Dementia And Movement
Alzheimer
Alzheimer disease (AD) accounts for 66% of all cases of dementia. AD is an acquired neurological disorder that causes behavioral and cognitive impairment which interferes with social and occupational functioning. (For more information on dementia vs delerium)
Pathogenesis
The cause of AD is unknown. There are, however, pathologic hallmarks of AD that have been identified. Neurofibrillary tangles (NFTs) and senile plaques (SPs) are the primary pathological constituents associated with AD. Both NFTs and SPs accumulate primarily within the hippocampus, an area of the brain that helps with memory storage and processing.
Senile plaques are focal collections of tortuous neuritic processes that surround a central amyloid core, also called amyloid beta protein.
Neurofibrillary tangles are bundles of neurofilaments located within the cytoplasm of neurons.
Demographics
The prevalence of AD increases with age and is typically seen in individuals older than 60 years of age. There are, however some forms of familial early-onset AD that can appear as early as the third decade.
The following risk factors have been identified within AD:
Down Syndrome is the result of a third copy of chromosome 21. Amyloid Precursor Protein (APP) gene is located on chromosome 21 and thus most patients with Down Syndrome will present with clinical features of AD by age 40.
Advancing age
Family history
Head trauma
Apolipoprotein E (APOE) genotype
Genetic mutations
There are several genes that have been linked to early-onset AD:
Amyloid Precursor Protein (APP) gene found on chromosome 21
Presenilin 1 (PS1) gene located on chromosome 14
Presenilin 2 (PS2) gene located on chromosome 1
The apolipoprotein E (APOE) gene located on chromosome 19 is another gene that has been shown to have an associated risk in developing most often late-onset AD. APOE exists in 3 alleles:
APOE 2 (least prevalent of the 3 alleles and is thought to have some protective effect in developing AD)
APOE 3 (shown to have an intermediate risk in developing AD)
APOE 4 (shown to have the most significant risk in developing AD)
Symptoms
Many patients with Alzheimer's Disease present with some form of progressive memory impairment that begins insidiously but progresses at a steady rate. Symptomatic presentation will vary from patient to patient as each area of the brain is affected differently and patients may also present with other coexisting forms of dementia (vascular dementia).
AD can typically be classified into 4 stages: - Preclinical – mild forgetfulness - Mild – increased amnesia, trouble handling daily tasks (paying bills), mood/personality changes - Moderate – problems recognizing friends, restlessness, wandering around, lack of impulse control, delusions, and even hallucinations - Severe – total dependence on others for functions of daily living, lose all sense of self, and become incommunicable
Progression through the stages typically occurs within 8-10 years and eventually death occurs from other forms of disease, such as aspiration pneumonia.
Diagnosis
Alzheimer's Disease is a clinical diagnosis and other pathologies (e.g. depression, metabolic deficiencies) must be excluded before a patient can be labeled as having AD. When a patient presents with signs/symptoms suggesting AD, a full neurological examination and mental status examination must be performed.
In AD the neurological examination is typically normal, while the mental status will help determine their level of memory impairment.
Mini Mental Status Examination (MMSE) ranges: - 20-26: mild functional dependence (managing finances) - 10-20: moderate impairment (inability to drive or go shopping) - < 10: severe mental impairment (total dependence and require constant supervision)
Laboratory tests are not useful when AD has been diagnosed, but are helpful in ruling out other secondary causes of dementia. Initial laboratory tests include:
Vitamin B12 to rule out psychosis related to B12 deficiency
Rapid plasma reagin (RPR) help rule out neurosyphilis
Thyroid stimulating hormone (TSH) to help rule out hypothyroidism
Liver Enzymes to help rule out hepatic encephalopathy
Genotyping for APOE or amyloid precursor protein and presenilin is offered in patients with a strong family history of AD or positive mutation has been identified with one of their relatives.
Imaging with an MRI or non-contrast CT is appropriate in the initial workup of patients with dementia. Imaging is done to help diagnose other treatable causes of cognitive impairment(e.g. brain masses, stroke, vascular disease, subdural hematoma, and normal pressure hydrocephalus). In patients with AD imaging will show diffuse cortical atrophy along with focal atrophy within the temporal regions of the brain.
Treatment
Currently there are only symptomatic treatment options for patients diagnosed with AD. The 2 drug classes approved for AD treatment include cholinesterase inhibitors and partial NMDA antagonists.
