Neurological Disorders

The term dementia, or, more formally, major neurocognitive disorder, describes a combination of symptoms and clinical findings, collectively called a syndrome, which interferes with people’s cognition or behavior, to the extent that the person requires some additional help compared to the past in pursuing daily activities. It is a term developed to help clinicians communicate a person’s presentation before going into more details; nothing more and nothing less.  This means that people with dementia have different levels of disease severity depending on specific symptoms, called a phenotype, and each dementia syndrome is associated with one or more underlying causes, with neurodegenerative brain pathologies and vascular brain disease being the most common.  It is also not uncommon for certain dementia syndromes to be accompanied or, even, preceded, by other disorders, such as sleep or seizure disorders.  We tend to organize dementia syndromes in the following categories, each having its own historic roots, and explaining the differences in how they are described.

Minor NCD or MCI describes a combination of symptoms and clinical findings, collectively called a syndrome, which affect people’s cognition or behavior, but not severe enough for the person to require help compared to the past in pursuing daily activities. Much like the term dementia, it is a term developed to help clinicians communicate a person’s presentation before going into more details; nothing more and nothing less. This means that people with MCI can present with a set of symptoms, called a phenotype, and each phenotype may be associated with one or more underlying causes, which can range from neurodegenerative brain pathologies, to vascular brain diseases, to metabolic disorders, or even seizure and sleep disorders. In fact, sleep disorders can present several years before cognitive disorders show up, raising the possibility that addressing sleep problems may in fact delay the onset of cognitive symptoms. Symptoms in MCI are organized in the following domains for defining a person’s phenotype: memory, executive function, language, visuospatial-constructional skills and behavior. Depending on the underlying cause of MCI, symptoms may progress, especially in neurodegenerative brain pathologies, remain stable, such as in vascular brain disease, or even improve, if they are caused by treatable sleep problems.

Much like in Minor Neurocognitive Disorder (NCD), people with SCC are concerned that their ability to perform certain cognitive tasks are not as good as they used to be, and out of proportion to getting older. But in contrast to Minor NCD, cognitive performance on standardized neuropsychological tests of people with SCC fall within the normal range. It is possible that these subjective complaints are the first signs of a developing cognitive impairment that will reveal itself over time and should be thoroughly evaluated and followed over time, but in many cases do not persist or lead to any impairments.​

Alzheimer’s dementia refers to four main syndromes that have historically been associated with a common brain pathology called Alzheimer’s disease, highlighting that Alzheimer’s dementia (i.e., what phenotype of symptoms that we see on the surface) and Alzheimer’s disease (i.e., what underlying pathology is present in their brain) do not refer to the same thing, although for both the abbreviation is “AD,” making things confusing at times. The common underlying pathology of the four syndromes, Alzheimer’s disease, was originally defined by observations in the early 20th century that certain proteins we all have in our brains, called beta-amyloid and tau, cluster in abnormal ways in certain brain areas, a process called proteinopathy, and interfere with normal brain function. Depending on the distribution of these proteins, especially tau, people develop different syndromic phenotypes. As we come to understand neurodegeneration better, it is becoming clearer that the so-called proteinopathy component of Alzheimer’s disease and other neurodegenerative diseases is only part of the whole picture, and instead several processes, such as immune, vascular, metabolic, and genetic, contribute at various degrees to the gradual functional and structural changes we see in people’s brains that give rise to symptoms. Sleep problems are present in most people with Alzheimer’s dementia, and range from sleep apnea , to insomnia and irregular sleep-wake cycles. For many, the brain enters a so-called twilight zone, where people never reach a fully alert state, and also fail to enter adequate deep sleep, invariably interfering with cognitive function during the daytime, but also accelerating proteinopathy.

