Areen T. Said, M.D.
1.Alzheimer Dementia
As all of you know, this is a progressive neurodegenerative disease that produces characteristic brain lesions and dementia.
Etiology:
- No definitive cause have been identified, but several of its abnormalities have been suggested as causes. Because none are absolutely pathognomonic for AD, a multifactorial etiology is plausible.
- Genetic lesions: Several genetic lesions may produce AD. Chromosome 21 is the locus most commonly impacted. It is the site of the gene for amyloid precursor protein, and AD is very common in patients with Down syndrome(trisomy21). Chromosomes 14 and 19 have also been implicated.
- Abnormal amyloid precursor protein metabolism: a product of amyloid precursor protein, beta/A4 (amyloid), is a major component of neuritic plaques.
- Tau protein: this substance, which is associated with cellular microtubules, is found in neurofibrilary tangles.
- Cholinergic neuronal dysfunction: cholinergic neurons in the hippocampus are affected early in the course of AD and cholinergic agonists (e.g., physostigmine and tacrine) may at least transiently improve some symptoms.
- Other abnormalities : aluminum has been implicated, as it is a component of neuritic plaques. Abnormal neuronal membrane phospholipid metabolism has also been suggested as a cause of AD.
Histopathology:
The classic histopathologic findings of AD are neuronal loss, neurofibrillary tangles, neuritic (i.e., amyloid, senile) plaques, granulovacular degeneration, and amyloid angiopathy. Meditemporal lobes are most severely affected.
Gross pathology:
Diffuse frontotemporal cerebral atrophy, widened cortical sulci, and enlarged cerebral ventricles are characteristic.
Epidemiology:
Dementia of Alzheimer type ( DAT) is responsible for approximately 55% of cases of dementia. It is seldom evident before age 50 and is slightly more common in women. Early-onset DAT is extremely common in individuals with Down syndrome.
Course:
- Onset is insidious.
- Course slowly progressive.
- Early deficits commonly involve recent memory disturbances, mood disturbances, emotional lability, and impulsivity.
- Late in the disease, motor disturbances supervene, especially gait disturbances, pathologic reflexes, and incontinence.
- Seizures occur in approximately 10% of cases.
- The duration from the onset of dementia to death is usually 8-10 years.
DDx.:
Remember always that the clinical diagnosis of DAT is one of exclusion and is usually confirmed at autopsy.
Treatment:
-Tacrine may be effective in transiently reversing or slowing cognitive decline in small percentage of cases.
Antipsychotic agents may be used to reduce agitationand psychosis.
2.Asymmetrical Cortical Degeneration Syndromes
This is a heterogeneous group of disorders that produce distinctive cortical syndromes including aphasia, apraxia, and agnosia but that have a more focal appearance thank Alzheimer’s dementia. These syndromes can be divided into four primary categories, each with several subtypes, including:
- Progressive aphasia.
- Progressive frontal lobe/frontotemporal syndromes (Pick’s Disease).
- Progressive perceptual – motor syndromes.
- Bitemporal syndromes.
Pathogenesis and pathophysiology:
Despite the semiological and pathological diversity of ACDS group, there is common nonspecific degenerative changes, consisting of neuronal loss, gliosis, and vaculation of neuropil predominantly affecting superficial cortical laminae. Thus, clinical presentation is dictated by the topographical distribution of degeneration.
Epidemiology and risk factors:
There are no incedence and prevalence studies of this group of disorders, but clinical experience suggests that they are, as a group, perhaps a tenth as common as AD.
This group of dementia complexes is divided into 4 major syndromes based on the degenerative focus in the brain (see the table below).
Clinical Features and associated disorders:
Because most patients are left-hemisphere dominant for language, most patients have left sided asymmetrical atrophy. Cognitive deficits other than those directly attributable to language may also occur, especially memory impairment and constructional apraxia.
Patients can presents with different clinical presentations based on the focus of brain degeneration. For example, patients with nonfluent progressive aphasia have effortful speech and some times may be dysarthric. Additionally, Naming and repetition is impaired. Verbal memory is typically impaired. On the other hand, patients with fluent aphasia, Anomic aphasia and Mixed progressive aphasia have different clinical picture based on the area of involvement (see table below for symptoms and signs).
What an interesting subject!
There are three pathological varieties of Pick’s disease:
- Lobar atrophy with swollen chromatolytic neurons (SCN) and pick bodies (Pick’s disease type A).
- Lobar atrophy with SCN but not pick bodies (Pick’s disease type B).
- Lobar atrophy without SCN or Pick bodies (Pick’s disease type C).
