Dr. Shahal Rozenblatt, Clinical Neuropsychologist, New York

Alzheimer’s Disease & Other Dementias

by / Wednesday, 19 February 2014 / Published in Latest News

1. Alzheimer Disease (AD)

The anatomic pathology of AD includes neurofibrillary tangles (NFTs) and senile plaques (SPs) at the microscopic level. While NFTs and SPs are characteristic of AD, they are not pathognomic, as they occur in multiple other neurodegenerative diseases such as progressive supranuclear palsy and dementia pugilistica, which will be discussed below. The presences of even low numbers of NFTs in the cerebral cortex is considered abnormal and indicates AD if present with SPs in that location. Granulovacuolar degeneration occurs almost exclusively at the hippocampus. NFTs are initially most prominent in the medial aspect and in the pole of the temporal lobe. They affect the entorhinal cortex and hippocampus most severely, both areas involved in memory. As AD progresses the NFTs accumulate in most other cortical regions, beginning with higher order association regions (areas of the brain that are responsible for integrating information from multiple brain regions) and less so in primary motor and sensory areas.

The pathophysiological mechanism of AD is corticocortical disconnection due to the loss of medium-sized pyramidal neurons effecting such connections. This means that brain areas become disconnected from each other and can no longer communicate effectively, thereby reducing the individual’s ability to function effectively.

More than 14% of individuals over age 65 have AD and the prevalence increases to at least 40% in those individuals over 80 years. It affects people of all races, but data is unclear about whether it affects one race more than others. AD affects both men and women. Data show that more women have the disease than men and it has been postulated that this difference is due to the loss of the neurotrophic effects (protective mechanisms) of estrogen in postmenopausal women. More than 90% of AD cases are sporadic, meaning that there is no known cause. There are forms of AD that are early onset and these are more likely to have a familial (genetic) component. The familial forms of AD account for less than 7% of the total cases.

Patients with AD most commonly present with insidiously progressive memory loss and other cognitive deficits over time. Patients may develop language disorders such as anomia (inability to name objects) and progressive aphasia (speech impairment that becomes worse over time) as well as impairment in visuospatial skills and executive functions.

The actual causes of AD are unknown. Most cases are believed to result from converging risk factors including advancing age, head injury and lipoprotein E-epsilon 4 genotype. AD is characterized by substantial loss of acetylcholine (ACh) in the cerebral cortex and severe neuronal loss in the subcortical ACh nuclei that project to the neocortex (e.g., nucleus basalis of Meynert) and the medial septal nuclei of the hippocampus.

Depression is observed in more than 30% of patients with AD and often begins before the disease clinically manifests.

The mainstay of therapy is the use of centrally acting cholinesterase inhibitors (cholinesterase degrades ACh and inhibition of this mechanism increase levels of ACh in the CNS) to palliate the depletion of ACh in the cerebral cortex and hippocampus. The benefits are temporary because the inhibitory impact on cholinesterase does not address the underlying cause: degeneration of cholinergic neurons, which continues during the disease. Such medications do lead to improvement cognitive performance, behavioral manifestations and vascular components during late stages of the disease.

2. Vascular Dementia

Vascular dementia is the second most common form of dementing process after Alzheimer disease. It is a group of syndromes relating to different vascular mechanisms and is preventable. Common areas of the brain associated with cognitive decline are the white matter of the cerebral hemispheres and the deep gray nuclei of the striatum and thalamus. The three most common mechanisms of vascular dementia are multiple cortical infarcts, a strategic single infarct and small vessel disease.

Mild vascular cognitive impairment can occur in elderly persons. It is associated with decline that is more than is expected based on age and education level but the effects are not as severe as would be the case in dementia.

Multi-infarct dementia involves the combined effects of different infarcts to produce cognitive decline by impacting the neural nets. In single infarct dementia different areas of the brain can be affected resulting in significant cognitive impairment. This may be observed in cases of parietal lobe infarcts, thalamic infarction, and cingulate gyrus infarction.

Small vessel disease affects all the small vessels of the brain and produces two major syndromes: Lacunar state and Binswanger disease. Lacunar disease due to small vessel occlusions produces small cavitary lesions within the brain itself and secondary occlusion of small penetrating arterial branches. The lacunae are typically found in the internal capsule, deep gray matter and white matter. Lacunar state is a condition in which numerous lacunae are present.