The best initial drug therapy includes 4 cholinesterase inhibitors:
Donepezil (Best Initial)
Tacrine (hepatotoxic)
Galantamine
Rivastigmine
As the disease progresses in AD, the cholinesterase inhibitors become less effective, thus a partial NMDA antagonist (Memantine) is added to the cholinesterase inhibitors. However, memantine has not been shown to be effective in the early stages of AD.
Recently, the use of high dose vitamin E has been shown to have modest effects in patients with mild to moderate AD, although it is not recommended for routine prevention of AD.
Other pharmacological agents are used to help treat the secondary symptoms (e.g. anxiety, depression, hallucinations, agitation) that develop in AD. Examples include:
Atypical antipsychotics (e.g. olanzapine, risperidone) to treat agitation and hallucinations
Antidepressants (e.g. sertraline, fluoxetine)
Vascular Dementia
Causes
Vascular dementia is the second most common type of dementia, caused by cerebral atherosclerosis and vascular insult.
Three major mechanisms of vascular insult include multiple cortical infarcts, single and strategic infarct, and small vessel disease.
Binswanger’s disease is a form of dementia caused by diffuse subcortical white matter infarcts, usually resulting from chronic hypertension and atherosclerosis.
Symptoms
Multi-infarct dementia occurs due to multiple, severe infarcts, ultimately causing a step-wise decline in cognitive function. Emphasis in treatment is on prevention of additional infarcts (anticoagulants like coumadin or aspirin).
Patients usually are suffering from HTN and/or DM.
Diagnosis
Diagnosis of vascular dementia can be made through history and physical. Patients will reveal a stepwise worsening decline (affecting executive function prior to memory impairment commonly) + multiple strokes. Deep white matter changes or lacunes on imaging are enough to suspect vascular dementia.
Treatment
Treatment of vascular dementia should focus on risk factor management to reduce the risk of a second infarct. This includes managing hypertension, diabetes, hyperlipidemia, and coagulation disorders. Specific goals and agents include:
Maintain SBP under 160 and diastolic BP 85 – 95 (further declines in diastolic BP are associated with worse cognitive functioning)
Donepezil + Memantine* (NMDA-R antagonist) are suspected to slow the progression of vascular dementia
*Rationale: Could be targeting a co-existing undiagnosed AD; rates of co-occurrence are fairly high.
Parkinson's
Parkinson’s disease (PD) is a degenerative brain disorder that manifests primarily with movement disorders and eventually with dementia.
Parkinsonism describes a group of disorders with Parkinson-like symptoms (discussed below).
Onset of Parkinson’s Disease is usually after 50 years of age.
Pathogenesis
PD results from the loss of dopamine producing neurons in the substantia nigra and locus ceruleus. It is associated with Lewy body formation along with a loss of cholinergic neurons in the nucleus basalis of Meynert. While the loss of dopamine correlates with the movement disorder, the dementia seen in Parkinson’s disease tends to correlate more with this loss of cholinergic activity.
There is increasing evidence that genetic factors may play a role in familial forms of PD, especially when the onset is before the age of 50. The genes most implicated in Parkinson’s disease include:
SNCA (α-synuclein) (Ch4q21)
Parkin (Ch6q25.2-q27)
PINK1 (Ch1p35-36)
Symptoms
The most common clinical presentation of Parkinson disease is movement abnormalities including:
Resting tremor that lessens or disappears with movement
“cogwheel” rigidity or a ratchet-like jerking
Bradykinesia
Shuffling gait
Postural instability
Masked or expressionless facies
The tremor in PD is a slow (3-5 Hz) resting tremor that lessens or disappears with movement and worsens when the affected limb, most often the hand, is at rest.
Nonmotor symptoms of Parkinson’s disease include:
Anosmia, the inability to perceive smells
Dementia
Autonomic dysfunction
Sleep disturbances
PD most often begins as an asymmetric tremor that slowly progresses over the course of many years. As many as 30% of patients develop cognitive impairment and dementia.
Diagnosis
Diagnosis of Parkinson’s disease is based on clinical evaluation.
Histologic examination on autopsy reveals a decrease in pigment within the substantia nigra, as well as the presence of Lewy bodies in degenerating neurons. Lewy bodies are eosinophilic intracellular inclusions composed of alpha-synuclein.
