD, such as reduced metabolism in both cortical and subcortical regions.

• In patients with suspected VaD or mixed dementia, imaging of the neck vessels (CT angiography, MR or Doppler US) should be considered 8, 29

• Typical findings of DLB may include:

• Relative preservation of the medial temporal structures on CT or MRI. Advanced MRI may show less hippocampal atrophy compared to AD, with greater atrophy in subcortical structures.

• In routine practice, the assessment of atrophy of specific areas of the brain is qualitative, but semiquantitative and recently available automated quantitative assessment on volumetric MRI using specialised software is recommended in specialised units 8, 9, 11.

• Lewy body dementia (LBD) is a term describing two related conditions: Parkinson disease dementia (PDD) and Dementia with Lewy bodies (DLB) 30.

• LBD is the second commonest neurodegenerative dementia

• It is characterized by the accumulation of misfolded alpha-synuclein aggregates, (Lewy bodies) 30, 31

• DLB is distinguished clinically from PDD only by the requirement that the dementia manifests more than 12 months after the onset of motor signs in the setting of PD. If dementia precedes or is concurrent with Parkinsonism, then DLB is diagnosed 30.

• LBD can be distinguished clinically from AD by: early and prominent deficits in visuospatial, executive, and attentional functions (as opposed to the marked episodic memory impairment that characterizes AD or language deficits of the progressive aphasias,); spontaneous Parkinsonism; visual hallucinations; rapid eye movement (REM) sleep behavioural disorder; cognitive fluctuations.

• Despite the above, differentiating DLB from PDD in clinical practice remains challenging due to the overlap in cognitive and motor symptoms, particularly in the early stages. Cognitive impairment in both conditions may present similarly, and some patients initially diagnosed with DLB may later meet criteria for PDD as the disease progresses. Additionally, early Parkinsonian features in DLB can complicate initial classification, particularly if motor symptoms and cognitive decline emerge simultaneously. 

• DLB is associated with relative preservation of the medial temporal structures on CT or MRI. Advanced MRI may show less hippocampal atrophy compared to AD, with greater atrophy in subcortical structures.

• In routine practice, the assessment of atrophy of specific areas of the brain is qualitative, but semiquantitative and recently available automated quantitative assessment on volumetric MRI using specialised software is recommended in specialised units 8, 9, 11.

• Hydrocephalus can be broadly divided into two categories:

• Obstructive (non-communicating) – secondary to a blockage of CSF flow through the ventricular and subarachnoid spaces, due to a congenital condition or acquired with the development of a brain lesion that exerts obstructive mass effect.

• Communicating hydrocephalus (of which Normal Pressure Hydrocephalus – NPH – is one form) is characterized by an increase in intracranial CSF content without a gross anatomic lesion obstructing flow

• NPH may be :

• idiopathic (iNPH)

• Secondary to infective, inflammatory, or haemorrhagic causes involving the subarachnoid space which leads to impaired CSF absorption at the arachnoid granulations

• Normal pressure Hydrocephalus (NPH) is a potentially reversible cause of dementia.

• Studies have shown that early shunt placement in carefully selected cases of NPH improves clinical outcomes 33

• The classic clinical presentation of NPH is insidiously progressive gait disturbance, urinary urgency followed by incontinence, and cognitive impairment

• The term “disproportionately enlarged subarachnoid space hydrocephalus (DESH)” has been used to describe prognostic MRI features in NPH, including a “tight high convexity” and enlargement of CSF spaces in the sylvian fissure. DESH is associated with a good response to shunting and is now included in in the Japanese guideline for management of NPH. “DESH” idiopathic NH is contrasted with “non-DESH”  34.

• Initial imaging in patients with suspected idiopathic NPH should include structural imaging with CT, or preferably MRI. 

• The role of imaging is to exclude other structural brain abnormalities which could mimic NPH, identify features that support the diagnosis and allow identification of prognostic  features 8.

• Imaging findings, such as Evans index and callosal angle measurements, are important for diagnosing iNPH and may predict the patient's response to therapeutic interventions like shunting.

• Non-contrast CT can demonstrate dilatation of the CSF spaces and tightness of the convexity as well as exclude many obstructive causes of CSF flow.