The cardinal pathological changes in Pick’s disease type A are lobar atrophy with corresponding neuronal loss that is most apparent in the first three cortical layers. Marked caudate and hippocampal atrophy are also typical findings. Pick bodies are argentophilic, eosinophilic rounded cytoplasmic masses that appear densely black on silver stains. They tend to predominate in the most severely atrophic cortical regions and in the hippocampi. Pick cells, on the other hand, are not regarded diagnostic of Pick’s disease because similar-appearing cells have been observed in several other disorders. The nucleus basalis is spared or only mildly affected in both Pick’s disease and FLD. Pick’s disease usually involves the frontal and anterior temporal lobe, but rare cases with preferential parietal lobe atrophy have also been described.
Clinical features and associated disorders:
The three main frontal lobe syndromes are a progressive neuropsychiatric syndrome (frontal and frontotemporal dementia), a progressive spastic syndrome, and a mixture of these two.
The progressive neuropsychiatric syndrome is the best known example of this group and has bee refrred as frontal lobe or frontotemporal dementia. Pick’s disease is prominently represented in this group. The major symptom is abulia. Some patients have greater disinhibition and emotional lability, crying at the least provocation, or laughing loud and long. Memory and language are typically impaired. Associated clinical abnormalities reflect dysfunction of other frontal lobe functions including spasticity and non-fluent aphasia. Because Pick’s disease has a predilection for the temporal as well as the frontal lobe, some patients also develop signs referable to the temporal lobe, particularly anomia.
The syndrome of progressive spasticity has been termed PLS. These patients presents with psychomotor slowing, spasticity and dysarthria (see table).
Cool!
This group of syndromes can be divided into: visual, motor and mixed syndromes based on the focus of degeneration and the clinical features.
Ø Visual syndrome:
Neuropathological studies of patients with dorsal visual syndromes have generally shown senile plaques and neurofibrillary tangle, which is typical of AD. The topographic distribution, however, differs from that seen in AD, with heaviest involvement of the primary and association visual cortices in the occipital lobes and, to a slightly lesser degree, in the parietal lobes. The nucleus basalis is involved in these cases. Patients have two broad types of complex visual disturbances:
- Progressive asimultanagnosia
Patients cannot integrate the numerous components of an ordinarily complex scene into a coherent whole. Occasional associated problems include alexia, acalculia, right-left disorientation, and mild deficits of memory and language.
- Visual agnosia.
Ø Motor syndromes:
O.K! Here, there is generalized but asymmetrical atrophy with the most severe focal degeneration generally occurring in the superomedial frontopariatal regions, primary motor cortex, and parietal convexity cortex, but other cortical regions, including Wernicke’s area, some times can be severely involved as well. The substantia nigra is also involved, but the nucleus basalis is spared in the absence of AD.
Clinical Features and associated disorders:
- Lateralized somatic deficits: Patients presents with slowly progressive hemispastisity, hemiparesis, hemisensory impairment and myoclonic jerks. Some patients may have hemirigid or hemidystonic syndromes with tremor.
- Severe and disabling apraxia, including limb apraxia, dressing apraxia, constructional apraxia, and apraxic agraphia.
Additional clinical abnormalities may include acalculia, psychomotor slowing, aphasia and supranuclear oculomotor disturbances.
The three syndromes in this category are:
- Progressive amnesia.
- Progresive prosopagnosia.
- Progressive neuropsychiatric syndrome.
Briefly, see table. What a great idea!
Differential diagnosis:
Evaluation:
The most important test is adequate structural neuroimaging. MRI is preferable to CT. MRA studies could be include to exclude relevant high grade stenosis. Formal neuropsychological assessment can be helpful to assess quality and severity of cognitive impairment. By the way, don’t forget your lab work up!
Management:
NH, PT, OT, ST. Carbidopa and Levodopa can be considered in CBGD. Clonazepam can be used for myoclonus in patients with CBGD. Aloha! Selective botulinium toxin injection can be considered for patients with severe dystonic posturing.
Prognosis:
Death will come soon after relentless progression.
3.ALS-Dementia Complex
Pathogenesis and pathophysiology:
The histological findings in the majority of cases are non specific, and include: neuronal loss, gliosis, and microvaculation or spongiform changes predominantly affecting the superficial cortical layers and subcortical white matter. Degeneration is usually greatest in the frontoemporal regions and to a lesser extent in the perisylvian language cortices.
Clinical Features and associated disorders:
Frontal lobe or frontotemporal dementia is the most common dementia pattern, followed by aphasic dementia. Bulbar symptoms has been consistently prominent.