Binswanger disease is also known as subcortical leukoencephalopathy. It is due to diffuse white matter disease in which the observed vascular changes are fibrohyalinosis of the small arteries and firbrinoid necrosis of the larger vessels inside the brain. Average onset is between the fourth and seventh decades of life and 80% of patients have a history of hypertension. Patients typically show progressive motor, cognitive, mood and behavioral changes over a period of five to 10 years with the mood and behavioral changes observed early. Patients may appear apathetic or abulic. Intellectual deficits are also observed early in the course of the disease and patients are frequently described as disoriented, having memory deficits, and inattentive. Patients with Binswanger dementia often have early-onset urinary incontinence and gait disturbances.

In cerebral amyloid angiopathy-associated vasculopathy, aneurysm formation and stenosis in the leptomeningeal and cortical vessels cause damage to the subcortical white matter. Onset of this disorder occurs between the third and fourth decades of life. The clinical picture is similar to Binswanger disease but without a history of hypertension and risk factors for cerebrovascular disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a rare autosomal dominant condition localized to chromosome 19q12. The disorder affects small vessel supplying the deep white matter. Multiple small infarcts are observed in the white matter, thalamus, basal ganglia and pons.

In general, patients with vascular dementia have mood and behavioral changes and are more prone to depression than individuals with Alzheimer disease. Patients with vascular dementia also tend to have better free recall and fewer recall intrusions errors in comparison to patients with Alzheimer disease. Apathy seen early in the disease is more suggestive of vascular dementia because it usually occurs later in Alzheimer disease. Patients with vascular dementia tend to have poor verbal fluency and more perseverative behavior compared with those who are diagnosed with Alzheimer disease. In patients with extensive deep white matter disease impairments may be observed on tests of psychomotor speed, dexterity, executive function and motor aspects of speech.

The absence of cerebrovascular lesions on CT scan or MRI is evidence against vascular etiology for the dementing process. The features on CT scan or MRI that are suggestive of vascular dementia are bilateral multiple infarcts located in the dominant hemisphere and limbic structures, multiple lacunar strokes or periventricular white matter lesions extending into the deep white matter.

3. Parkinson Disease (PD)

PD is a progressive neurodegenerative disorder associated with loss of dopaminergic nigrostriatal neurons. The major neuropathological findings in PD are a loss of pigmented dopaminergic neurons in the substantia nigra (primarily the ventral lateral area) and the presence of Lewy bodies. Approximately 60-80% of the dopaminergic neurons are lost before motor signs of PD emerge.

Lewy bodies are eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic but not pathognomic of idiopathic PD. Lewy bodies are also found in the nucleus basalis (involved in memory and learning), locus ceruleus (involved in reactions to stress and fear) and the intermediolateral column of the spinal cord (involved in bladder function).

Motor Circuit in PD

The basal ganglia motor circuit modulates cortical output necessary for normal movement. Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the globus pallidus interna (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement. Two pathways exist within the basal ganglia circuit: direct and indirect. In the direct pathway, outflow from the striatum directly inhibits GPi and SNr. The direct pathway involves D1 striatal neurons and its action leads to an increase in motor behavior. The indirect pathway comprises inhibitory connections between the striatum and the globus pallidus externa (GPe) and the GPe and subthalamic nucleus (STN). The STN exerts an excitatory influence on the GPi and SNr, which sends inhibitory output to the ventral later (VL) nucleus of the thalamus. This pathway involved D2 striatal neurons and reduces motor activity.

Dopamine is released from nigrostriatal (SNc) neurons to activate the direct pathway and inhibit the indirect pathway. In PD, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr. This increases the inhibition of the thalamocortical pathway, which suppresses movement.

Onset of PD is typically asymmetric with the most common finding being an asymmetric resting tremor in an upper extremity (e.g., the arm). Over time patients notice symptoms related to progressive bradykinesia (slowed movement), rigidity and gait difficulty. The tremors increase with stress and remit during sleep. The initial symptoms of PD can be nonspecific and include fatigue, depression, constipation and sleep problems. The 3 cardinal symptoms of PD are resting tremor, bradykinesia and rigidity. Postural instability is a 4th cardinal sign that appears late in the disease progression. Dementia occurs in 15-30% of PD patients and includes impaired short-term memory and visuospatial function.