• However, MRI (non-contrast) is preferable as it can also demonstrate cerebral aqueduct flow void and may be unable to detect small obstructing lesions along the course of the ventricular system causing obstructive hydrocephalus

• Classic imaging features of NPH  on MRI include ventriculomegaly out of proportion to the degree of brain parenchymal volume loss, enlargement of lateral ventricular frontal and temporal horns, periventricular white matter T2 signal changes, thinning of the corpus callosum, relative effacement of sulci near along the high convexities near the vertex and disproportionate expansion of the sylvian fissures, a flow void in the cerebral aqueduct, and lack of an obstructing lesion 8, 35.

Although controversial, with conflicting reports, there is some evidence that shows quantification of CSF stroke volume in NPH may predict shunt responsiveness in some patients 36.

Phase contrast MRI

• Phase contrast MRI can be used to demonstrate a high velocity aqueductal flow void in patients with NPH 

DTPA Cisternography

• In patients with NPH, DTPA cisternography shows persistent radiotracer activity in the lateral ventricles and, on delayed imaging, absence of radiotracer activity over the cerebral convexities 37

• Combining the technique with SPECT/CT can result in improved anatomical localization of radiotracer activity compared to simple planar imaging. 

• Some studies have shown that DTPA findings of NPH may correlate with positive response to shunting, but there is insufficient evidence determine the requirement for shunting based upon DTPA cisternography findings alone 37, 38

• Compared to standard MRI-based assessments, such as the Evans index and callosal angle measurements, DTPA cisternography is invasive and not routinely recommended. MRI remains the preferred modality for diagnosing and prognosticating NPH, with DTPA cisternography reserved for select cases where conventional imaging is inconclusive.

Diffusion Tensor MRI

• There are significant correlations between Diffusion Tensor Imaging (DTI) and clinical symptoms in iNPH patients 39.

• There are different DTI patterns in patients with iNPH compared to those with Alzheimer or Parkinson diseases 39.

• Imaging is pivotal in the dementia diagnostic pathway for excluding organic pathologies and visualising structural changes in the brain. 

• Functional imaging techniques, such as fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), can play a crucial role in identifying metabolic patterns indicative of specific dementia types 40, 41.

• In practice, NICE 7 and other professional bodies recommend that:

  • FDG-PET (fluorodeoxyglucose-PET-CT), or perfusion SPECT (single-photon emission CT) if FDG-PET is unavailable or

  • Examining cerebrospinal fluid (CSF) for: either total tau or total tau and phosphorylated-tau 181 and either amyloid beta 1–42 or amyloid beta 1–42 and amyloid beta 1–40.

  •  If a diagnosis cannot be made after one of these tests, consider using the other one 42

• If the diagnosis is uncertain and Alzheimer’s disease is suspected, consider either:

¹⁸F- FDG-PET / PET-CT

¹⁸ F-FDG PET imaging is used to measure brain metabolism.

The pattern of hypometabolism in patients with AD is distinct from that seen in other dementias with overlapping symptomatology, such as Parkinson’s Disease Dementia, DLB, or FTD 10

The advantages of ¹⁸F -FDG PET include the following:

• If the diagnosis of AD is uncertain ,¹⁸F- FDG-PET can depict a relatively early stage of neurodegeneration when structural changes are still minimal 43.

• FDG-PET accurately discriminates AD patients from normal subjects with a sensitivity of 96% and specificity of 100% 8

• FDG-PET can Identify patterns of reduced glucose uptake in the brain to support the diagnosis of dementia and in the differential diagnosis of its type.

• It is useful for distinguishing between the patterns of AD versus VaD 10, 44 and between AD and FTD 27, 43.

• FDG-PET demonstrates distinct patterns of decreased uptake for Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) as well as its multiple subtypes such as behavioural variant FTD 43.

• ¹⁸F- FDG-PET can differentiate the subtypes of FTD (27) (sens 60%, PPV 78.5% 8

• There is some overlap in patterns of uptake with AD. However, metabolism in the posterior cingulate cortex is known to be relatively preserved in DLB and visual assessment of the “cingulate island sign” is a helpful tool in the analysis of 18F-FDG-PET43, 45 . FDG-PET has been reported as being of high diagnostic performance in predicting DLB versus AD 46.

