Dementia w/up

Dementia is described as a persistent state of serious cognitive, functional, and emotional deterioration from a previously higher level of functioning.  

Epidemiology:

• • Prevalence:

    • 1% to 2% at age 65

    • 10% to 15% of persons at age 80

  • 20-40% of person at 90 have clinically identifiable memory loss. 

• African American, and low education have higher incidence..

  • 4th or 5th leading cause of death.

Dementias in order of frequency:

Alzheimer's disease (AD) > Vascular Dementia (VaD) > Dementia with Lewy Bodies (DLB) > Frontotemporal lobar degeneration (FTLD).

Early onset dementia in order of frequency: 

The four most common etiologies in the cohort were AD (34 percent), vascular dementia (18 percent), FTD (12 percent), and alcohol-related dementia (10 percent). Notably, the prevalence of dementia doubled every 5 years after age 35.  This was followed by autoimmune/inflammatory disease (21 percent), unknown causes (18 percent), and metabolic disease, including mitochondrial and storage diseases (11 percent).

Potentially modifiable risk factors for EOD identified in one large population-based study include alcohol intoxication, drug intoxication, depression, and hypertension .

The median age of onset of FTD is approximately 58 years, with a reported range from 20 to 80 years. Causative mutations have been identified in up to 40 percent of all cases. Identified genetic mutations include C9ORF72 (the most common cause of familial FTD), microtubule-associated protein tau (MAPT), and progranulin (GRN). 

Causes of early onset dementia: 

Neurodegenerative:  AD, FTD, CBD, PSP, DLB, PD-dementia, 

Vascular:  VaD, CADASIL, CAA, PACNS, Secondary CNS vasculitis

Infectious:  Prion disease, HIV associated neurocognitive disorder (HAND), HSV, Whipple, Neurosyphilis, PML, 

Inflammatory and autoimmune diseases:  MS, Paraneoplastic and autoimmune encephalitis, other nonparaneoplastic autoimmune encephalitis, encephalopathy associated with systemic autoimmune diseases

Nonmetabolic diseases:  Mitochondrial, leukodystrophies, Adult neuronal ceroid lipofucinosis, 

Others: CTE, complications of alcohol abuse, NPH, Wilson disease, Huntingtion disease.

Risk factors:

• • Nonmodifiable risk factors: 

    • Increasing age

    • Female sex

    • Unfavorable perinatal conditions and early life development and growth

    • Family history of AD, ApOE4 gene for AD

• Modifiable risk factors:

  • • Vascular: HTN, obesity, HLP, DM, CHF, AF, PAD, CVA, heavy alcohol intake, and cigarette smoking

      • Oldest old with high blood pressure have been associated with lowest risk of dementia. 

      • High blood pressure in midlife has been associated with increased risk of developing both vascular dementia and AD. 

    • Psychosocial: Low education, poor social network, low mental or physical activity.

    • Elevated homocysteine

Potential protective factors (putative): Statins, Vitamin B group, Mediterranean diet, NSAID, antioxidants, omega-3-fatty acids, physical, and mental exercise.

Clinical Presentations of AD and other Degenerative Dementias

Degenerative Dementias - Pathological Classification:

• • Amyloid/Tau:  Alzheimer's disease

  • Tau: AD, FTD, CBD, PSP, Pick's disease, FTDP-17 (Parkinson linked to chromosome 17 - tau mutations), argyrophilic grain disease (abundant argyrophilic grains and coiled bodies),  Down syndrome, Dementia pugilistica, and Multiple system tauopathy

  • Alpha-synuclein: Lewy body disease, Parkinson's disease with dementia, mutisystem atrophy, pure autonomic failure.

  • Tau/Ubiquitin: FTD-U, FTD-MND, ALS 

    • TDP-43+ (transactivation response DNA binding protein 43 is seen in most cases of FTLD-MND. 

  • FTD:  A hexagonal repeat expansion in C90RF72 in chromosome 9, is the most common mutation, followed by mutations in familial bvFTD in gene for progranulin and MAPT (on chromosome 17)

    • Mutations in the microtubule-associated protein tau gene (MAPT) can cause frontotemporal dementia is also associated with AD.

  • Other: Huntington's disease, dementia lacking distinctive histological features, progressive subcortical gliosis. 

Dementing conditions with amyloid deposition include Alzheimer disease, Lewy body dementia, some prion disorders, and cerebral amyloid angiopathy. 

Conditions without amyloid deposition include frontotemporal dementias, corticobasal degeneration, progressive supranuclear palsy, and vascular dementia without amyloid angiopathy

Degenerative Dementias - Syndromic Classification:

• • MCI

    • Single domain: amnestic, non-amnestic

    • Multiple domain: amnestic, non-amnestic

• FTD:  Behavior(bvFTD) and primary progressive aphasia (PPA) subtypes.

  • bvFTD subtype can carry the simpler acronym FTD, while each of the PPAs is referred to more specifically as a nonfluent/ agrammatic, semantic, or logopenic var- iant of PPA.

• CBD syndrome

  • Posterior cortical atrophy

FH of dementia: 

• • Memory problems

  • Ages and health of siblings and children: Huntington's disease

  • Patients with late-onset AD have family h/o AD.

  • Younger patient with positive family history (autosomal dominant):

    • Familial forms of AD, FTD, Huntington's disease, SCA, or prion d/o.

 Warning Signs of Early Dementia:

• • Memory loss that affect job skills

  • Difficulty remembering familiar tasks

  • Problems with language

  • Disorientation to time and palce

  • Decreased judgment

  • Problems with abstract thinking

  • Misplacing objects

  • Changes in mood or behavior

  • Changes in personality

  • Loss of initiative.

All except the last three items deal with language and praxis, the last three items reflect abnormal mood, behavior, and personality.

Difficulty remembering familiar faces or family members, famililar tasks - right hemisphere function.

MMSE

MoCA SCALE: http://www.mocatest.org/pdf_files/test/MoCA-Test-English_7_1.pdf

MOCA instruction sheet

SLUMS (Saint Louis Univ Mental Status exam):  http://medschool.slu.edu/agingsuccessfully/pdfsurveys/slumsexam_05.pdf

MMSE is short and easy to use and has been used extensively for may years.  MoCA is recent, and so is used less extensively.  It is a little longer than MMSE, but it assess a broader rage of cognitive domains.  Users of MMSE are supposed to pay a fee of $1.20 to the copyright holder each time they administer the test.  MMSE is not very sensitive for mild dementia.

Labs: 

According to the guidelines by the NINCDS-ADRDA, the routine evaluation of the patient with dementia should include the following laboratory tests: 

• (1) complete blood count, 

• (2) serum electrolytes, 

• (3) glucose, 

• (4) blood urea nitrogen/creatinine, 

• (5) serum B12 levels, 

• (6) depression screening, 

• (7) liver function test, and 

• (8) thyroid function test. 

• Depression screening 

  • Further testing including HIV, VDRL, lumbar puncture, and heavy metals are not recommended unless there is a specific clinical indication.

CBC, CMP, TSH, RPR, HIV, CT, VDRL, BC x 2 with sensitivity, UA complete , Urine C&S, UDS, ALT, AST, T. Bili, D. Bili, prealbumin, albumin, total protein, Alk Phos, amylase, lipase, LDH, CPK, PTT, PT, INR, Sr. NH3(ammonia), Vit B12, Folate, Sr. Cortisol, ACTH, urine heavy metal screen, copper or ceruloplasmin. 

EEG, ECG, ABGs. CXR. Apolipoprotein E. PTH,  LP (if indicated). Large volume tap (30-50 mL) in NPH

CXR for (reason), US-renal for (reason)

CT without contrast to rule out mass lesion, NPH, and SDH.

MRI brain

SPECT

PET scan approved by medicare is used to differentiate between AD and FTD.