• Late Age of Onset Alzheimer’s Dementia (LOAD) – Amnestic predominant: This is the most common presentation of Alzheimer’s dementia for the majority of people, affecting primarily people over the age of 65, and with the earliest and predominant symptom being difficulty with memory. It is not uncommon that caregivers will report that their loved ones forget appointments or conversations they recently had, despite being able to recall remote events in detail. Although the majority of people have Alzheimer’s disease in areas of the brain involved in memory consolidation, called the hippocampi, we are becoming aware that, more often than not, people tend to have more than one underlying brain pathology, much like people who have hypertension are more likely to also have high cholesterol or diabetes. As such, a significant number of people also have vascular brain disease or other neurodegenerative diseases when we observe brains under the microscope. This variability of what happens in people’s brains is characteristic in those presenting with Alzheimer’s dementia above the age of 80 where, instead of Alzheimer’s disease, a pathology termed LATE (i.e., Limbic-predominant Age-related TDP-43 Encephalopathy) is the predominant brain pathology. The above highlight the need for expert multidisciplinary approaches in caring for patients with dementia.
• Posterior Cortical Atrophy (PCA) – Visuospatial predominant: First described by Dr. D. Frank Benson, PCA is less common than LOAD and presents in people of a somewhat younger age. Its unique features involve difficulty in visually recognizing complex shapes, such as a face, or exact distances or movement, such as a moving car, despite people having intact elementary visual abilities, such as being able to perceive colors or static shapes. This is because the brain is unable to synchronize its function and combine individual elements of an image into a gestalt percept. PCA takes its name from the fact that areas responsible for these visual functions are in the posterior part of the brain. Many people delay being diagnosed because they assume their problems are caused by poor eyesight, and because other cognitive abilities, such as memory, are intact. Even more, they often suffer from depression that is incorrectly attributed to social causes rather than brain dysfunction. The underlying pathology of PCA is almost exclusively Alzheimer’s disease.
• Logopenic Primary Progressive Aphasia (lvPPA) – Language predominant: The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. The first is one of the Alzheimer’s dementia syndromes, whereas the latter two fall under Frontotemporal Dementia Syndromes. People with lvPPA have a predominant language deficit of word-finding difficulties, which is the result of left posterior temporal lobe dysfunction. People present with marked pauses between words when speaking because they search for the right word, even though they know what words mean, and often use a roundabout way in expressing themselves. It is also common they retain less information when spoken to because it is difficult for them to grasp at once long sentences. This explains why being spoken to with short and direct sentences is a more effective way of communicating with them. For a subset of patients with lvPPA, a history of dyslexia is common, whereas the underlying pathology is almost exclusively Alzheimer’s disease.
• Early Age of Onset Alzheimer’s Dementia (EOAD) – Dysexecutive-Behavioral predominant: A less common phenotype of Alzheimer’s dementia is EOAD, where symptoms start at an age younger than 65 years old. In contrast to its counterpart, LOAD, memory difficulties may not be the predominant deficit, and instead difficulty in organizing and planning (key features of executive function), or marked apathy, are often driving daily difficulties. Furthermore, and in contrast to the other three Alzheimer’s dementia syndromes, brain atrophy is less pronounced, often requiring specific biomarkers of Alzheimer’s disease neurodegeneration to verify the diagnosis. Patients with EOAD are often misdiagnosed as having other types of neurodegenerative diseases, such as Frontotemporal dementia, highlighting the importance of expert team protocols in their diagnosis.

FT-NCD, better known by the term Frontotemporal Dementia (FTD), refers to three dementia syndromes that share in common neurodegeneration of frontal or anterior temporal lobes. This pattern of neurodegeneration is called Frontotemporal Lobar Degeneration (FTLD) and symptoms of abnormal social behavior (bvFTD) or language difficulties (nfvPPA and svPPA) define their clinical presentation. Furthermore, the proteinopathies involved in FTD are much more diverse than in Alzheimer’s disease, with certain syndromes being more frequently associated with certain proteinopathies, and in which genetic causes are not uncommon for a subset of patients. Parkinsonism defined as a variable combination of slowness in movement (bradykinesia), muscle stiffness, tremor, or imbalance, is very common in certain FTD syndromes, especially if the underlying pathology is a tauopathy. Sleep problems are also common and present in at least three out of four people, especially insomnia and sleep apnea.