Treatment
There is no cure for Parkinson disease, however many pharmaceutical agents exist to aid in the treatment of Parkinson Disease.
Levodopa is the primary treatment for PD. Dopamine is unable to cross the blood-brain-barrier. Levodopa can cross, and after crossing, is metabolized to dopamine by dopamine decarboxylase.
Carbidopa is a peripheral decarboxylase inhibitor that reduces the peripheral conversion of levodopa to dopamine.
Short-term adverse effects that are associated with the initiation of levodopa/carbidopa therapy in older patients include:
Confusion
Hallucinations
Delusions
Long-term adverse effects of levodopa/carbidopa that typically occur after 5-10 years of therapy include involuntary movements (e.g. dyskinesia) and dystonia.
Long-term levodopa use also results in decreased drug efficacy:
Wearing-off: The longer the patient uses the drug, the quicker the effects of the drug wear off.
On-off: Similar to wearing off, except off periods are unpredictable. Patients will rapidly and unpredictably alternate between periods of disabling parkinsonism, and normal movement with dyskinesias.
Due to these side effects, many physicians begin treatment with another agent. However, nearly all patients will eventually require levodopa.
Tolcapone and entacapone are COMT (catechol-O-methyltransferase) inhibitors. Similar to carbidopa, they increase the amount of levodopa that reaches the CNS.
Dopamine agonists include ergot derivatives (e.g. bromocriptine) and non-ergot agonists, which include:
Pramipexole
Ropinirole
Rotigotine
Dopamine agonists are less likely to cause wearing-off or on-off side effects and are usually the first treatment used in Parkinson’s disease. They can be used along with levodopa.
Central MAO-B inhibitors include selegiline and rasagiline. They block central breakdown of dopamine. It is an adjunctive treatment typically used in early disease.
Central acting anticholinergics include trihexyphenidyl and benztropine. They mostly decrease tremor, but have many side effects such as urinary dysfunction, glaucoma, cognitive impairment.
Amantadine (an antiviral) is used to reduce mild dyskinesias in Parkinson’s disease. It acts by increasing dopamine availability.
If patient does not respond to medications, deep brain stimulation of either the subthalamic nucleus or the globus pallidus pars interna can be performed. The stimulator improves the motor symptoms seen with Parkinson’s disease.
Complications in Parkinson’s disease result from motor disability, and can include increased risk of falls, dysphagia, and aspiration.
Lewy Body Dementia
DLB (dementia with Lewy bodies) has distinctive clinical features (in addition to dementia) that include:
Fluctuating cognition
Visual hallucinations—recurrent and often quite detailed
Parkinsonism—“pill-rolling” tremor; rigidity (cogwheeling may be present); bradykinesia; stooped, unstable posture; festinating gait; mask-like facies (i.e. decreased range of facial expression)
DLB patients often have symptoms of Alzheimer's disease in association with parkinsonian motor symptoms.
Lewy bodies—Parkinson disease vs. DLB:
In both Parkinson disease and DLB, Lewy bodies are intracytoplasmic, eosinophilic inclusions with a dense core (predominantly α-synuclein) surrounded by a pale halo.
In Parkinson disease, Lewy bodies can only be found in a narrow range of locations including the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, and the basal nucleus of Meynert. In other words, Lewy bodies do not typically occur in cerebral cortical locations in patients with Parkinson disease.
On the other hand, Lewy bodies in patients with DLB can be found in a wide range of locations throughout the cerebral cortex in addition to the locations where they are characteristically found in Parkinson disease(e.g. substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, basal nucleus of Meynert)
Diagnosis
Diagnosis of Lewy body dementia is based on clinical presentation. Patients that present with visual hallucinations, waxing and waning cognition, parkinsonian features and REM sleep disorder (patients act out their dreams) are telling signs of the disease.
Treatment
Treatment of dementia with Lewy bodies is the same as Alzheimer's Disease.This includes the use of donepezil (acetyl choline esterase inhibitor) and memantine (NMDA receptor antagonist)
For disabling psychotic symptoms, initiate a low dose ATYPICAL neuroleptic agent (most of them end in –pine except for risperidone and paliperidone). However, patients with Lewy body dementia are very sensitive to neuroleptic agents which can lead to worsening parkinsonian symptoms, autonomic instability and confusion and therefore should be monitored closely.