Angiogram

Brain bx

EEG

Formal neuropsychological testing, depression screening:  PHQ9, Geriatric depression scale (short form)

Diagnostic biomarkers:

• • CSF amyloid beta and tau proteins: 89% sensitive; 90% specific for AD

    • Reduction in the ratio of A[beta]-42 to total-tau (A[beta]-42/total-tau and A[beta]-42/hyperphosphorylated-tau is helpful in distinguishing AD patients from those with MCI who later develop AD.

    • In patients with MCI, biomarkers associated with an increased likelihood of developing Alzheimer disease dementia include medial temporal lobe atrophy on MRI, temporoparietal hypometabolism on FDG-PET, diffuse uptake on amyloid positron emission tomography (PET), low levels of A"42 in CSF, high levels of tau protein in CSF, and the presence of the (APOE) (4 haplotype)

    • CSF level for 1-4-3-3 protein to support the Dx of CJD; 94% sensitive and 93% specific.

  • Presenilin-1 mutation testing: genetic counseling is required before and after testing. 

  • ApoE4 is not recommended by AMA in diagnosis of AD

  • Imaging techniques to evaluate structure:

    • Voxel-based morphometry

    • Hippocampal volumetric measurement

    • FDG-PET

    • MRS

    • Direct amyloid imaging (fMRI/PET)

The molecular basis for degenerative dementia

Clinical differentiation of the major dementias

A Framework for the Administration of Anti‑amyloid Monoclonal Antibody Treatments in Early‑Stage Alzheimer’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11182839/pdf/40263_2024_Article_1097.pdf

There are no therapies that can prevent the conversion of MCI to AD.  Some suggest trying AChEIs.

Alzheimer's disease: It is the most common form of dementia in the U.S. 5th leading cause of death.

• Dementia of the Alzheimer type accounted for 70% of dementia cases, ranging from 47% among those aged 71 to 75 years to 80% in the age 90+ group.

Predilection for the association cortex, hippocampus, amygdala, and deep frontal nuclei, such as the nucleus basalis of Meynert (cholinergic system), and brainstem monoaminergic nuclei.

Dubois Diagnostic Criteria for Alzheimer Disease

Probable Alzheimer Disease

Evidence satisfying the core diagnostic criteria (A) plus one or more supportive features (B-E)

Core diagnostic criteria:

A. Presence of an early and significant episodic memory impairment that includes the following features:

• Gradual progressive change in memory function reported by patients or informants over more than 6 months

• Objective evidence of significantly impaired episodic memory on testing

• Episodic memory impairment can be isolated or associated with other cognitive changes at the onset of AD or as AD advances.

Supportive features:

B. Presence of medial temporal lobe atrophy:

• Volume loss of hippocampi, entorhinal cortex, and/or amygdala evidenced on MRI with qualitative ratings using visual scoring (referenced to well-characterized population with age norms) or quantitative volumetry of regions of interest (referenced to well-characterized population with age norms)

C. Abnormal cerebrospinal fluid biomarkers:

• Low amyloid β1-42, increased total tau or phospho-tau concentrations, or combinations of the three

D. Specific pattern on functional neuroimaging with PET:

• Amyloid-beta PET and FDG PET are measuring two different things, with the former measuring the content of brain amyloid-beta and the latter measuring the regional utilization of glucose in the brain (a putative surrogate for neuronal loss).

• Reduced glucose metabolism in FDG PET, bilateral temporoparietal regions

• Other well-validated ligands, including Pittsburg Compound B or FDDNP

  • PET using Pittsburgh compound-B is currently the most specific in vivo reflection of amyloid-beta protein load.  

  • Florbetapir 18F is a radioactive diagnostic agent indicated for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer disease.   A negative florbetapir PET scan suggests sparse to no neuritic amyloid plaques and is inconsistent with a diagnosis of Alzheimer disease. A positive scan suggests the presence of moderate neuritic amyloid plaques and is consistent with a diagnosis of Alzheimer disease (AD). 

  • Fluorodeoxyglucose or FDG PET shows decreased metabolism usually in bilateral parietal and temporal brain regions but it does not estimate neuritic plaque density.

  • Amyloid-beta 42 in CSF is very suggestive of AD if the levels are low. However, it and amyloid-beta 40 in CSF are not estimates of neuritic plaque density in the brain.

  • 60% of patients with MCI have amyloid positivity by PET imaging based on Pittsburg Compound B; 30% to 40% for normal older individuals, and 90% for clinically diagnosed AD.

    • Given its 80% to 100% reported sensitivity, amyloid-PET, it is likely that a normal amyloid imaging study will have very good negative predictive value against AD neuropathology. However, it may have a poor positive predictive value, as its diagnostic accuracy is dependent on age. An age-related increased prevalence of amyloid tracer uptake exists, with up to 40% of asymptomatic people over 70 years of age having high cortical Pittsburgh Compound B (PiB) uptake. Amyloid imaging also shows little significant change over time and correlates poorly with clinical progression of disease. It may be useful the differential diagnosis of dementia as amyloid accumulations in frontotemporal lobar degeneration are low, similar to healthy controls.

E. Proven autosomal dominant AD mutation within the immediate family

• • Autosomal dominant AD has been traced to three genetic mutations in the amyloid precursor protein (APP) gene and the presenilin-1 and presenilin-2 (PS1, PS2) genes. 

    • These cases typically affect the middle-aged population.

Exclusion Criteria

History:

• Sudden onset

• Early occurrence of the following symptoms: gait disturbances, seizures, behavioral changes

Clinical features:

• Focal neurological features including hemiparesis, sensory loss, visual-field deficits

• Early extrapyramidal signs

• Other medical disorders severe enough to account for memory and related symptoms:

  • Non-AD dementia

  • Major depression

  • Cerebrovascular disease

  • Toxic and metabolic abnormalities, all of which may require specific investigations

  • MRI FLAIR or T2 signal abnormalities in the medial temporal lobe that are consistent with infectious or vascular insults

Criteria for Definite Alzheimer Disease

• Both clinical and histopathological (brain biopsy or autopsy) evidence of the disease

• Both clinical and genetic evidence (mutation on chromosome 1, 14, or 21) of AD

Risk factors:

• Age

  • African Americans

  • Cardiovascular risk factors

    • High blood pressure is associated with lowest risk of dementia in the oldest old. 

  • Genetic/familial predisposition plays a role for early onset AD and not for late onset AD (sporadic).

    • There may be family history of dementia in first-degree relatives

  • Familial AD with genes linked to the following chromosomes: 21 (amyloid precursor protein [APP]), also a link with Down's syndrome, 14 (presenilin-1 [PS-1]), 1 (PS-2) 

  • EOFAD:  Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by early onset dementia (age at onset < 65 years) and a positive family history for dementia. To date, 230 mutations in presenilin (PS1, PS2) and amyloid precursor protein (APP) genes have been identified in EOFAD. The mutations within these three genes (PS1/PS2/APP) affect a common pathogenic pathway in APP synthesis and proteolysis, which lead to excessive production of amyloid β. Compared with sporadic Alzheimer's disease (AD), EOFAD has some distinctive features including early age at onset, positive familial history, a variety of non-cognitive neurological symptoms and signs, and a more aggressive course. There is marked phenotypic heterogeneity among different mutations of EOFAD.  Studies in presymptomatic mutation carriers reveal biomarker abnormalities.  EOFAD diagnosis is based on clinical and family history, neurological symptoms and examination, biomarker features, and genotyping in some cases. New therapeutic agents targeting amyloid formation may benefit EOFAD individuals. 

    • PS1 mutations are the most common cause of familial AD.  Majority are missense mutations causing amino acid substitutions.  Presenilin 1 protein (PS1) was identified to be the catalytic site of the gamma secretase complex that cleaves APP protein to produce A-beta fragments.  By causing conformational changes in PS1, the majority of the pathogenic PS1 mutations cause an increased absolute or relative production of A-beta 42, and it is thought that this is the mechanism through which they cause AD.