¹⁸F-Amyloid PET-CT

• Amyloid PET utilizes a ligand that binds selectively to amyloid plaques 

• Amyloid PET/CT is of limited availability and largely confined to specialist and research centres

• The following are noteworthy regarding Amyloid PET/CT: 8

• Amyloid PET/CT has been shown to be positive in up to 60% of patients with Mild Cognitive Impairment  (MCI) 8.

• Patients with MCI and positive amyloid PET/CT are more likely to progress to AD than patients with MCI and negative amyloid PET/CT 8.

•  Patients with MCI and positive amyloid PET/CT have greater cognitive decline than those with negative amyloid PET/CT 8.

• Amyloid PET/CT and fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT are complementary and when combined have better accuracy at predicting conversion of patients with MCI to AD

• Amyloid PET has a high sensitivity and specificity in distinguishing AD vs normal 8.

• Imaging with amyloid-specific PET tracers demonstrates widespread amyloid deposition throughout the cortex in patients with AD 10

• Amyloid PET is useful in assessing for mixed vascular cognitive impairment and AD 29.

• Appropriate Use Criteria (AUC) for amyloid PET PET/CT were recently published by the Society of Nuclear Medicine Imaging and Molecular Imaging (2024) 22.

• This AUC document states that amyloid PET/CT is most appropriate in:

• Patients presenting with MCI or dementia <65 years old and in whom AD is suspected

• Patients presenting with MCI or dementia syndrome that is often consistent with AD pathology (amnesic presentation) with onset at 65 years or older

• Patients presenting with MCI or dementia consistent with AD but with atypical features

• Patients presenting with MCI or dementia with equivocal or inconclusive results on CSF biomarkers

• to inform the prognosis of patients with MCI due to suspected AD pathology

• to determine eligibility for treatment with amyloid-targeting therapy

• to monitor response to amyloid-targeting therapy

• Despite its advantages, the impact of positive amyloid PET on clinical decision-making remains debated, particularly in asymptomatic or minimally symptomatic individuals. 

• The presence of amyloid plaques does not necessarily correlate with cognitive decline, leading to concerns about potential over diagnosis and unnecessary interventions. 

• Clinicians should carefully weigh the benefits and limitations of amyloid PET before requesting the test, considering both patient-specific factors and the availability of disease-modifying treatments.

Diffusion Tensor MRI

• Diffusion tensor imaging is an advanced magnetic resonance technique that uses the Brownian motion of water molecules to provide data for images, allowing investigation of the detailed architecture of the brain. By depicting the direction and magnitude of water diffusion, DTI neural pathways can be visualised 47.

• Diffusion tensor imaging (DTI) MRI and FDG PET have proven particularly useful in differentiating FTD from AD by revealing distinctive atrophy patterns and metabolic profiles 27

• DTI  can demonstrate high sensitivity for assessing white matter damage in FTD and have been shown to be more accurate in classifying FTD subtypes than atrophy patterns 48.

• DTI may aid in  distinguishing mixed dementia from pure VaD and AD  29, 49

SPECT or SPECT/CT brain imaging

This may take two forms:

1. Brain perfusion SPECT (single-photon emission CT) or SPECT/CT

• In suspected AD, considered an adjunct to other structural, functional, and metabolic imaging modalities 8

• A specific pattern of bilateral posterior hypoperfusion on brain perfusion SPECT increases the likelihood of a diagnosis of AD rather than VaD or FTD 8

• Brain perfusion SPECT or SPECT/CT may aid in distinguishing  patients with DLB from those with AD 8

2. Dopamine transporter single-photon emission computed tomography (SPECT) or SPECT/CT.

• Receptor-binding radiotracers are used which bind specifically to Dopamine brain receptors.

• Otherwise known as SPECT or SPECT/CT Brain Striatal

• A normal pattern of radiotracer uptake in the striatum on brain striatal SPECT or SPECT/CT can help distinguish patients with AD from those with DLB 8, 30