DDx.:
- CJD, especially in patients with rapidly progressive nature. Also, carcinomatous meningitis should be in mind in patients with rapidly progressive course as it may cause encephalopathy and polyradiculopathy, which can be mistaken for ALS-Dementia complex.
- H&N tumors with brain metastases.
- Neuromuscular weakness due to ALS, myasthenia gravis, acid maltase deficiency, myotonic dystrophy, and any other disease of sufficient severity to compromise ventilatory capacity may lead to hypoxic encephalopathy that, in the absense of corroborating history, might be mistaken for ALS-Dementia complex.
Evaluation:
EMG, EEG, ABG, MRI, Ach-R ab, CPK, Neuropsychiatric testing.
Management:
Read ALS!
Prognosis:
Death occur within 3 to 5 years.
This include a variety of syndromes;
- Parkinson’s disease with dementia.
- Multiple system atrophy.
- Progressive supranuclear palsy.
- Huntington’s disease.
In each case of Parkinson disease when dementia is described, it is most consistent with a subcortical pattern to distinguish it from typical Alzheimer-type dementia.
Pathogenesis and pathophysiology:
Histological components of the Parkinson’s dementia picture include both Parkinson’s and Alzheimer-type pathology. Concomitant AD changes meeting diagnostic criteria for AD diagnosis have been found in up to 50 % of patients with PD dementia.
Clinical Features and associated disorders:
Subcortical dementia-related memory impairment is benefited more by cuing than memory disturbance in of cortical dementia. Patients have equal or greater difficulty learning new material but have relatively less difficulty retrieving it. Subcortical dementia is not usually accompanied by aphasia, apraxia, and agnosia. However, it is accompanied by psychomotor slowing, an early feature of Parkinson’s dementia. Nondegenerative quasparkinsonian syndromes in which cognitive impairment is present can have many etiologies including multi-infarct dementia, normal pressure hydrocephalus, and post-encephalitic parkinsonism.
DDx.:
Extesive, but to make it easy and fun, it includes but not limited to: PSP, MSA, DLBD, CBGD, Pick’s disease, Frontal lobe meningiomas, Multi-infarct dementia, NPH.
Evaluation:
MRI.
Management:
As for PD. However, certain considerations apply here.
This is an uncommon and heterogeneous group of disorders generally characterized by atypical, relative dopamine-unresponsive parkinsonism with variable degrees of cognitive impairment. This subcategory of subcortical dementias includes:
Ø OPCA.
Ø Striatinigral degeneration.
Ø Shy-drager syndrome.
Clinical Features:
Patients with dominantly inherited OPCA have frontal-lobe related cognitive impairments, but the apparent mild intellectual decline in most OPCA patients may be related to motor impairment and depression without actual dementia and without evidence of aphasi, agnosia or apraxia.
The incidence of PSP is about 3 new cases per million per year, and the prevalence is 1.5 cases per million, making it about 1% as common as PD. Median survival after symptom onset is approximately 6-7 years. No clear predisposing or genetic factors have been identified yet.
Clinical features and associated symptoms:
PD symptoms. Rarely exhibit tremors. More profound postural instability. Some patients with PSP also develop severe palilalia, emotional incontinence, and other evidence of bilateral frontal lobe syndrome. VOGP(vertical ocular gaze paresis) and dementia.
DDx.:
Look above!
Evaluation:
SPECT and PET may show frontal and basal ganglia hypometabolism.
Management:
Severe dementia and psychosis is les common in PSP than in Parkinson’s disease dementia, although treatment considerations are otherwise similar for Parkinson’s disease.
Prognosis:
Median survival after symptom onset is 6-7 years, and patients are typically wheelchair bound at least a year before that.
The cognitive impairment in HD, like other subcortical dementias, primarily reflects frontostriatal dysfunction, and there is pathological evidence of both subcortical and cortical pathology. Grossly, the cortical gyri appear normal to slightly atrophic. Coronal sections reveal striking caudate greater than putamen and pallidal atrophy. Several neurotransmitters are decreased in the striatum, most notably GABA and Ach. Glutamic acid decarboxylase and choline acetyltransferase are also diminished. Other milder degenerative changes occur in the neocortex and thalamus.
Clinical Features and associated syndromes:
- 90% of patients are demented by a mean age of 48.3 years.
- Dementia precedes chorea in about 24%.
Three areas of particular interest in the dementia of HD are frontal-lobe related or fronto-striatal related neuropsychiatric deficits, declarative memory impairment, and motor learning difficulties. Visuospatial disturbances have been demonstrated in some studies.