      • PS1 mutation tend to cause the youngest age of sx onset (44-46 years).

      • PS1 mutation carrier have atypical features that sometimes accompany familial AD, including spastic paraparesis, early myoclonus, and sz.  Memory complaints are early feature, gait abnormalities, pseudobulbar affect.  If such features are present in a young-onset case of AD when the family history is unavailable, genetic testing can be considered. 

    • Autosomal dominant forms of AD typically present at early age (40-70 years)

    • Presenilin-2 (PS2) mutations are rare and tend to have the oldest and most variable age of onset.  Mean age of onset is 54 years.

  • Presenilin-1 is the most common mutation found in patients with early-onset familial Alzheimer disease. The mutation is 100% penetrant; therefore, all patients who harbor this mutation will develop Alzheimer disease. The APOE protein is a stratifier of risk and does not guarantee development of disease. However, patients with an ε4 allele may be at higher risk and may have lower age of onset of disease.

  • Female sex (likely a survival effect based on age)

  • Low level of education

  • Down's syndrome

    • Patients with Down syndrome eventually develop AD lesions (usually after the age of 30 years), but this is considered a distinct entity. Mothers of children with Down syndrome are considered at greater risk for developing AD than the general population

    • Virtually 100% of Down's synd. patients who live past age of 40 have pathological changes of AD in their brains.

    • https://www.the-ntg.org/_files/ugd/c53c74_6b1f8d20f969401b87a6328c679d71c4.pdf

  • Head trauma, especially repeated or severe trauma, as in dementia pugilistica

  • APP is incorrectly cleaved by β- and γ-secretase, producing insoluble toxic Aβ protein (Aβ1-42, Aβ1-40)

  • Amyloid starts as an amyloid precursor protein. It is normally cleaved by a series of enzymes (alpha-secretase) into a short version that is soluble and can easily be excreted by the body. In pathological conditions such as Alzheimer’s disease, amyloid is incorrectly cleaved by beta-secretase and gamma-secretase. Presenilin-1 assists gamma-secretase in cleaving the amyloid precursor protein. This abnormal cleaving results in amyloid aggregation that ultimately leads to plaque formation.

    • Presenilin-1 is one of the secretase enzymes that breaks down APP into the βeta protein, a 40-42 amino acid peptide which appears to accumulate in the plaques, and also in arteries, and may be toxic to neurons.

• APOE ε4 as susceptibility gene on chromosome 19. 

  • ApoE's normal role is in cholesterol metabolism. It acts as a scaffold in HDL particles and is highly expressed in the liver and CNS, where it is made by astrocytes and microglia.  ApoE also binds to Amyloid beta 42.

  • Inheritance of the E4 allele of the apolipoprotein E (ApoE) gene remains the most established genetic risk factor for AD

  • ApoE has 3 alleles and are involved in transport of amyloid beta.  

  • The e4 allele is defective in its transport of amyloid beta. It is clearly associated with an increased risk for heart disease and Alzheimer disease. 

  • The ε3 allele is involved in neuronal growth regulation. 

  • The ε2 allele stabilizes tau protein on microtubules and may decrease the risk for Alzheimer disease.  It clears amyloid beta 42 effectively.

• Homozygous ε4/ε4, carrying two genes are at increased risk of developing AD by age 85.

  • 10-15 fold increase in homozygotes vs 3-4 fold increase in heterozygotes.

    • Effect is predominantly on age at onset rather than on development of disease and is seen in both heterozygotes and homozygotes

    • APOE genotyping should not be used for diagnosis or risk assessment because many APOE ε4 carriers never develop AD (AAN recommendations), lack of specific predictive value and lack of proved preventive therapy.   Presence of APOE ε4 cannot rule in AD, and absence of APOE ε4 cannot rule out AD.

The National Institute on Aging (NIA) and the Alzheimer's Association 2011 diagnostic guidelines for Alzheimer disease (AD) specify 3 stages of AD: 

• • Preclinical AD

  • Mild cognitive impairment (MCI) due to AD

  • AD dementia. 

Possible, probable, or definite

The National Institute of Neurological and Communicative Disorders and Stroke and the Alz's and related dz assoc criteria (NINCDS-ADRDA):

• 1. Criteria for the clinical dx of probable Alz dz

     1. Dementia established by means of clinical exam and documented with the MMSE, Blessed Dementia rating scale, and other similar exam, and confirmed with neuropsychological tests.

     2. Deficits in two or more areas of cognition

     3. Progressive worsening of memory and other congnitive functions

     4. No disturbance of consciousness

     5. Onset between ages 40-90 yrs, most often >65 yrs

     6. Absence of systemic d/o or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition

  2. Supporting findings in the diagnosis of probable Alz dz.

• • • Progressive deterioration of specific cognitive functions: aphasia, apraxia, agnosia

    • Impaired ADL and altered pattern of behavior

    • FH of similar d/o

    • Lab:

      • LP: normal

      • EEG: normal or nonspecific (slow-wave activity)

      • CT evidence of atrophy, with progression documented by means of serial observation.

• 3. Other clinical features consistent with diagnosis of prob Alzheimer's disease, after exclusion of causes of dementia other than Alzheimer's disease.

• • • Plateaus in the course of illness

    • Associated symptoms: insomnia, depression, incontinence, delusions, illusion, hallucination, catastrophic verbal, emotional, or physical outbursts, sexual d/o and wt. loss.

    • Other neurological abnomalities: increased muscle tone, myoclonus, or gait d/o

    • Seizure in advanced disease

    • CT findings normal for age.

Clinical diagnosis of possible Alzheimer's disease:

• • May be based on dementia syndrome in absence of other neurologic, psychiatric, or systemic disorder sufficient to cause dementia and in the presence of variations in onset, presentation, or clinical course.

  • May be made in the presence of a second systemic or brain d/o sufficient to produce dementia, which is not considered to be the principal cause of dementia.

Criteria for definite diagnosis of Alzheimer's disease: 

• • Clinical criteria fro probable Alzheimer's disease + histopathathological evidence obtained on biopsy or autopsy.

Alzheimer's disease with cerebrovascular disease: Patient has clinical criteria for possible AD + CVA on brain imaging. 

Clinical features:

• AD is a progressive disorder of recent episodic memory, language, visuospatial function, and executive function associated with high frequency of neurobehavioral abnormalities at some point in the course

• Onset of AD usually is in late life.

• If onset age is younger than 45 years, an autosomal dominant pedigree usually is involved. Most commonly, a PS1 mutation is the cause. 

• In elderly individuals presenting with mild memory loss, serial follow-up evaluations may be necessary to establish decline and a characteristic pattern of dementia. 

• If memory is not a prominent early complaint, other potential causes of dementia should be considered. 

• Episodic memory impairment is more prominent in AD

  • Semantic memory is also impaired but relatively later in the disease course. 

  • Verbal fluency and word finding, generally is an early feature of AD

  • AD patients will produce more words beginning with a given letter (phonemic fluency task) than animals (semantic fluency task). This may be particularly useful in differentiating early AD from the effects of depression, in which the opposite pattern is seen.

  • Apraxia may be a prominent early feature.

  • Decline in visuospatial skills is a common symptom.

  • Anosognosia, or unawareness of the cognitive deficit, can be an early feature of AD.

  • Neuropsychiatric behavioral abnormalities:

    • Irritability, agitation

  • Sundowning

  • Hallucinations

  • Paranoid delusions

  • Apathy is common

    • Anhedonia, aloofness, diminished spontaneity and emotional behavior, and reduced motivation.

      • Reflects disruption of the connections within the frontosubcortical–anterior cingulate circuitry and their connections with other cortical regions. 

    • Apathy can be distinguished from primary depression on the basis of its neutral affect and the absence of vegetative signs.

    • Depression is quite common in the form of mild dysphoria.