Genetic factors tend to be less important when the disease has its onset after age 50 as both dizygotic and monozygotic twins have similar concordance rates. Early onset does have a more prominent genetic component.

4. Huntington Disease (HD)

HD is an incurable autosomal dominant inherited disorder associated with cell loss in the basal ganglia and cortex. It is associated with progressive disability and death that is usually due to intercurrent illness (for example, an opportunistic such as pneumonia). Characteristic features of HD include involuntary movements, dementia and behavioral changes. The most striking pathological changes occur within the neostriatum (area involved in motor control), in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Pathological changes have also been noted in the globus pallidus, thalamus, subthalamic nucleus, substantia nigra and cerebellum.

HD can be graded based upon severity of gross striatal atrophy (0-4):

- Grades 0 to 1: no striatal atrophy is observed. Grade 0 cases have no detectable histological neuropathology in the presence of a typical clinical picture and positive family history suggesting HD. Grade 1 cases have neuropathological changes that can be detected microscopically, but without gross atrophy.

- Grade 2: striatal pathology is present but the caudate nucleus remains convex.

- Grade 3: striatal atrophy is more pronounced and the caudate nucleus is flat.

- Grade 4: striatal atrophy is severe and the medial surface of the caudate is concave.

The genetic basis of HD is an expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine in the N-terminus of the protein product called huntingtin. The CAG repeat correlates inversely with the age of onset with a higher level of repeats being associated with earlier onset. Juvenile forms of HD (occurring in patients younger than 20) are most often inherited from the father and account for 5-10% of all HD cases. Onset after age 20 is associated with maternal inheritance. Most studies show an age of onset between 35 & 44 years and most patients survive 10-25 years after the onset of the illness. Pneumonia and cardiovascular disease are the most common primary causes of death.

The clinical features of HD include a movement disorder, cognitive disorder and behavioral disorder. Chorea is the most common movement disorder in HD, which in mild forms may appear as fidgetiness, but in severe forms may appear as ballism (e.g., involuntary flailing of the arms due to damage to the subthalamic nucleus). As HD progresses, the chorea initially exists in conjunction with dystonia (slow, involuntary and arrhythmic movements) and parkinsonian features such as bradykinesia, rigidity and postural instability. As HD progresses patients develop an akinetic-rigid syndrome as well as spasticity, clonus and extensor plantar responses. Dysphagia and dysarthria are common and eye movement abnormalities may be seen early on in the disease process. Cognitive decline is characteristic of HD, but the rate of progression varies. Dementia and psychiatric issues are early signs of functional impairment.

The dementia syndrome associated with HD involves early onset behavioral changes such as irritability, untidiness, and loss of interest. Slowing of cognition (bradyphrenia), impaired intellectual function and memory disturbance are seen later. This pattern corresponds with subcortical dementia and is suggested to reflect dysfunction of the frontal-subcortical neuronal circuitry. The early stages of HD are characterized by deficits in short-term memory, followed by motor dysfunction and a variety of cognitive deficits that include diminished verbal fluency, problems with attention, executive function, visuospatial processing and abstract reasoning. Depression is prevalent.

Chorea is defined as a state of excessive spontaneous movements, irregularly timed, randomly distributed and abrupt.

Dystonia is a syndrome that involves sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal posture.

Benzodiazepines can be used to treat chorea while rigidity and bradykinesia may benefit from levodopa or dopamine agonists. SSRIs are used to treat depression.

5. Pick Disease

Pick disease is defined pathologically by severe atrophy, neuronal loss, and gliosis. The disease is marked by Pick cells which are neurons that have ballooned and argentophilic neuronal inclusions known as Pick bodies. These pathological markers of Pick disease occur primarily in the frontal and temporal lobes.