DDx.:
- Tardive dyskinesia, CNS vasculitis, Wilson’s disease, Sydenham’s chorea, toxin exposure.
- Other subcortical dementias.
- Chronic progressive encephalopathies.
Both boxed dementias are included in the differential when there is absence of chorea and family history!
Evaluation:
Clinical examination can provide compelling evidence for HD, which can be confirmed genetically. MRI or CT may show caudate atrophy. SPECT or PET scan to show caudate hypometabolism. Neuropsychological testing to document the nature and severity of cognitive decline, particularly in mild to moderate stages of the disease.
Management:
As for HD: Dopamine receptor-blocking agents and dopamine depleting agents reduce the choreic movements but may not improve other symptoms of HD. The pharmacological management of dementia and chorea often involves dopaminergic antagonists including neuroleptic drugs but is far from adequate.
Prognosis:
Death occurs within 10-20 years after onset, although suicide is more prevalent in at –risk and early-onset HD patients (Remember for the In-service!).
Fun now begins!
Two major categories:
- Corticobasal Ganglionic Degeneration(CBGD)
- Diffuse Lewy Body Disease( Lewy Body Dementia)
Pathogenesis and Pathophysiology:
The characteristic pathological changes in CBGD include asymmetrical frontoparietal cortical atrophy with corresponding neuronal loss and gliosis, substantia nigra degeneration and swollen achromatic neurons. Variable degree of other subcortical nuclei also occur. The profile of cognitive impairment reflects dysfunction predominantly of the frontal and parietal cortices , includind apraxia, psychomotor slowing and visuoperceptual disturbances. Memory is also impaired. However, CBGD pathology has also been observed in occasional patients with FTD and progressive aphasia( you remember, just mentioned earlier!).
Epidemiology:
The prevalence may be similar to that of PSP or about 1% that of PD. There has been little evidence of a familial tendency.
Clinical features and associated disorders:
- Majority have exhibited a progressive perceptual-motor syndrome( see earlier in the text), and the term progressive asymmetrical rigidity and apraxia has been proposed.
- Less common presentations with similar histology include frontotemporal dementia and progressive aphasia.
- Asymmetrical hyperreflexia, postural instability, frontal release signs, occulomotor impairmen, and hypokinetic dysarthria commonly occur.
- Dysphagia begins insidiously in the latter stages of the disease, and eventually aspiration pneumonia and death ensue.
DDx.:
- stroke, PD, AD.
- Other degenerative processes.
Evaluation:
-CT/MRI: Asymmetrical cortical atrophy, which is predominantly parietal with variable involvement of contiguous regions.
-SPECT: Asymmetrical cortical and subcortical hypoperfusion.
-PET: Asymmetrical FDG cortical hypometabolism and asymmetrical striatal flurodopa hypometabolism.
The neurological and neuropsychological pattern of deficits should not be mistaken for an A/P-type dementia.
Management:
- Levodopa may be reasonable and provide modest symptomatic amelioration of rigidity.
- Clonazepam my yield modest improvement in myoclonus, but it may cause sedation with worsening of balance and cognitive function.
- Botox has a space also here for those with dystonic extremities.
- OT, ST, PT.
Prognosis:
Most patients succumb to the disease in 7-10 years.
Will update soon!
These include multiple different medical conditions that may be associated with dementia; I will summarize it in exiting way, hopefully, and will make easy to read and follow. This group of disorders is the most important common diseases that may be associated with dementia. However, Further, other rare, disorders may be associated with dementia but I don’t see need to mention them here.
Ø Dementia due to HIV disease:
Diffuse multifocal destruction of the brain structures occurs, and cognitive impairment follows. Motor findings include gait disturbances, hypertonia, hyperreflexia, frontal release signs and occulomotor deficits.
Ø Dementia due to Cretzfeldt-Jakob disease:
Dementia, myolconus, and EEG abnormalities(sharp, triphasic, synchronous discharges). Rapidly progressive and subsequently results in dementia over a course of few months. Other findings include visual and gait disturbances, choreoathetosis.
Ø Progressive multifocal leukoencephalopathy:
Usually occurs in immunocompromised hosts. Rapidly progressive cognitive deficits followed by death.
Dementia due to head trauma is usually non progressive and may persist indefinitely, or may gradually ameliorate over many months or years. It is often accompanied by emotional lability and impulsivity. A history of head trauma is a risk factor for development of dementias due neurodegenerative disorders.
·Korsakoff syndrome.
References,
Dear colleagues,
I hope that you enjoyed reading this brief summary of dementing disorders.
Keep the hard working that you are doing, and I wish you always best of luck.
Areen T. Said
May 14,2000