    • Anxiety is another early feature of AD.

  • Any patient with Alzheimer's disease who acutely develops symptoms of a confusional state and behavioral changes first warrants a workup to look for the underlying cause. Even mild changes in metabolic status, medications, or an infection such as of the urinary tract may precipitate confusion and behavioral changes.

Pathology:

• • It involves a generalized cortical atrophy.

  • Begins in the entorhinal cortex, spreads to the hippocampus, and then moves to posterior temporal and parietal neocortex, eventually causing a diffuse degeneration throughout the cortex. 

  • It is a tauopathy like corticobasal ganglionic degeneration, FTD with parkinsonism, Pick's disease, and PSP.

  • Amyloid deposition, granulovaculoar degeneration, Hirano bodies, neuritic plaques, and neurofibrillary tangles. 

  • Neuritic or amyloid plaques consisting of dystrophic neurites clustered around a central amyloid core

  • Neurofibrillary tangle, consisting of intraneuronal staining in a fibrillar pattern

  • Gene for amyloid beta-precursor protein is on chromosome 21.

  • The 42-residue form of beta-amyloid (A-beta) a.k.a A-beta1-42 is the most toxic form of beta-amyloid.

• β-Amyloid deposits can be seen in the cerebral blood vessels of all patients with AD (CAA)

Diagnostics:

• • Neuropsychological testing.

  • Functional imaging such as FDG-PET provides a measure of how the brain is functioning. In patients with probable Alzheimer disease (AD), the PET pattern reveals bilateral posterior temporal and parietal hypometabolism. One of the earliest regions to demonstrate hypometabolism is the medial portion of the parietal cortex and the posterior cingulate. As the disease advances, the typical temporal/parietal pattern of hypometabolism is more evident.

  • Changes occur typically in the following order:

    • Mesial temporal lobes, including the entorhinal cortex, hippocampal formation (especially CA1), and amygdala are considered typical for the prodromal AD stages

  • In the dementia stage, global brain atrophy— more striking in the temporoparietal than in the frontal regions—and ventricular enlargement are also pronounced.

    • Cell loss and neurofibrillary tangles are also prominent in the nucleus basalis, septal nuclei, and nucleus of the diagonal band, where cholinergic projections arise, and to a lesser extent in the locus ceruleus (NE), and raphe nuclei (serotonin).

  • Positron emission tomography (PET) and single photon emission computed tomography (SPECT): glucose hypometabolism (on PET) and hypoperfusion (on SPECT) of bilateral posterior temporal and parietal structures, followed by changes in frontal association in advanced stages

    • Florbetapir PET scan is approved with beta-amyloid PET imaging agent florbetapir (Amyvid) which can help to rule out Alzheimier's disease as a cause of cognitive decline.

      • Areas of early amyloid accumulation include the middle frontal gyri and the parietal/precuneus/posterior cingulate regions.

      • A negative amyloid PET study signifies few or no amyloid deposits and indicates that the likelihood of cognitive impairment due to AD is low.

      • It is important to recognize in considering the high image-to-pathology correlation is that amyloid positivity does not reliably distinguish clinical diagnoses.

  • Routine MRI could show differential frontal atrophy in the FTD patients and hippocampal atrophy in the probable AD patients, but these findings are subtle.

  • Cerebrospinal fluid (CSF) tau levels in Alzheimer disease (AD) patients are thought to be elevated occur after being released from dying and damaged neurons. The CSF levels of beta-amyloid -42 are decreased secondary to the accumulation of amyloid in the neuritic plaques. This pattern has been shown to have sensitivity and specificity of 85% in predicting conversion from mild cognitive impairment (MCI) to AD.

  • Elevations in total and phosphorylated tau (P-tau) and a reduction of CSF A[beta]--42 is associated with progression to AD in people with MCI.

  • Reduction in the ratio of A[beta]-42 to P-tau is helpful in distinguishing AD patients from those with MCI who later develop AD.

  • EEG may show diffuse slowing of the background

Guidelines for Genetic Testing in AD:

• • Comprehensive family history to check if there is a dementia or AD death in family

  • Inform patient of the limitations of understanding the genetics of AD and the ability to treat or prevent it.

  • Testing in pediatric population is not recommended

  • Revealing testing for risk susceptibility genes such as APOE is not widely recommended except in the context of fully informed patients and families, as in research studies.

  • Scientific literature and mutation databases such as the AD and FTD mutation database www.molgen.ua.ac.be/ADMutations should be consulted. 

Treatment:  None of the following medications have been proven to be more effective than the other. 

• • Donepezil (Aricept) is a pure acetylcholinesterase inhibitor.

    • Long acting reversible

    • Time to maximum concentration (Tmax) is 3 to 4 hours

    • Once-daily regimen. Introduced at 5 mg/d for 1 month, then increased to 10 mg once daily,  or 23 mg daily after meals.

    • Major side effects: anorexia, nausea, vomiting, diarrhea, vivid dreams. Best tolerated of all available cholinesterase inhibitors. Better tolerated if taken in morning on full stomach.

    • Metabolized extensively in liver and excreted unchanged in urine; long elimination half life of 70 hours, and steady state occurs in approximately 2 weeks. 

    • No significant effects on loss of function, NH placement, or health economic measures  over 2 years. 

  • Galantamine (Reminyl).  Reversible competitive Acetylcholinesterase inhibitor and allosteric nicotinic modulator thus enhancing cholinergic rcps.

    • Administered twice daily. Initial dose of 4 mg twice daily for at least 1 month,

  • increased to 8 mg twice daily, and then 12 mg twice daily after 1 month

    • • anorexia, nausea, vomiting, diarrhea, vivid dreams are more frequent than with donepezil.

  • Rivastigmine (Exelon).  Pseudoirreversible Acetylcholinesterase and butyrylcholinesterase inhibitor

  • Administered twice daily. Dose escalation preferably in monthly increments because of the relatively higher side effect rate than with other cholinesterase inhibitors: initial starting dose of 1.5 mg twice daily, then 3 mg twice daily after 2 weeks, and 4.5 mg (and possibly 6 mg) twice daily after 2 weeks.

    • Higher side effect profile than other cholinesterase inhibitors, may need to slow down the titration schedule

    • Transdermal patch formulation 5.6 mg (5 cm2)/day and increased to 9.5 mg (10 cm2)/day after 4 weeks, if tolerated is available and has fewer adverse effects. A13.3 mg (15 cm2)/day patch is also available.  Maximum concentration occurs in 8-16 hours and a 3 hours elimination half life after the patch is removed. 

    • Little protein binding  and is well absorbed

    • Elimination half-life is 2 hours, but enzyme inhibition last 9 hours

    • Not metabolized in liver.  It is slowly hydrolyzed and then excreted by the kidneys.

• Memantine (Namenda). Low affinity non-competitive NMDA receptor (glutamate rcp) modulator with rapid onset and offset of action

  • • Goal of therapy is short-term NMDA receptor activation that may promote memory and learning and avoidance of chronic low-grade NMDA activation that may promote excessive calcium influx and resultant apoptosis.  It may protect against overstimulation of NMDA receptors that may occur in AD as well as consequent glutamate and calcium mediated neurotoxicity.

    • Therapeutic mechanism of action is not known, but may act as an open-channel NMDA receptor antagonist that does not have apparent pharmacologic action until higher glutamate level trigger the receptor and cause the channel to open.  It enters the channel, blocking it and prevents influx of calcium and thus depolarization, and hyperactivation of the neuron. 

    • Plasma protein binding is 45%, achieves max conc: 3-7 hrs; elimination half life is 60-80 hrs.

    • Not metabolized by the liver.  Mostly excreted in the urine unchanged. 

    • Reported side effects: confusion, headaches, dizziness, somnolence, and infrequent hallucinations.  

    • Initial therapy for patients with moderate to severe dementia. 