Of individuals diagnosed with dementia 10 to 15% have clinical characteristics suggestive of pick disease. It is the third most common neurodegenerative cortical dementia after AD and diffuse Lewy body disease. The disorders progresses and runs a shorter course than AD by about six years. In those individuals whose main symptoms are a disturbance of speech and language, the course may be slower. Familial forms of pick complex dementia are linked to chromosome 17q. More men are affected than women. Pick disease occurs at a younger age than Alzheimer disease.

The onset of behavioral and cognitive dysfunction is insidious. The primary impairment in cognition normally does not involve an abnormal level of consciousness or distractibility, but during the first two years involves psychiatric abnormalities that seem to respect the pattern of the classic frontal lobe syndromes. Patients with orbitofrontal dysfunction become aggressive and socially inappropriate. They may steal or demonstrated obsessive or repetitive stereotyped behaviors. Patients with the dorsal medial or dorsal lateral frontal dysfunction may demonstrate a lack of concern, apathy or decreased spontaneity. Patients may be depressed early in the disease and the mood changes often predate amnesia. Speech and language abnormalities often begin early and progress rapidly. Patients usually have little limb apraxia and/or visuospatial dysfunction which distinguishes them from individuals with diffuse bihemispheric impairment. The issues with speech and language and behavior tend to be more severe than memory impairment. Incontinence can occur early but is usually a later symptom in Alzheimer disease. Parkinsonism, which includes problems with gait and rigidity often occurs, but severe parkinsonism suggest an alternate diagnoses such as Cortical Basal Ganglionic Degeneration, Defuse Lewy Body Disease or Progressive Supranuclear Palsy.

Patients with Pick disease are often unkempt at an earlier stage than individuals with Alzheimer disease and exhibit abnormal spontaneous behaviors that include inappropriate jocularity, echolalia, echopraxia and disinhibited approach or utilization behaviors. Primitive reflexes such as grasp, suck and snout (but not palmomental) reflexes are often present as are akinesia, plastic rigidity and paratonia. The presence of a resting tremor is uncommon and may suggest Parkinson or a Parkinson-plus syndrome. Verbal output is often nonfluent and patients have difficulty naming common objects.

6. Creutzfeldt-Jakob Disease (CJD)

CJD is a neurodegenerative disease that evokes no apparent immune or inflammatory response and results in dementia, cortical blindness (due to damage to the visual areas of the brain rather than the eyes), motor disorders, rigidity and myoclonus (muscle spasms). Death usually occurs within 6 months of onset. Approximately 15% of cases appear to be inherited in an autosomal dominant pattern of gene expression. The rest of the cases are sporadic with uncertainty as to cause. Sporadic cases of CJD are typically characterized by rapidly progressive multifocal neurological dysfunction, myoclonic jerks, and a terminal state of global severe cognitive impairment. About 40% of patients with sporadic CJD present with rapidly progressive cognitive impairment, 40% with cerebellar dysfunction and the remaining 20% with a combination of both.

Gerstmann-Straussler-Scheinker Syndrome (GSS) is a variant of CJD that has an earlier onset (4th decade of life) and involves dementia, cerebellar ataxia and pyramidal signs, with death as the final result, occurring between three and eight years following initial presentation. GSS includes prominent involvement of the brainstem with extensive and invariable amyloid deposition in addition to the typical spongiform change, gliosis and neuronal loss. NFTs can also be extensive.

Variant Creutzfeldt-Jakob disease (vCJD) differs from sporadic CJD in that psychiatric abnormalities and sensory symptoms are more common components of vCJD. The most common initial symptoms are cognitive impairment and ataxia with cerebellar dysfunction being present in all patients as opposed to only 40% of those with sporadic CJD.

7. Progressive Supranuclear Palsy (PSP)

PSP is a neurodegenerative disease that affects cognition, eye movements, and posture. Characteristics include supranuclear, primarily vertical, gaze dysfunction accompanied by extrapyramidal symptoms and cognitive dysfunction. The disease usually develops after the sixth decade of life, with a purely clinical diagnosis and no proven effective therapy. PSP is usually fatal within approximately 6 years of onset primarily due to pulmonary complications such as pneumonia that are associated with immobility.

