What is Dementia?

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• Prevalence and Causes of Dementia (Types)
• General Symptoms of Dementia
• Diagnosis of Dementia
• Treatment of Dementia
• Alzheimer's Disease (AD)
• Vascular Dementia (VaD)
• Dementia with Lewy Bodies (DLB)
• Frontotemporal Dementia (FTD)
• Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)
• Posterior Cortical Atrophy (PCA)

Dementia refers to a group of progressive neurological conditions and symptoms characterized by a gradual decline in one's cognitive abilities (memory, thinking, communication and behavior) as well as impairing one's activities of daily living. Dementia includes several notable conditions, each being a separate disease in its own right, which can lead to the general symptoms discussed below. At present, there is no cure for dementia though some treatments are available to slow down the symptomatic decline.

Prevalence and Causes of Dementia (Types)

Dementia affects approximately 50 million people globally (as of 2018) and is expected to increase to over 150 million by 2050. Within the UK, 1 million people will have dementia by 2025, and this will double to 2 million by 2050.

The most common causes of dementia are (discussed in more detail below):

• Alzheimer's Disease (AD)
• Vascular Dementia (VaD)
• Dementia with Lewy Bodies (DLB)
• Frontotemporal Dementia (FTD)
• Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)
• Posterior Cortical Atrophy (PCA)

Other conditions can also lead to symptoms of dementia:

• Parkinson's Disease (PD)
• Huntington's Disease (HD)
• Down Syndrome
• Creutzfeldt-Jakob Disease
• Korsakoff Syndrome

It is possible to have two or more of the conditions listed at the same time in what is known as mixed dementia, such as AD and VaD, or AD & LATE.

Other forms of acute memory deficit may be reversible and could be attributed to hypothyroidism, vitamin B12 deficiency, Lyme disease, HIV infection, hearing loss, or neurosyphilis. Therefore, a correct diagnosis is needed to determine the cause and type of dementia that is clinically manifested.

General Symptoms of Dementia

The symptoms of dementia can vary considerably depending on the type of dementia (listed above), the age of onset, severity, and stage of disease course. By the time the first noticeable symptoms occur, severe pathological changes within the brain have already taken place.

Unlike occasional forgetfulness or decrease in mental functioning that is attributed to advanced age, dementia is more pronounced and gradually (or rapidly in some cases) deteriorates within a few years.

Symptoms that are common to most forms of dementia include:

• Progressive memory deficits
• Language and attention deficits
• Problem-solving and thinking difficulties
• Depression & anxiety
• Irritability, agitation, and aggression
• Decreased motivation & apathy
• Delusions and hallucinations
• Changes to sleep and eating routines
• Sometimes there are visual perception changes

Diagnosis of Dementia

Diagnoses of the different types of dementia is usually carried out by using an array of structural and functional neuroimaging techniques (e.g. MRI, PET/SPECT, and CT scans) in addition to cognitive tests (e.g., MMSE), motor tests as well as blood/urine biochemical tests to rule out other conditions, infections, and diseases.

Differential diagnosis between the different types of dementia is also critical for a better prognosis as some medications used to treat some of the diseases may worsen some of the symptoms of others.

Though some diagnoses may reveal mixed dementia (having two or more of the dementia diseases), which may be more complicated to diagnosed and manage.

Treatment of Dementia

There is currently no cure for any of the different dementias. Limited medications are routinely administered to manage some of the cognitive and behavioral symptoms associated with dementia, though none are able to modify disease course (i.e., slow down disease progression).

Specific examples are mentioned for each disease. For all dementias, only palliative care can be offered to manage the decline in activities of daily living, leading to full-time care.

Specific forms of dementia are discussed in more detail below.

Alzheimer's Disease (AD)

AD: The most common form of dementia and is a progressive neurodegenerative disease typically starting later in life around their 70s/80s (though there are some cases of early-onset AD). Patients usually die within 3-9 years after disease onset.

Prevalence: 50-60% of all dementia cases worldwide.  

Causes & Pathology: The exact causes for a majority of cases are still mostly unknown. However, there are key genes implicated in some familial cases (e.g., familial mutations to APP and PSEN1).

Pathologically, amyloid-beta plaques and neurofibrillary tangles of hyperphosphorylated-tau protein contribute to the neurodegeneration within the cortex and hippocampus, leading to the generalized cortical and hippocampal atrophy with ventricular enlargement.

Symptoms: Progressive memory loss (names, faces, events), mood changes (anxiousness, frustration, and impulsive behaviors), depressive symptoms, and anxiety with the loss of motivation and apathy, possible delusions, and hallucinations, insomnia and speech and language problems.