      • May be used as monotherapy or in conjunction with cholinesterase inhibitors and vitamin E (polytherapy well tolerated)

      • Dose escalation, preferably in weekly increments: starting dose of 5 mg once daily in the evening, for a week, then next 5 mg twice daily, followed by 10mg every morning and 5mg in the evening, and then 10 mg twice daily.  28 mg SR daily is approved by USFDA and not yet available. 

    • Should not be administered with medications with similar mechanism of action

• Namzaric (formerly MDX-8704) is a once-daily capsule for patients currently taking memantine (10 mg twice daily or 28 mg XR once-daily) plus donepezil 10 mg. The capsules can be opened and sprinkled on food for patients who have difficulty swallowing.

• • Namzaric will be available in two strengths: 28/10 mg (memantine/donepezil) and 14/10 mg (memantine/donepezil) for patients with severe renal impairment.

Multi-infarct dementia (MID) was a term replaced by vascular dementia (VaD) due to the recognition of the small strategically placed lesion that is capable of meeting the DSM IV-R criteria of dementia (ie, a long- and short-term memory impairment, accompanied by a decline in another cognitive domain [ie, executive, language/praxis, or visuospatial function] that significantly interferes with social and occupational function). The only lesion that can cause dementia, is 0.5 cm in size,in the left dorsomedial thalamus since it is capable of disrupting the encoding circuit (producing an amnesia) and also the frontal-subcortical circuits (producing profound executive and behavioral dysfunction).

Frontotemporal dementias (FTDs) 

Group of neurodegenerative dementias of varied etiology in which the frontal or temporal lobes, or both, are affected out of proportion to the rest of the brain, with variable degrees of subcortical pathology and degeneration. 

It is a clinical syndrome of frontal lobe degeneration of non-Alzheimer type with onset typically between the ages of 50 and 60 years and featuring insidious personality change, disinhibition, and subsequent gradual loss of speech output.

The FTD spectrum is a clinically and pathologically inhomogeneous group. Several distinct clinical phenotypes have been described: one behavioral variant, frontal-variant FTD (fvFTD); two language variants, primary progressive aphasia (PPA) and semantic dementia (SD); and one variant with associated motor neuron disease (MND), FTD-MND.

Age: 45 and 65 years of age, except for SD, where the typical age of onset is 70 years.

Proposed General Criteria for the Frontotemporal Dementia Spectrum Disorders used in clinical practice:

1. Development of behavioral or cognitive deficit manifested by either:

   • Early and progressive change in personality, characterized by difficulty in modulating behavior, often resulting in inappropriate responses or activities or

   • Early and progressive change in language, characterized by problems with expression of language or severe naming difficulty and semantic knowledge (loss of word meaning)

2. The behavioral or language deficits cause significant impairment in social and/or occupational functioning and represent a significant decline from a previous level of functioning

3. The course of progression is gradual and continuous 

4. The behavioral or language deficits are not due to other neurologic, systemic, psychiatric or substance abuse condition 

5. The behavioral or language deficits are not due to delirium or depression.

Neary Criteria for Frontal-Variant Frontotemporal Dementia

1. Core Diagnostic Features

   • Insidious onset and gradual progression 

   • Early (<2 yrs) decline of interpersonal conduct 

   • Early (<2 yrs) decline in regulation of personal conduct 

   • Early (<2 yrs) emotional blunting 

   • Early (<2 yrs) loss of insight

2.  Supportive Diagnostic Features 

   • Behavioral disorder: decline in personal hygiene and grooming, mental inflexibility, distractibility or impersistence, hyperorality or dietary changes, preservative or stereotyped behavior, utilization behavior

   • Speech and language: altered speech output, stereotypy of speech, echolalia, perseverations

   • Physical signs: Primitive reflexes, akinesia, rigidity, or tremor

Genetics of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). 

• TDP-43-positive pathology, seen in the vast majority of ALS cases and in 50% of FTD cases, is the result of TARDBP or GRN mutations. 

• The second most common genetic cause for FTD is MAPT gene mutations. 

• A smaller portion of cases present with FUS gene mutations and inclusions.

• Recent studies also have identified mutations in the valosin gene on chromosome 9 and the CHMP2B gene on chromosome 3 associated with FTD. 

  • The FTD cases related to valosin mutations are very rare and may include Paget disease and inclusion body myositis as part of the clinical manifestations. 

  • FTD cases with CHMP2B mutations are similarly rare and can be associated with MND.

  • A hexagonal repeat expansion (GGGGCC) in C90RF72 is the most common mutation, followed by mutations in familial bvFTD in gene for progranulin and MAPT

Treatment:

• Atypical antipsychotic medications or SSRIs generally are used to suppress disruptive or aggressive behaviors. Numerous studies have shown a serotonergic deficit in patients with FTD.  Experts in the field advocate treating Pt's with FTD with SSRIs even in the absence of depression.

• Trazodone is found to have a beneficial effect on behavioral and psychiatric symptoms in patients with FTD.

  • Little or no response to levodopa for motor function

  • Paradoxical worsening if acetylcholinesterase inhibitors are used. 

Patients with semantic dementia, a category of frontotemporal dementia, have an insidiously progressive yet relatively focal disease until late in the course of their illness. These patients have fluent yet empty speech, coupled with naming impairment and failure to understand the meaning of words. The latter may eventually manifest as an agnosia and apraxia for the object. It is common for patients to use semantic paraphasias and idiosyncratic words or phrases as substitute fillers for names they cannot recall. They may also develop difficulty identifying familiar people by name. As the disease progresses, features of social disinhibition such as those seen with frontal lobe dementia begin to emerge. The MRI findings typically demonstrate dominant hemisphere anterior temporal atrophy with relative sparing of the hippocampal formation.

FTD

The text and image of this Test Your Knowledge item are from Viskontas I, Miller M. Frontotemporal dementia. Continuum Lifelong Learning Neurol 2007;13(2):87-108.

1. General Information

Although frontotemporal lobar degeneration (FTLD) is still described as a single diagnostic entity, recent findings suggest that frontotemporal dementia (FTD), semantic dementia (SD), and nonfluent aphasia (NFA) differ in prevalence, age of onset, sex distributions, genetic susceptibilities, coassociations with other degenerative conditions, and neuropathologic features. For example, FTD accounts for approximately 56% of all FTLD cases, is male predominant by two to one, has the earliest age of onset (approximately 58 years at diagnosis), progresses the most rapidly from time of diagnosis (3.4 years from diagnosis to death), has the highest genetic susceptibility (up to 20% of cases show an autosomal dominant pattern of inheritance), has a strong association with ALS, and often shows equal percentages of cases with ubiquitin or tau inclusions postmortem. SD accounts for less than 20% of all FTLD cases, has a similar age of onset to FTD, shows the slowest rate of progression of all the FTLD subtypes (5.2 years from diagnosis to death), has a low percentage of cases with an autosomal dominant pattern of inheritance, and usually shows ubiquitin inclusions postmortem. Finally, NFA accounts for approximately 25% of all FTLD cases, is intermediate in rates of progression (4.3 years from diagnosis) and genetic propensity, has a high association with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and cases nearly always show tau inclusions postmortem.

2. Symptoms and Signs FTD, the prototypical FTLD syndrome, is characterized by a multitude of behavioral changes that often herald the onset of the dementia. These include alterations in social decorum and personal regulation including disinhibition, apathy, overeating, emotional blunting, personality changes toward coldness and submissiveness, repetitive motor behaviors, and impairment in judgment and insight. With these behavioral changes, deficits in executive control emerge and patients have problems with planning, organizing, shifting patterns, and generating ideas. As FTD may be considered a midlife problem of adjustment or a psychiatric disorder, patients often do not reach the neurologist until they have made profound lapses in financial or interpersonal judgment. Unlike in AD, where family and acquaintances are sympathetic due to the sparing of social decorum, colleagues and family may resent patients with FTD because of their rudeness, coldness, and deficits in social modulation. Approximately 15% of patients develop ALS, and extrapyramidal deficits are common. Shortly after the onset of dementia, patients develop weakness and wasting of limb muscles. Typically, the respiratory complications of bulbar palsy are the cause of death, and patients live approximately 1.4 years after diagnosis.