Onset of PSP is typically insidious and frequently involves a prolonged phase that includes fatigue, headaches, arthralgia, dizziness, and depression. Personality changes, memory problems and pseudo-bulbar symptoms may also be noted. The most common symptoms at disease onset or postural instability and falls (63%), dysarthria (35%), bradykinesia (13%) and visual disturbances such as diplopia, blurred vision, burning eyes, and light sensitivity (13%).

The cardinal manifestations of progressive supranuclear palsy are supranuclear opthalmoplegia, pseudobulbar palsy, prominent neck dystonia, parkinsonism, behavioral and cognitive impairment, and gait disturbances that cause imbalance and frequent falls. Supranuclear refers to the fact that lesion is usually above the occulomotor nuclei. Often the early symptoms relate to imbalance and dysarthria, the imbalance being part of an extrapyramidal syndrome that includes postural reflexes, rigidity, and dysarthria. A resting tremor is unusual. The early appearance of gait and balance disturbance in PSP contrasts it with Parkinson disease where postural issues tend to occur late in the disease process. Bradykinesia with masked facies and a startled expression are frequent findings. In terms of visual symptoms one of the earliest signs often involves slowing vertical saccades. The vertical supranuclear palsy occurs later on in the disease process. While cognitive dysfunction and personality change are common, they are generally milder in degree compared to other diseases such as Alzheimer disease. Slowed cognitive processing, sequencing and planning difficulties, mild memory difficulty and apathy are typical.

Histological findings involve diffuse brainstem disease, neuronal loss, NFTs, and gliosis that affect the reticular formation and occulomotor nuclei. Early pathology is evident primarily in the midbrain but various pontine nuclei are also impacted.

8. Frontotemporal Dementia

Primary Progressive Aphasia (PPA) involves the deterioration of language function. Other aspect of cognitive functioning may initially seem entirely normal. In fact, patients who do not depend on their verbal skills for their livelihoods may continue to function at work. Artistic expressions may even increase or be taken on his new hobbies in these patients. The most common presenting symptom is word finding difficulty. However decreased fluency or hesitancy in producing speech, difficulty with language comprehension and motor difficulties (e.g., dysarthria) are also common. There are two patterns of PPA: 1) a progressive, nonfluent aphasia and 2) fluent aphasia with anomia. Semantic dementia is a subgroup of PPA that is characterized by progressive loss of naming ability and loss of the ability to understand the meaning of words. The aphasia is fluent except for word-finding pauses.

In FTD, presenting symptoms often involve alterations in personality and social conduct. Particularly with the frontal variant of FTD, a person may become disinhibited, developing a fatuous sense of humor. Conversely, the person may become apathetic, with little spontaneous speech activity. Neglect of personal hygiene is common as is the tendency to lose sensitivity to the effects of their behavior on others. Some individuals develop hyperorality, utilization behavior and inappropriate sexuality. Language function is described as reduced and output is characterized by perseveration, stereotyped responses and echolalia. A subgroup of individuals with FTD develops signs and symptoms of motor neuron disease including fasciculations, muscle wasting and weakness, and bulbar symptoms. These patients have ubiquitin pathology.

FTD can be distinguished from other focal lesions such as those that involve abscesses, strokes and tumors by the more gradual process that is involved in FTD. PPA patients have preserved memory and visuospatial functions, while those with AD present with nearly universal deficits in these functions. Patients with PPA perform worse than those with AD on syntactic and speech fluency tasks and have more severe impairment of attention. Moreover, FTT and its PPA variants typically affect the frontal and temporal lobes, particularly in the left hemisphere as compared to AD which affects the hippocampus and parietal lobes.

Many patients have a nonfluent speech pattern and virtually all have some degree of difficulty in naming or word finding. Ideation tends to be concrete with poor abstraction and organization of responses and delayed shifting of cognitive sets. Visual and spatial functions and constructional tasks are much less affected, except as influenced by behavioral and organizational difficulties. Motor skills are spared except for perseverative or inattentive responses and difficulty with the temporal sequencing of tasks. Memory is usually preserved for orientation although information retrieval may be problematic.