• Behavioral Variant Frontotemporal Dementia (bvFTD): In the characteristic syndrome of bvFTD, patients often have their first symptoms in their 50s where they may become socially disinhibited, lose empathy, perseverate, develop unique eating habits or binge eat, become apathetic, or have trouble in organizing and planning complex tasks. Their socially inappropriate behaviors can range from unprovoked swearing to pronounced flirtatious behavior, whereas the lack of empathy and self-centered behavior is especially hurtful to their loved ones who believe that patients no longer care for them. Many patients even divorce and find a new partner, before symptoms interfere with daily independence, which explains why their behaviors are often misinterpreted as a midlife crisis and diagnosis is delayed. The executive-behavioral deficits of bvFTD are also a common reason for families becoming bankrupt and enter debt. A subset of people is also affected by Motor Neuron Disease in the form of Amyotrophic Lateral Sclerosis (ALS), where people lose control of voluntary movement and become weak. This gives rise to the combined syndrome of bvFTD-ALS, highlighting the need for early comprehensive evaluation by a multidisciplinary team of experts. The common proteinopathies of bvFTD involve abnormal clustering of the proteins tau and TDP-43 (TAR DNA binding protein 43), whereas Alzheimer’s disease is only present in few patients.
• Non-fluent/Agrammatic Primary Progressive Aphasia (nfvPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. Logopenic variant is one of the Alzheimer’s dementia syndromes, whereas the other two are Frontotemporal Dementia Syndromes.  People with nfvPPA have a predominant deficit in speech or language planning and organization, which is the result of impaired left frontal lobe function.  This is perceived as either a difficulty (a) in precisely organizing the motor sequences of effective speech, or (b) in properly applying grammar when speaking.  As a result, symptoms may include stuttering speech, poor articulation, or omission of words in a sentence. Some people may become mute even if other cognitive functions, such as memory, are relatively intact.  It is also not uncommon for people with nfvPPA to overlap with other neurodegenerative diseases, such as PSPS (Progressive Supranuclear Palsy Syndrome) or bvFTD, depending on the underlying proteinopathy that caused the symptoms in the first place.  As in most FTD, the most common proteinopathies relate to abnormal clustering of tau or TDP-43 proteins.
• Semantic Variant Primary Progressive Aphasia (svPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. Logopenic variant is one of the Alzheimer’s dementia syndromes, whereas the latter two are Frontotemporal Dementia Syndromes. The characteristic feature of svPPA is that people lose their ability to understand the meaning of words, as a result of left anterior temporal lobe dysfunction. As a result, people are unable to follow a conversation, but also reveal a disorganized thought process, because language is one of the cornerstones of analytical thinking. In contrast, patients with svPPA often develop a visual artistic interest as they lose their language abilities, and many paint elaborate colorful paintings, or mold clay in unique ways. As the disease progresses to involve the right anterior temporal lobe, many people lose their ability to understand others’ emotions and often become more rigid in their thinking, showing perseverating and hoarding behaviors. Eating habits can be quite distinct, where people may eat only one type or color of food. For people whose brain is first affected at the right anterior temporal lobe, a key area of behavior, these abnormal social behaviors will precede the language deficits. The underlying cause of anterior temporal lobe neurodegeneration is almost exclusively a TDP-43 proteinopathy. Some studies suggest that it is more likely for people with svPPA, or their direct relatives, to have a history of autoimmune disease or cancer, suggesting that certain therapies implemented in those conditions may help in svPPA, however, clinical trials are lacking due to their rare presentation and delayed diagnosis.

In PSPS people tend to have difficulties in moving their eyes vertically or maintain their balance. As a result, they often have unexpected falls and report a difficulty reading through lines in a book. Cognitive-behavioral symptoms are practically always present, especially with difficulties in speech fluency, motivation, and planning. Sleep problems are almost invariably present, with insomnia interfering significantly with people’s lives. The most typical characteristic of PSPS is parkinsonism with muscle stiffness and slowness in movement, explaining people often being misdiagnosed having Parkinson disease. In contrast, however, to Parkinson disease where the underlying pathology is due to abnormal synuclein protein deposition, PSPS almost always have an abnormal underlying tau proteinopathy.

CBS is one of the most variable dementia syndromes, where people have difficulties in perceiving the position of their limbs in space or in controlling their movements accurately. In some people, the so-called alien limb phenomenon is present, where limbs seem to move as if they have a mind of their own. For example, hands may compete with each other when buttoning shirts. In other instances, people may not realize being touched if they don’t look at that part of the body, a phenomenon called neglect. Symptoms of parkinsonism are present in most people, becoming stiff and having difficulty in moving, further delaying accurate diagnosis. CBS takes its name from the cortical and basal ganglia of the brain being affected in the disease process, but the cause of the syndrome ranges from a tauopathy in more than half of people, to Alzheimer’s disease in a third of people.