3. Diagnosis

Both structural and functional imaging are helpful and typically show abnormalities in the right greater than the left frontal regions. The ventral and medial frontal and insular regions-all paralimbic structures-are hit early in FTD, driving the disinhibition, apathy, and eating disorders.

Bilateral frontal hypoperfusion is observed in patients with FTD using Tc99-hexamethylyl-propyleneamine (HMPAO)-SPECT and fluorodeoxyglucose PET (FDG-PET). Furthermore, cortical atrophy in the ventromedial frontal cortex, posterior orbitofrontal cortex, insula, anterior cingulate cortex, right dorsolateral frontal cortex, and left premotor cortex, as seen in T1-weighted structural MRI scans marks fv-FTD. Finally, patients with FTD show faster rates of frontal atrophy (4.1% to 4.5% per year) as seen on longitudinal MRI scans but similar rates of parieto-occipital atrophy (2.2% to 2.4% per year) when compared with patients with AD.

4. Treatment

Unfortunately, no effective pharmacologic treatments are available to reverse or halt the progression of FTLD. Current treatment of patients with FTD involves treating specific symptoms and improving quality of life. Acetylcholinesterase inhibitors developed to improve symptoms of AD do not seem to be effective in managing symptoms of FTD, perhaps because the cholinergic neurons in the nucleus basalis of Meynert are relatively spared in FTLD. Furthermore, acetylcholinesterase inhibitors may cause agitation in patients with FTLD and are particularly dangerous for patients with FTD-MND, since they may cause increased production of oral secretions.

Selective serotonin reuptake inhibitors (SSRIs), in contrast, have shown some success in treating compulsions and carbohydrate cravings in patients with FTLD. Generally, SSRIs are well tolerated by patients. Patients who do not respond to SSRIs and who show aggressive or delusional behaviors may benefit from low doses of atypical antipsychotics such as olanzapine, quetiapine, or risperidone. Typical antipsychotics known to result in extrapyramidal side effects should be avoided, since patients with FTLD are likely to show parkinsonism. In the only placebo-controlled study of FTLD, the antidepressant trazodone was shown to be effective compared with placebo in controlling behavior. Because behavioral changes figure prominently in the disease, the safety of the patient and those with whom the patient interacts must be a primary concern. Removing dangerous items from the home, eliminating driving later in the disease, and educating caregivers are all methods of preventing injury and distress. In addition to education, caregivers should also be provided with support and respite. Depression in caregivers is common and leads patients to earlier nursing home placement.

PPA - FTD

1. General Information

PPA is a syndrome of fluent aphasia and semantic amnesia that occurs in the setting of asymmetric (left greater than right) atrophy of the anterior temporal lobes, as demonstrated on the above imaging studies. The characteristic leading symptom is anomia, which is followed by deficient auditory comprehension, visual agnosia, and more pervasive semantic impairment. The aphasia in this case could be characterized as anomic aphasia in the early phase and later as transcortical sensory aphasia.

Based on clinical evaluation and imaging characteristics, PPA can be divided into subgroups. However, this is an evolving field and new subgroups are being continually defined with considerable debate in the literature. It is commonly accepted that there are at least three subgroups including progressive nonfluent aphasia, semantic dementia (semantic variant) and logopenic aphasia.

2. Symptoms and Signs

The diagnosis and classification of each subgroup is based on neuropsychometric testing. Nonfluent aphasia presents with slow, stuttering speech with intact comprehension whereas semantic aphasia variant is characterized by fluent speech, anomia, and sensory aphasia. Logopenic aphasia has similarities to non-fluent aphasia but also demonstrates memory impairment, a function which is often intact in patients with the non-fluent aphasia type. These memory impairments result in difficulty holding onto lengthy information, and, therefore, these patients may have trouble understanding long or complex verbal information.

There is some evidence to suggest that radiographic findings may correlate with these subgroups. For example, dominant hemisphere anterior temporal lobe atrophy and hypometabolism often accompanies the semantic variant of PPA, as in this case. In contrast, dominant frontal lobe atrophy and hypometabolism may accompany progressive nonfluent aphasia. Lastly, atrophy to the dominant posterior temporal cortex and inferior parietal lobule may be present in the logopenic variant.

Frontotemporal dementia subtypes have different clinical presentations and share different underlying histopathologies including tau (50%), TDP-43 (40%), FUS (Fused in Sarcoma – an RNA-binding protein; 5% to 10%) and dementia lacking distinctive histology (DLDH; 5%). In general, the semantic variant has been associated with TAR DNA-binding protein of about 43 kDa (TDP-43), which is the main ubiquitinated peptide in tau-negative frontotemporal lobar degeneration. Logopenic forms have been associated with neurofibrillary tangles and beta amyloid plaques (eg, Alzheimer disease) whereas progressive nonfluent aphasia has been associated with tau protein inclusions (eg, frontotemporal dementia and corticobasal ganglionic degeneration).

3. Treatment

There is no known effective treatment for PPA. Acetylcholinesterase inhibitors and NMDA receptor antagonists have been used, but are not clinically proven. Because of a higher risk of concomitant depression, this possibility should be considered and if present addressed. Similarly, behavioral issues may need to be addressed.

Parkinsonian dementia syndromes

• Primary degenerative syndromes:

  • Sporadic or inherited

    •  Synucleinopathies:

      • Dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and multisystem atrophy (MSA)

    • Tauopathies:

      • Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and familial FTD

• Secondary parkinsonian syndromes, attributable to a variety of cerebral insults including drug-induced cognitive-motor syndromes. 

• Intermediate (and less common) category of disorders that feature extrapyramidal dysfunction and associated cognitive alterations includes systemic metabolic derangements involving the excess accumulation of heavy metals or minerals in basal ganglia structures.

DEMENTIAL WITH LEWY BODIES:  DLB is distinct from AD and PD, but substantial clinical and pathological overlap with both AD and PD is recognized.

Part of Parkinson dementia syndromes.

McKeith Criteria:

CORE FEATURES

• Fluctuating cognition:  Variable timing of altered level of attention or arousal; distinct from sundowning seen in 60%-80%

• Visual hallucinations: Recurrent; typically involve animate subjects; variable degree of insight; reminiscent of anticholinergic delirium seen in 50%-75%

• Parkinsonian motor signs: Spontaneous parkinsonism, PIGD; rigidity and bradykinesia most common; intention tremor more common than resting tremor seen in 80% - 90%

SUGGESTIVE FEATURES

• REM sleep behavior disorder:  Loss of atonia during REM sleep; individuals appear to act out dreams; may be combative or violent in 25%-50%

• Neuroleptic sensitivity:  Severe cognitive and motor adverse reaction to antipsychotic agents; may increase mortality in 50%

• Decreased tracer uptake: 

  • In basal ganglia on SPECT dopamine transporter imaging denoting reduced striatal dopamine transported activity.

  • On MIBG myocardial scintigraphy (postganglionic sympathetic terminals)

SUPPORTIVE FEATURES (COMMON BUT LACKING DIAGNOSTIC SPECIFICITY)

• Repeated falls and syncope

• Transient unexplained loss of consciousness

• Systematized delusions

• Hallucinations in other modalities

• Relative preservation of medial temporal lobe on CT or MRI scan

• Decreased tracer uptake on SPECT or PET imaging in occipital regions

• Prominent slow-wave activity on EEG with temporal lobe transient sharp waves

REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. When any of these are present with one of the primary findings of visual hallucinations, parkinsonism, or fluctuating attention, then the diagnosis of probable DLB is supported.