9. Dementia with Lewy Bodies (DLB)

When dementia precedes motor signs, particularly with visual hallucinations and episodes of reduced responsiveness, a diagnosis of DLB should be considered. Postmortem examinations of both PD and DLB patients demonstrates the presence of Lewy bodies in the substantia nigra and possibly in the locus ceruleus, dorsal raphe, substantia innominata, and dorsal motor nucleus of the vagus. Lewy bodies are found in the neocortex of many patients with idiopathic PD and in all patients with the DLB.

Symptoms and signs of DLB likely result in part from disruption of bi-directional information flow from the striatum to the neocortex, especially the frontal lobe. The cause of DLB is multifactorial but is partly due to altered neurotransmitter levels, specifically ACh and dopamine.

DLB is a progressive degenerative dementia that accountants for up to 20% of all dementia cases. The clinical features that help distinguish DLB from AD include fluctuations in cognitive function with varying levels of alertness and attention, visual hallucinations, Parkinsonian motor features, extrapyramidal features that occur relatively early in the course (as opposed to AD where they occur later on), more prominent executive function deficits and visual impairment than is noted in AD and the presence of non-visual hallucinations, delusions, unexplained syncope, rapid eye movement, sleep disorder and neuroleptic sensitivity. Mental status testing reveals that patients have periods of being alert, coherent and oriented that alternate with periods of being confused and unresponsive to questions despite being fully awake. This fluctuation is a specific feature of DLB. Retrieval of information from memory tends to be relatively worse than memory storage. Patients will do relatively well with confrontation naming tests and poorly on test of visuospatial skills such as clock drawing and copying figures. Some patients will have Parkinsonian sings but these are usually too mild to meet criteria for PD. Mild gait impairment is relatively frequent but resting tremor is less frequent than in PD. Myoclonus may occur before severe dementia sets in. Apolipoprotein E subtype 4 (ApoE4) genotype is overrepresented only when DLB occurs with concomitant AD.

Vascular dementia can cause symptoms that are similar to those found in individuals with DLB. Brain MRI is indicated to distinguish DLB from vascular dementia. Patients with vascular dementia often have white matter lesions on MRI whereas patients with DLB do not. MRI is also superior to CT scan in for identifying hippocampal atrophy. Patients with DLB usually have less hippocampal atrophy than patients with AD, but more so than control subjects. The utility of this difference between the two conditions is currently under investigation. Single-photon emission CT scan and positron emission tomography scanning may show decreased occipital low blood flow or metabolism in DLB but not in AD. Reduced dopamine transporter activity in the basal ganglia is often seen with positron emission tomography scanning.

The characteristic lesion in DLB is the Lewy body, an eosinophilic round inclusion found in the cytoplasm of substantia nigra cells and in the nucleus basalis of Meynert, locus ceruleus, dorsal raphe, and the dorsal motor nucleus of cranial nerve X.

10. Dementia Due to Head Trauma

This dementia is usually of the subcortical type with the associated impairments in memory, language, praxis and sensation, which tend to be less prominent than in Alzheimer disease or other cortical dementias. Changes in personality, disturbed executive functioning, and altered experience and expression of emotion are relatively more apparent.

Post traumatic amnesia (PTA) describes the mental state of patients immediately following closed head injury or after waking from coma. It is a form of delirium that may persist for hours or weeks and occasionally months. Patients with PTA are alert and capable of complex behavior; however, they experience memory problems, feelings of confusion, and ability to learn new information and poor concentration.

Injury to the thalamus following closed head injury produces post traumatic thalamic syndrome. In this condition the person progresses from generalize numbness to episodes of spontaneous pain or pain in response to noxious stimuli. Patients also experience constant or episodic unpleasant sensations, paresthesias, outbursts of fear or anger, aphasia, abusive behavior and signs of frontal of dysfunction.

The second injury syndrome (SIS) occurs when someone not yet fully recovered from a head injury experiences another head injury or upper body injury. After a brief delay, the person suddenly loses consciousness. Signs of brainstem compression follow, leading to death or permanent coma.

Postconcussive syndrome involves irritability, fatigue, headaches, dizziness, sensitivity to noise, cognitive slowing, memory impairment, poor concentration, sadness and anxiety. It has variable manifestations that do not correlate well with tissue injury.