Activities of daily living become impaired, and patients require full-time care and assistance. AD symptoms begin subtly but gradually worsen, and patients become more withdrawn from life.

Diagnosis: Usually, neuroimaging techniques are used to assess neurological damage and are combined with a standardized questionnaire called the mini-mental state examination (MMSE) is used to test cognitive ability. Only after the exclusion of other causes can a definite diagnosis be made.

Treatments: There is currently no cure for AD. The most common medications used to treat the symptoms of AD are called acetylcholinesterase inhibitors, which modulate acetylcholine levels within the brain (which is typically reduced in AD) – these include rivastigmine and donepezil.

As of 2019, a drug called Aducanumab has been shown to be a promising drug that can slow down the rate at which AD progresses but is still unable to reverse or cure the disease.

More details about AD pathology, causes, symptoms, diagnosis, and treatment can be found here.

Vascular Dementia (VaD)

VaD: Second most common form of dementia worldwide and is caused by cardiovascular disease (CVD) and stroke with the most significant risk factors being atherosclerosis (plaque build-up in the arteries) and arteriosclerosis of blood vessels (carotids and cerebral arteries), cerebral small vessel disease (inflammation and the disruption of the integrity of the blood-brain-barrier (BBB)), hypertension (increased blood pressure), smoking, hypercholesterolemia (elevated blood cholesterol), celiac disease & diabetes mellitus.

Prevalence: 25% of all dementia cases worldwide with up to 20% of all people with AD also having some degree of VaD, leading to the most common form of mixed dementia.

Causes & Pathology: Vascular lesions (atherosclerosis of major and small arteries), lipid deposits, ischaemic areas caused by reduced blood flow, clotted blood in vessels, small vessel disease leading to significant neuroinflammation along vessels and disruption of the BBB are all typical pathological hallmarks of VaD.

White matter atrophy and microinfarcts in the grey matter also occur. Some cases of VaD can be triggered by the presence of cerebral amyloid angiopathy (CAA) caused by an accumulation of amyloid-beta in and around blood vessels – also why VaD and AD can present together.

Symptoms: Similar to the symptoms of stroke including vision impairment, motor dysfunction (hemiparesis, bradykinesia, hyperreflexia, gait and swallowing problems) as well as cognitive and behavioral symptoms of dementia that occur over a period of 5-10 years, although these can suddenly worsen if another ischaemic stroke occurs (multi-infarct dementia).

Diagnosis: Neuroimaging by CT and MRI scans to assess the location and extent of the lesions, as well as SPECT or PET scanning for multi-infarct dementia.

With most dementia diagnoses, a mental status examination is also required to assess cognitive deficits. Blood tests for anemia, vitamin deficiency, infection, C-reactive protein levels, and erythrocyte sedimentation rate are also required. Mixed dementia can be diagnosed in combination with a definite diagnosis for AD.

Treatments: No current cure or medications for the treatment of VaD. Some cognitive deficits can be alleviated by the use of acetylcholinesterase inhibitors and NMDA-receptors used to treat AD. As there is an increased risk of VaD for those with celiac disease, a strict gluten-free diet may be beneficial. Other cardiovascular disease-related strategies may also provide some benefits, especially in earlier stages.

Dementia with Lewy Bodies (DLB)

DLB: DLB is the 3^rd most common form of dementia worldwide and is a neurodegenerative disease that results in a progressive decline in cognition, behavior, and movement. Due to pathological and symptomatic similarities and overlap with Parkinson's disease (PD), DLB is grouped with Parkinson's disease dementia (PDD – which is dementia after the onset of PD as compared to dementia followed by motor symptoms of PD). DLB usually starts around or after the age of 50, and the average survival is approximately eight years after diagnosis.

Prevalence: ~10% of all dementia cases worldwide

Causes & Pathology: The cause of DLB (a synucleinopathy) is still mostly unknown however within the brain widespread accumulation of alpha-synuclein protein aggregates; called Lewy bodies, can be found (as in PD), that lead to the loss of many different brain regions including the loss of cholinergic neurons like in AD (leading to cognitive and behavioral symptoms) as well as dopaminergic neurons (leading to PD, mood, motivation, sleep and autonomic symptoms).

DLB is not usually genetically inherited (only around 10%) but may have a genetic basis in most cases, such as having the APOE4 allele (a risk factor for AD) amongst polymorphisms to PD genes PARK11 and GBA.