Pertinent h/o DLB:

Hallucinations, delusions, and fluctuations, which can also predate the onset of cognitive decline, point to DLB

• • Does the patient have good days and bad days?

  • What can't the patient do specifically on bad days?

  • Visual hallucinations?

  • Act out dreams at night (REM sleep d/o)

  • Any changes of personality and behavior that is concerning:

    • Reckless driving

    • Poor table manners

    • Ritualistic and do things repetitively?

  • DLB is defined as cognitive or neuropsychiatric features like visual hallucination antedating Parkinsonian features..  

  • If motor signs appear more than 1 year before cognitive or neuropsychiatric symptoms, patients are typically diagnosed with PDD.

• H/o multiple sex partners, IDU ---> HIV, Hepatitis, CNS infection. TB exposure.

• Dopaminergic agents commonly used to treat motor dysfunction may provoke or exacerbate psychosis. 

• Antipsychotic agents may induce or worsen motor disability. Careful questioning regarding the relative temporal onset of various signs and symptoms and their possible relationship to medication adjustment is important.  The complex interplay of disease effects and treatment side effects often poses an ongoing challenge in the management of DLB.

• Dysautonomia is usually seen later in the disease course, although some cases with dysautonomia at initial presentation have been reported, as well as frequent falls, dysphagia, and urinary incontinence. 

• A rapidly progressive course with aphasia, dyspraxia, and severe visuospatial disturbances can be seen. 

• Some DLB patients progress to end stages and death within 1 to 2 years 

• Treatment: 

  • Rivastigmine inhibits acetylcholinesterase and thus augments cholinergic activity and can lessen fluctuations in sensorium and hallucinations in DLB that is a cholinergic-deficient state. 

  • Patients with DLB are often pathologically sensitive to standard neuroleptics which can cause severe parkinsonism and neuroleptic malignant syndrome. This is an absolute contraindication.

  • Over-the-counter antihistamine and prescription anticholinergic agents should be avoided. 

  • Memantine has not been shown to be beneficial for this indication.

  • In most cases the symptoms of the parkinsonian syndrome (akinesia, rigidity, tremor) can be improved by levodopa and 300 mg/d is the maximal dose because of psychiatric side effects.

  • While neuroleptic sensitivity has been reported with the use of both typical and atypical antipsychotic medications, visual hallucinations and delusions can be improved by therapy with atypical neuroleptics (clozapine, risperidone, quetiapine). 

    • Clozapine seems to be the drug of first choice. Doses of 3 x 12.5 up to 3 x 50 mg/d can be used. Rarely atypical neuroleptics worsen parkinsonian symptoms and state of consciousness. Decreases in neuroleptic sensitivity can often be achieved by dose reductions, although neuroleptic discontinuation is sometimes necessary. 

    • Haloperidol is a typical antipsychotic with a higher risk of neurologic worsening. 

PSP: (Steele-Richardson-Olszewski syndrome). Type of Parkinsonian Dementia

Early postural instability and falls, vertical supranuclear palsy with downgaze paresis, and akinetic-rigid symmetrical parkinsonism are the most common clinical features.

• Rest tremor is not a prominent feature

• Axial (neck and trunk) rigidity, retrocollis, more than limb rigidity

• Severe dysarthria and dysphagia as a result of the supranuclear palsy

• Gait and balance impairment

• Limitation in voluntary downward gaze that can be overcome with the doll’s eyes head maneuver (“supranuclear” gaze palsy).

• Apathy, dysphoria, and anxiety are common neuropsychiatric concomitants of PSP.

  • Pathological laughing and crying (pseudobulbar affect) frequently are present and have to be distinguished from a primary mood disturbance.

  • MRI:  

    • Humming-bird sign (atrophy of mid-brain tegmentum).

  • 3rd ventricle enlargement, signal increase in the midbrain and inferior olives. 

  • Mild to moderate frontal and temporal cortical atrophy can be seen in PSP

• Neuropathology of progressive supranuclear palsy (PSP). 

  • At autopsy, globoid neurofibrillary tangles are characteristically found in substantia nigra, brainstem tegmentum, putamen, and select cortical areas. These are immunoreactive for tau. Also seen are tau-positive astrocytic inclusions, so called tufted astrocytes. Tufted astrocytes are almost exclusively seen in progressive supranuclear palsy (PSP) and can be found in striatum, thalamus, subthalamic nucleus and precentral gyrus and are rare to absent in a similar disorder, corticobasal degeneration.

National Institute of Neurological Disorders and Stroke Clinical Criteria for Progressive Supranuclear Palsy

Probable Progressive Supranuclear Palsy

a. Gradually progressive disorder

b. Onset at age of 40 years or older 

c. Vertical (upward or downward) gaze ophthalmoparesis and marked postural instability and falls in the first year of symptom

onset.

Possible Progressive Supranuclear Palsy

a. Gradually progressive disorder

b. Onset at age of 40 years or older

c. Either vertical supranuclear ophthalmoparesis or slowing of vertical saccades, plus marked instability and falls within 1 year

of symptom onset

Tx: 

• Symptomatic pharmacological therapy of PSP is very limited. 

• Transient improvement in motor function has been observed with l-dopa and other dopaminergic agonists, but the adverse effects (i.e., orthostatic hypotension, psychosis) often outweigh the benefits. 

• No significant improvement with AChEI, donepezil.

• Depression, anxiety, and pseudobulbar affect may respond to SSRI agents, which generally are well tolerated.

Multisystem atrophy refers to a degenerative parkinsonian disorder with variable associated features including autonomic, cerebellar, and pyramidal tract dysfunction. 

Three clinical variants of MSA were initially recognized: (1) striatonigral degeneration, (2) Shy-Drager syndrome, and (3) olivo- pontocerebellar atrophy (OPCA). All share a common pathological substrate of α-synuclein–containing glial cytoplasmic inclusions, which are distributed variably in the cortex, subcortical regions, cerebellum, spinal cord, and dorsal root ganglia. 

Newer consensus diagnostic criteria for MSA have suggested two main types based on the predominant clinical feature: (1) MSA-parkinsonian (MSA-P) and (2) MSA-cerebellar (MSA-C). Accordingly, previously described cases of striatonigral degeneration and Shy- Drager syndrome are now classified as MSA-P, and sporadic OPCA conforms to MSA-C. 

Of importance, however, most cases of MSA have some degree of parkinsonism and autonomic dysfunction, and about half will have either cerebellar or pyramidal tract dysfunction. REM sleep behavior disorder is associated with MSA, just as with PD and DLB, suggesting that this disorder may be a common manifestation of synucleinopathies.

In MSA-P, neuronal loss typically is severe in the putamen and substantia nigra compared with PD, and the disorder generally is distinguished on clinical grounds by the absence of a resting tremor, more severe autonomic dysfunction, and evidence of pyramidal tract involvement (e.g., spasticity, presence of a Babinski sign). Cognitive functioning in MSA-P is relatively preserved, although executive deficits characteristically are observed on formal neuropsychological testing. 

In MSA-C, severe dysautonomic manifestations early in the course, such as orthostatic hypotension, impotence, urinary problems, constipation, and hyperhidrosis, also are common.  MSA-C (formerly sporadic OPCA) is distinguished primarily by the presence of dysarthria and ataxia in association with marked cerebellopontine atrophy on brain MRI. Parkinsonian motor signs and autonomic dysfunction are present to a variable degree. Impaired saccadic eye movements and vertical gaze palsy also may occur. Pathologically distinct hereditary forms of OPCA (MCA-C) due to trinucleotide repeat have been described. These have been also be classified as a hereditary spinocerebellar ataxia syndrome. Distinguishing clinical signs of hereditary forms of OPCA may include concomitant optic atrophy, retinal degeneration, neuropathic signs, or spastic paraparesis.