The pathophysiology of closed head injury results from contusions and diffuse axonal injury (DAI). Contusions are most common were the brain contacts with the bony protuberances of the skull. Typically, these are the basal areas of the frontal, temporal, and occipital lobes. Contusions may also occur at the side of the impact (coup) or at the opposite pole of the brain (contrecoup). The shearing forces of the impact cause axons to stretch and break, which triggers a cascade of further insults including calcium influx, excitotoxin release, phospholipase activation, and lipid peroxidation.

In dementia from white matter injury, cognitive impairment is mild and progresses slowly. Personality remains relatively intact unless other brain areas are also affected. If damage is extensive, patients experience subcortical dementia with bradyphrenia (cognitive slowing), bradykinesia, avolition, mood changes, and motor abnormalities, with little apraxia, agnosia or aphasia (the latter being associated with cortical damage). Other pathophysiological processes that may follow head injury include subdural, epidural or intracerebral hematomas; hydrocephalus; and epilepsy, especially partial complex epilepsy. Post traumatic epilepsy occurs mainly after penetrating head injuries that cause scarring and gliosis, creating epileptic foci.

Symptoms related to particular brain areas include the following:

  • Prefrontal cortex-disinhibition, apathy, personality change, decreased fluency of speech, obsessions, hypochondriasis and delusions.
  • Basal ganglia-depression, mania, tremor, cog wheeling, bradykinesia, obsessions, compulsions.
  • Thalamus-apathy, irritability, pathological crying, paresthesias, pain, hypersomnia.
  • White matter-apathy, lability, loss of spontaneity, transient hemiparesis or hemiplegia, bradykinesia, bradyphrenia.
  • Cerebellum/Pons-mild avolition, disinhibition, cerebellar signs, loss of ability to execute motor routines automatically.

11. Dementia Due to HIV Disease

HIV-induced dementia is a common source of morbidity that is usually observed in late stages of HIV disease. Pathological changes are predominantly subcortical, involving the deep gray (e.g., basal ganglia and thalamus) and white matter regions. The primary mechanism of neuronal dysfunction is the infiltration of infected microphages or microglial cells into the brain, which then elaborate pro-inflammatory diffusable cellular neurotoxins, including tumor necrosis factor-alpha, cytokines and interleukins. HIV does not directly affect the neuron but the neuron is damaged by the effects of the various pro-inflammatory neurotoxins. The rate of HIV dementia in patients with late-stage disease ranges from 7-27%. Milder forms of AIDS dementia complex (ADC) affect an additional 30-40% of patients.

Patients with ADC present with a triad of cognitive, motor and behavioral symptoms. HIV-associated myelopathy predominately manifests with motor symptoms including paraparesis, lower extremity spasticity, ataxia, and extensor-plantar responses in the absence of spinal cord abnormalities. Patients with ADC can initially present solely with psychiatric symptoms such as depression, mania or psychosis.

ADC is broadly divided into two clinical categories. The first is the more severe type and includes HIV-associated dementia complex and myelopathy. The second less severe form is associated with minor cognitive and/or motor disorders consistent with HIV-associated neurocognitive disorder. In the less severe form patients initially report poor short-term memory and concentration, behavior problems and personality changes. Patients with HIV dementia commonly present with psychiatric symptoms of depression and anxiety and behavioral changes that include apathy, lethargy, loss of sexual drive and diminish behavioral responsiveness. They may become withdrawn, irritable emotionally labile and inflexible. HIV dementia may manifest with acute onset psychotic symptoms including delusions and hallucinations, putting these patients at higher risk for suicidal and homicidal ideation. Early motor symptoms include unsteady gait, leg weakness, clumsiness, slowing of fine motor movements and tremor.

In the more severe form, HIV-associated dementia complex, HIV-associated myelopathy, patients exhibit progressive cognitive and motor difficulties. In the late stages of the disease patients develop an akinetic mute or vegetative state in which they lie awake but do not respond to their surroundings. They may also have quadraparesis or paraparesis, myoclonus and incontinence. In the more severe forms of HIV-ADC, the neurological examination findings show frontal release signs, slowed rapid movements, antisaccadic movements and coordination, abnormal gait, hyperreflexia, hypertonia, extensor-plantar response weakness, and peripheral neuropathy. Cortical signs, including apraxia, aphasia and agnosia are typically absent.