Lewy bodies primarily affect neurons of the central nervous system and the autonomic nervous system (midbrain). As such, the symptoms of DLB are more complex.

Symptoms: Specific symptoms that are unique to DLB are that of REM sleep disturbances (loss of paralysis during REM sleep to act out dreams), visual hallucinations, attention deficits, slowness of movement (bradykinesia), GI tract motor disturbances, sexual dysfunction, walking difficulties such as shuffling gait and rigidity (core symptoms of PD).

In initial stages, the first symptoms to appear are that constipation and dizziness as well as the reduced sensation of smell (also the same in PD) as well as the emergence of REM sleep disturbances. As such, distinguishing DLB from AD and other dementias is easier, though not initially if both present simultaneously.

As with most other dementias, as the disease progresses, there is a decline in cognition and behavior, including loss of episodic memory (memory impairment) but only much later in the disease.

Diagnosis: A combination of neuroimaging techniques, including PET/SPECT, MRI, and CT imaging. DLB can often present together with AD, often complicating diagnosis with AD treatments not necessarily working for DLB symptoms and may worsen some symptoms if not promptly diagnosed. A combination of cognitive tests (MMSE, Montreal Cognitive Assessment) and motor and sleep tests may further aid a correct diagnosis.

Treatments: There is no cure for DLB, and the management of symptoms of DLB are much more complicated than other forms of dementia.

People with DLB are hypersensitive to antipsychotic treatments (as used in AD and other dementias) and may lead to irreversible side effects. For DLB, only palliative care can be offered with no medications being able to modify the disease course. This is because the mix of cognitive, behavioral, psychiatric, and motor symptoms makes managing symptoms difficult.

This is why acetylcholinesterase inhibitors are not typically used due to the worsening of psychiatric symptoms in DLB.

Frontotemporal Dementia (FTD)

FTD: FTD refers to several types of dementia involving pathology within the frontal and temporal lobes of the brain. Unlike AD and VaD, FTD seems to be more genetic in their etiology. Some of the types of FTD include semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, corticobasal syndrome, progressive supranuclear palsy and FTD related to motor-neuron disease/amyotrophic lateral sclerosis (MND/ALS). Unlike most other forms of dementia such as AD and VaD, FTD occurs earlier on in life around their 50s.

Prevalence: ~10% of all dementia cases worldwide.

Causes & Pathology: Frontotemporal lobar degeneration (FTLD) results in the degeneration of around 70% of spindle neurons across these lobes.

Three key pathological variants of FTLD are FTLD-tau (those with tau tangles and Pick bodies), FTLD-TDP (those with TDP-43), and FTLD-FUS (those with FUS). These pathological changes occur to genetic alterations leading to the different forms of the disease.

Tau-positive FTD with parkinsonism is caused by mutations to MAPT encoding Tau (also affected in AD), leading to neurofibrillary tangles and Pick bodies. FTD can also be caused by mutations to TARDBP encoding TDP-43 and the hexanucleotide repeat expansion of C9orf72 that contributes to a large proportion of cases even without ALS (both genes are related to ALS/MND).

Symptoms: Typically a gradual onset of symptoms in the 5^th or 6^th decade of life with changes to social and personal behaviors including loss of social awareness and poor impulse control, apathy, blunting of emotions and semantic dementia which refers to deficits in the reception (word comprehension) of language and/or progressive non-fluent aphasia which is the progressive inability to produce speech.

Perception, spatial skills, motor planning, and memory are typically preserved in FTD, though executive functioning and working memory are impaired.

Those with ALS who develop FTD, the prognosis overall is worsened by a year. Initially, FTD is similar to AD in terms of symptoms due to the lack of noticeable motor symptoms and may confuse.

Diagnosis: MRI scans are used to identify frontal lobe and temporal lobe atrophy is mid-stage and advanced stages of FTD, either bilaterally or unilaterally/asymmetrically. Repeat scans can reveal progressive degeneration. FDG-PET scans can reveal reduced functioning and metabolism in frontotemporal lobes to differentially diagnose FTD to AD.

As mentioned, the differential diagnosis between FTD and AD in the initial stages is difficult, but the correct neuropsychological test can then confirm the diagnosis to confirm disinhibition, apathy, loss of sympathy/empathy, and compulsiveness. Apathy is also a feature of advanced AD.

Treatments: There is no cure for FTD though there are treatments available to manage the behavioral symptoms of FTD, such as the use of SSRIs for disinhibition and compulsiveness. As cholinergic dysfunction is not present in FTD, acetylcholinesterase inhibitors used to treat AD cannot be used for FTD.

Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)

LATE: A newly identified form of dementia that primarily affects older adults over the age of 80, which is similar to AD but has different pathogenesis. LATE may account for a quarter of all dementia cases over 80 and usually presents comorbidly with AD, FTD and amyotrophic lateral sclerosis (ALS).

Prevalence: Potentially, around 25-30% of all dementia cases over the age of 80 worldwide, with up to a third of all AD cases over 85, may being LATE rather than AD pathologically. As this is a newly identified form of dementia, the exact statistics are still unknown.

Causes & Pathology: Unlike amyloid plaques found in AD, LATE is characterized by the presence of TDP-43 protein aggregates (similarities to FTD and ALS) found mainly in the amygdala, hippocampus and middle frontal gyrus (medial temporal lobe structures).

There may or may not be significant hippocampal sclerosis. Furthermore, compared to FTLD-TDP, TDP-43 pathology is much more restricted neuroanatomically.

As LATE often presents alongside AD, there may also be beta-amyloid plaques and tau pathology. Genetic analyses have shown risk genes being GRN, TMEM106B, ABCC9, KCNMB2, and APOE – thus being related to both AD and FTD, but also being a distinct disease. As this is a newly identified disease, much more research (cell and animal models) is needed.

Symptoms: Mostly overlapped with symptoms of AD (retrograde amnesic dementia).

Diagnosis: At present, there is no real differential diagnosis of LATE from AD in the clinic, only post-mortem. Unlike FTLD-TDP, which starts around 50 years of age, LATE starts much later with much more restricted pathology.

The development of an effective disease biomarker (such as in the blood or CSF, or imaging) would significantly advance diagnosis much earlier and more accurately as well as importantly distinguishing from AD in the clinic, aside from advanced age.

Treatments: There is no cure or disease-modifying treatment for LATE, though some acetylcholinesterase treatments used for AD as well as the monoclonal antibody aducanumab may potentially have some benefit. As this is a newly identified disease, treatments used to treat AD may not necessarily work for LATE; hence more research is needed at this stage.

Posterior Cortical Atrophy (PCA)

PCA: PCA, also known as Benson's syndrome, is a rare variant of AD, which leads to specific symptoms associated with degeneration of the posterior regions of the cerebral cortex leading to visual symptoms.

Prevalence: Up to 5% of people diagnosed with AD have PCA, though the exact prevalence of PCA alone is unknown. This is due to the lack of established diagnostic criteria. As PCA symptoms often go unrecognized, the actual prevalence may be higher.

Causes & Pathology: For the vast majority of people with PCA, the cause is AD itself with the presence of amyloid-beta plaques and neurofibrillary tangles of tau (as seen in AD) but concentrated in regions of the brain in the occipital lobe leading to cortical atrophy in the posterior regions. Very few posterior patients with PCA may have their condition attributed to DLBs, corticobasal degeneration, and prion disease, and some may not have significant cortical atrophy.

Symptoms: Damage to the posterior regions of the cerebral cortex, namely the occipital lobe, can lead to impaired visual processing (visuospatial, visuoperceptual) and praxic skills. Cortical degeneration of the visual cortex can lead to difficulties in basic visual tasks such as reading, judging distances (depth perception), inability to perceive motion, and distinguish between moving and stationary objects, spatial disorientation, and the inability in identifying objects.

In early stages, patients may be aware that they have issues with visual processing, but later in the disease, once other cognitive deficits occur, patients may forget that they have specific visual issues.

Diagnosis: As PCA is relatively rare compared to other dementias and unusual symptoms, PCA is often misdiagnosed. Furthermore, there are no established diagnostic criteria or tests for PCA.

A combination of neuroimaging and visual tests (to eliminate visual or retinal conditions that may also cause such symptoms), as well as a gradual onset of symptoms around the age of 50-60, may be used for a definite diagnosis. Diagnoses will have to rule out strokes, tumors, and other visual conditions where the eye itself remains fully functional and intact.

Treatments: There are no cures or treatments for PCA that can slow down or stop the disease. AD treatments have not been proven to be any use for PCA due to the difference in the brain regions involved.

Further Reading

• All Dementia Content
• What Causes Dementia?
• Differences Between Alzheimer’s and Dementia
• Dementia Diagnosis
• Dementia Prevention

Written by

Osman Shabir

Osman is a Neuroscience PhD Research Student at the University of Sheffield studying the impact of cardiovascular disease and Alzheimer's disease on neurovascular coupling using pre-clinical models and neuroimaging techniques.