SA-NCD refers to three syndromes with overlapping clinical symptoms, namely Lewy Body Dementia (LBD), Parkinson Disease Dementia (PDD), and Multiple System Atrophy (MSA), that usually affect people over age 50 and share α-synuclein proteinopathy as the common underlying pathology. This pathology is distributed differently across the brain and body between the three syndromes, leading to the three overlapping, but different, phenotypes. Even though people with any of the three have some level of parkinsonism symptoms, the predominant symptoms early in the disease process are different between them. Specifically, people with LBD mostly have cognitive-behavioral symptoms, people with MSA have pronounced autonomic deficits, whereas people with PDD predominantly have parkinsonism motor symptoms upon which other symptoms may follow. That said, all of the above symptoms tend to be present at different frequencies between the three as α-synuclein pathology spreads across the nervous system, explaining why physicians give a diagnosis of synucleinopathy rather than of an individual syndrome. Sleep disorders are very common and pronounced in synucleinopathies, with people being sleepy or going in and out of sleep frequently within the day, having sleep apnea, and almost four out of five having the telling symptom of REM-behavior disorder (RBD), which may present several years before parkinsonism occurs. For older people with SA-NCD, it is not uncommon for additional brain pathologies to be present, such as Alzheimer’s disease or vascular brain disease, contributing to symptom severity.

• Lewy Body Dementia (LBD): The cognitive-behavioral symptoms of LBD are usually affecting executive functions of planning, organizing, multitasking, and thinking fast, as well as visuospatial functions of constructing complex objects or perceiving things. It is not uncommon for people to mention visual hallucinations, often misperceiving things in poorly lit environments and in settings where they get sleepy. Similarly, they may report a sense of shadows at the edge of their vision as if someone is following them, which disappear when they turn to look. A fluctuating level of alertness within several minutes makes all the above symptoms even more pronounced and can help in making a diagnosis. Autonomic symptoms of constipation, dizziness upon standing suddenly, and erectile dysfunction are also common, but may not be troubling to many patients. Similarly, parkinsonism invariably presents in all people as symptoms progress, but may not be pronounced from the very beginning.
• Multiple System Atrophy (MSA): In MSA, autonomic symptoms are often severe and have patients seek medical help. People tend to faint frequently due to orthostatic hypotension or slow heart rate, and erectile dysfunction is commonly present even years before other symptoms. Motor symptoms are invariably present and distinguish two MSA phenotypes depending if they are predominantly parkinsonian (MSA-P), with stiff slow movements, or cerebellar (MSA-C), with poor coordination of goal-directed movements and imbalance. Fluctuating levels of alertness and cognitive symptoms of slow processing speed are also present but not often the ones that trigger the first visit to the physician’s office. When noticed, cognitive difficulties affect executive function of planning and organization of thinking, whereas memory is relatively spared. A concerning symptom to caregivers is the loud noise during sleep called stridor, highlighting sleep disordered breathing and the need for sleep study testing and treatment.
• Parkinson’s Disease Dementia (PDD): In PDD, people are mainly affected by motor symptoms of bradykinesia (slowness in movement), rigidity (muscle stiffness), imbalance and resting tremor that are usually worse on one side of the body. Not all symptoms need to be present, although bradykinesia and stiffness are almost always present. Most people have a decreased facial expression, termed masked facies, that is often interpreted as depression when combined with bradykinesia, even though patients may not complain of depression. The accompanying symptoms of REM-behavior disorder (RBD), constipation, erectile dysfunction and decreased ability to smell are usually present, with RBD presenting several years before motor symptoms. As in other synucleinopathies, cognitive features affect executive function of organizing and planning with decreased processing speed, but are milder than in other synucleinopathies, and the fluctuations in level of alertness are not as pronounced.

VaD refers to cognitive impairment whose cause is an underlying vascular injury such as an ischemic stroke or intracerebral hemorrhage. Symptoms are highly variable depending on the location and extent of the vascular injury, with executive, language, and visuospatial symptoms presenting more frequently, but also learning and memory, as well as behavioral symptoms interfering with daily life. People may become unable to attend or process information fast, plan or make effective decisions and prevent mistakes, speak or understand what they are told, perceive visual or other stimuli, recall information effectively, or remain motivated or even empathize. Motor symptoms are also present and usually recognized by others before cognitive symptoms. Symptoms may present suddenly right after a large stroke or a stroke affecting a critical brain area, or gradually as a result of extensive vascular injury to the small brain vessels. The specific cause of the stroke can range from clots forming in atherosclerotic large vessels feeding the brain or in the heart of people with atrial fibrillation, which in turn travel to the brain and cause ischemia, to direct injury of brain vessels leading to local ischemia or bleeding. Vascular risk factors that can be modified and prevent future strokes are hypertension, hyperlipidemia, diabetes, smoking and sleep apnea, whereas regular moderate exercise and a Mediterranean diet further help vascular integrity.