MRI findings typically showed diffuse nonenhancing white matter hyperintensity, cerebral atrophy and ventricular enlargement. Decreased metabolism has been noted in the basal ganglia and thalamus in the early stages of ADC.

12. Cortical Basal Ganglionic Degeneration (CBGD)

The defining clinical characteristics of CBGD include progressive dementia, parkinsonism and limb apraxia. Both cortical and subcortical abnormalities are seen. Ballooned swollen neurons with loss of cytoplasmic staining are present in the cortex and may also be seen in the basal ganglia. As in pick disease and progressive supranuclear palsy, tau-immunoreactive neuronal and glial inclusions may be seen in cortical (pyramidal and nonpyramidal) neurons as well as in subcortical regions.

The pathology of cortical basal ganglionic degeneration includes a chronic progressive course, asymmetric onset of extrapyramidal dysfunction, higher cortical dysfunction including apraxia and alien limb, movement disorder (rigid/akinetic syndrome resistant to therapeutic doses of levodopa; dystonic limb posturing; spontaneous and reflex focal myoclonus; and occasional action tremor). Amnesia may be present as well as frontal-executive deficits such as distractibility, perseveration, impaired judgment and motor planning deficits. Cortical atrophy usually occurs and can be localized to the central sulci/supplementary motor area.

13. Multiple System Atrophy (MSA)

MSA is defined as a sporadic, progressive, neurodegenerative disease of undetermined etiology. It is characterized by pyramidal, extrapyramidal, cerebellar and autonomic dysfunction in any combination. Pathologically, MSA is characterized by cell loss, gliosis and glial cytoplasmic inclusions (GCI’s) and several brain and spinal cord structures. MSA is classified as possible, probable or definite on the basis of its features and criteria in three clinical domains: autonomic and/or urinary dysfunction, parkinsonism, and cerebellar dysfunction.

The etiology of cell loss in MSA is unknown but is characterized by progressive loss of both neuronal and oligodendroglial cells in the CNS. The damage primarily affects white matter and includes extensive myelin degeneration. The disease progresses rapidly with an average rate of 9.5 years after onset of illness.

The disease most typically manifests after age 40 with autonomic and/or urinary tract dysfunction developing first. Patients with MSA may have Parkinsonian symptoms and a response to levodopa therapy has poor. Orthostatic hypotension occurs in approximately 68% of patients and can be associated with lightheadedness, dizziness, dimming vision, head, neck, or shoulder pain, altered mentation, leg weakness, fatigue, slurred speech and syncope. Regarding parkinsonism, akinesia and rigidity predominate although tremor can be present in a significant minority. Cerebellar dysfunction commonly causes gait and limb ataxia. Tremor, pyramidal signs and myoclonus are less common findings.

Differentiation of MSA from PD is difficult but is suggested when the disease progresses rapidly, response to levodopa is poor, the presence of autonomic dysfunction (urinary retention or incontinence; orthostatic hypotension) and when rigidity and bradykinesia are out of proportion to tremor.

MSA needs to be distinguished from a number of other disorders with which it shares symptoms. Pure Autonomic Failure (PAF) involves autonomic nervous system failure in the absence of extrapyramidal, pyramidal and cerebellar abnormalities. Sympathetic and parasympathetic system abnormalities are central in MSA, but peripheral in PAF. Moreover, the progression of MSA is faster than that of PAF and prognosis poor. PAF is characterized by the presence of Lewy bodies while patients with MSA have oligodendroglial cytoplasmic inclusions. In addition, low plasma norepinephrine levels usually indicate PAF.

MSA also needs to be differentiated from PSP. This is often done through analysis of the horizontal and vertical eye movements which are impaired in PSP but not MSA. In addition PSP involves the slowing of saccades, which is not the case in MSA. The presence of cardiovascular autonomic dysfunction is an exclusionary criterion in for a diagnosis of PSP but is central to MSA.

CBGD differs from MSA in that onset is typically unilateral, with marked rigidity-dystonia in the involved arm, which differs from MSA. Cortical signs such as alien limb and apraxia also distinguish between CBGD and MSA.

For more information, contact Dr. Rozenblatt at (866) 840-9790 or