For parkinsonian symptoms levodopa can be used; start at low dose and titrate up since levodopa can exacerbate the psychotic symptoms
For REM sleep disorder, low doses of clonazepam or melatonin can be given at bedtime.
Picks
Frontotemporal lobar degeneration (Pick’s disease) is a neuropathological disorder characterized by disturbances in behavior, personality and language accompanied by focal degeneration of the frontal and/or temporal lobes.
Frontotemporal lobar dementia is one of the more common causes of early-onset dementia.
Grossly, frontotemporal lobar degeneration causes pronounced atrophy of the frontal and temporal lobes with sparing of the posterior 2/3rds of the superior temporal gyrus.
Histology
Microscopically, most cases of frontotemporal lobar degeneration demonstrate microvacuolation and neuronal loss, associated with swollen neurons, decreased myelin, and astrocytic gliosis.
In addition, some patients have abnormal protein inclusions in the cytoplasm and nuclei of neuronal and glial cells called Pick bodies. The inclusions are made up of hyperphosphorylated tau protein.
Normally, tau is an axonal microtubule-associated protein that binds microtubules and facilitates their assembly; when damaged or distorted due to mutation or hyperphosphorylation, tau loses its ability to bind microtubules and instead tends to bind itself, forming aggregates.
Symptoms
Frontotemporal lobar degeneration typically presents as either a progressive change in personality and social behavior or as a progressive form of aphasia; in both cases continuing ultimately to a global dementia.
Diagnosis
Frontotemporal lobar degeneration is highly heritable. Mutations in the C9ORF72, MAPT, and GRN genes together explain approximately 15 percent of familial cohorts.
Frontotemporal lobar degeneration is a clinical diagnosis. Neuroimaging is important to exclude other pathologies and may provide supportive findings, such as frontotemporal lobe atrophy.
Treatment
Pharmacologic treatment of frontotemporal lobar degeneration is aimed at alleviating symptoms. Some medications used include:
SSRIs to decrease anxiety, disinhibition, impulsivity and repetitive behaviors
Antipsychotics to control agitation
Huntington's
Pathogenesis
Huntington’s disease is an autosomal dominant neurodegenerative disease caused by trinucleotide repeats of CAG on chromosome 4 that encodes the protein huntingtin. “Hunt 4 an animal and put it in a CAGe”
Mutant huntingtin is expressed in the brain. A key neuropathologic feature of HD is selective neuronal loss in the caudate and putamen (striatum). Because the caudate nucleus borders the lateral ventral ventricles, atrophy of the caudate nucleus can lead to hydrocephalus ex vacuo (i.e. the loss of brain matter bordering the ventricles makes the ventricles larger).
Patients with Huntington’s disease also tend to have decreased cholinergic and GABAergic neurons leading to decreased Ach and GABA.
Huntington’s disease exhibits anticipation. Anticipation means the disease presents at an earlier age with increased severity in each successive generation in correlation with the number of CAG repeats.
Huntington’s disease typically presents between ages 30-40.
Symptoms
Clinically, Huntington’s disease is characterized by chorea, psychiatric illness, and dementia that begins insidiously with movement and psychiatric abnormalities.
Chorea is a rapid, involuntary, nonrepetitive or arrhythmic movement involving the face, trunk, and limbs. The patient may not realize they are making these movements and typically incorporate them into purposeful movements.
In advanced disease the chorea may be replaced by a parkinsonism rigid state.
Patients with Huntington’s disease may present with irritability and depression up to several years prior to the onset of chorea.
Cognitive decline and dementia are inevitable in advanced Huntington’s disease.
Diagnosis
Clinical diagnosis of Huntington’s disease is based on presenting symptoms and family history of the disease followed by genetic testing to confirm the disease.
CT and MRI studies will reveal caudate and putamen atrophy along with increased ventricular size (hydrocephalus ex vacuo).
Treatment
There is no cure for Huntington’s disease and treatment is based on supportive/ palliative care.
Dopamine antagonists and haloperidol, an antipsychotic, have been shown to improve chorea.
SSRI can be used in the management of depression in these patients.
Tetrabenazine inhibits vesicular monoamine transporter (VMAT), thereby decreasing the uptake of dopamine into vesicles in the presynaptic terminal. The resulting decrease in dopamine release improves dyskinesia in patients with Huntington disease.
Huntington’s disease is usually fatal in less than 20 years after diagnosis.
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