MSA can show several characteristic features on MRI. These include atrophy and hyperintensity of the putamen, slit-like hyperintensity of the posterolateral margin of the putamen, brainstem atrophy, hyperintensity of the middle cerebellar peduncles, and cruciform hyperintensity of the pons (the so-called hot cross bun sign). As expected MSA-C also shows significant cerebellar atrophy.

Pathologically MSA is characterized by extensive oligodendroglial α-synuclein pathology known as glial cytoplasmic inclusions. Dystrophic neurites can be found in the putamen, inferior olive, and brainstem nuclei.

Patients with MSA-P initially may respond to L-dopa, but the duration of benefit typically is short lived, and treatment in many cases is not well tolerated. Orthostatic hypotension may be particularly disabling and can be exacerbated by L-dopa and other dopaminergic drugs. Fludrocortisone (Florinef) and midodrine (Proamatine) often provide a measure of symptomatic relief.

Neuropsychiatric symptoms and signs in Dementia:

It is common, morbid, and distressing and occur in predictable clusters.

4 categories:

• 1. Agitated:  verbal or physical aggression toward self, others, or objects; verbal or physical disruptiveness; resistance to care; socially inappropriate behavior. 

  2. Depressive:  sad affect, tearfulness, low mood, guilt, low self esteem or nihilistic ideation, suicidality, vegetative features, irritability; anxious features almost always co-occur.

  3. Apathetic: lack of initiative, limited affective response, psychomotor slowing.

  4. Psychotic:  delusions, suspiciousness, persecutory ideation, misidentification, misperception, hallucinations.

The NPI as a checklist for behavioral issues:  

Are the following features present/absent?

• • Delusions

  • Hallucinations

  • Agitation/aggression

  • Depression

  • Anxiety

  • Elation

  • Apathy

  • Disinhibition

  • Irritability

  • Aberrant motor behavior

  • Sleep disturbances

  • Eating disturbances

New-onset agitation should be presumed to be related to delirium until proven otherwise; in as many as 50% of cases, delirium proves to be culprit. 

Nonpharmacological interventions should be pursued first, if it is not enough pharmacological alternatives can be considered.

• No medication for treatment of neuropsychiatric signs and symptoms in dementia is approved by USFDA, although this does not preclude clinician judgement regarding clinical necessity

• Cholinesterase inhibitors and memantine are approved by the USFDA for treatment of dementia due to AD and may mitigate neuropsychiatric signs and symptoms in dementia

• Atypical antipsychotics may be the first-line treatment for clinically significant psychosis but should be discontinued if ineffective

Modified Consensus Guideline for Treatment of Psychiatric and Behavioral Symptoms in AD:

• • Use antidementia agents first for severe symptoms

    • Cholinesterase inhibitors

    • Memantine

    • Both cholinesterase inhibitors and memantine

  • Atypical antipsychotics: first-line for psychosis with or without agitation

    • Atypical antipsychotics are less likely than typical antipsychotics (especially haloperidol) to cause or exacerbate EPS and tardive dyskinesia in patients with dementia, but not other advantages in terms of efficacy or safety have been demonstrated. 

• Haloperidol is associated with more EPS than atypical agents

• Risperidone, olanzapine, and aripiprazole have increased risk of CVAEs

No first-line recommendation for agitation without psychosis:  consider antipsychotic alone or with another agent, or another agent alone

• • Mood stabilizers

  • Serotonergic compounds

    • Trazodone:  negative trials but positive clinical experience

    • Sertraline:  anecdotal only

    • Citalopram:  preliminary evidence for possible effect

    • Escitalopram:  only by inference

Pimavanserin effective and well tolerated in patients with Alzheimer's Disease and Parkinson's disease Psychosis

Three recently developed drugs—lecanemab (Leqembi), aducanumab (Aduhelm), and donanemab—each target a different form of amyloid plaque in the brain.

Lecanemab has been approved by the U.S. Food and Drug Administration (FDA) after a phase 3 trial found that the drug reduced markers of amyloid in early Alzheimer's disease at 18 months and slowed disease progression. The agency previously approved aducanumab under its Accelerated Approval pathway, which gives tentative clearance to drugs that have a therapeutic benefit for people with serious illnesses but whose clinical benefits may be uncertain. Results of the phase 3 trial of donanemab found that the drug significantly slowed progression at 76 weeks in people with early symptomatic Alzheimer's disease and amyloid and tau pathology.

Approval of these drugs has met with mixed response. Whether lecanemab “has a meaningful net benefit is not obvious given the data we have,” says James F. Burke, MD, professor of neurology at the Ohio State University Wexner Medical Center and author of an editorial in Neurology about lecanemab.

The debate is about the degree to which lecanemab slows decline and whether that decline is clinically meaningful, says David A. Wolk, MD, FAAN, director of the Alzheimer's Disease Research Center at the University of Pennsylvania. “Some argue that, despite a 25 to 35 percent slowing [of disease progression], the absolute amount is within a range that would be difficult to recognize.”

How They Work

The brain naturally makes amyloid protein, but in some people, the proteins start to clump together, forming plaques and putting them at risk of developing memory loss and Alzheimer's, says Erik S. Musiek, MD, PhD, endowed professor of neurology at the Knight Alzheimer Disease Research Center at the Washington University School of Medicine in St. Louis. “Lecanemab doesn't cure the disease, and it doesn't bring back memory. It slows the course,” Dr. Musiek says. “Assuming it takes an average of three to four years to progress from mild to moderate dementia, this drug could provide a year of extra time in the mild stage.”

How They Are Administered

The drugs are delivered intravenously. Lecanemab is given every two weeks, aducanumab and donanemab every four weeks. Infusions last about 45 to 60 minutes. Patients may find infusion centers in their communities; some must go to centers affiliated with large hospitals or universities, Dr. Musiek says. Additionally, they must undergo one MRI before treatment and then one before the fifth, seventh, and 14th infusions—and at one year. Over the next year, they must have more MRIs and checkups with a neurologist every six months, Dr. Musiek says. That “substantial inconvenience” is another reason Dr. Burke questions the idea of requiring people with cognitive problems to travel frequently for treatment, scans, and related appointments.

Who Is Eligible

Patients must have very mild symptoms consistent with Alzheimer's disease and meet certain criteria on cognitive tests, Dr. Musiek says. People who have other cognitive disorders, cancer, kidney issues, or other serious diseases may be ineligible. Patients who pass basic eligibility requirements must undergo biomarker testing through amyloid PET imaging or a spinal fluid test to determine if they have amyloid buildup in their brains. Medicare announced coverage for PET amyloid scans in October, but they are still expensive and infrequently used outside of academic medical centers. A new blood test is not yet widely available, Dr. Musiek adds.

How Much They Cost

The annual price of the drug is $28,200 for aducanumab and $26,500 for lecanemab, according to makers Biogen and Eisai, respectively. This does not include the cost of infusion, initial eligibility testing, or safety monitoring. While the Centers for Medicare and Medicaid Services (CMS) will not cover aducanumab except when taken during a clinical trial, it will cover FDA-approved drugs as long as patients have mild cognitive impairment from Alzheimer's or mild Alzheimer's dementia plus amyloid consistent with the disease. CMS will require patients using lecanemab to enroll in a registry so it can gather information about how the drug works. Medicare covers 80 percent of all costs related to these drugs, and supplemental plans may cover some of the rest. Medicare Advantage plans and many other insurance companies may offer coverage of lecanemab, but the details are still evolving, says Dr. Musiek. For Dr. Burke, the cost is an astronomical problem. “If the drug's entire target population were treated, the aggregate medication expenditures would be $120 billion per year,” he and his colleagues wrote.

Possible Side Effects

Brain swelling, small brain bleeds, headache, and falls are some of the reported side effects of aducanumab. In the donanemab clinical trial, side effects included infusion-related reactions, hypersensitivity, anaphylactic reactions, microhemorrhages, and amyloid-related imaging abnormalities (ARIA), which can result in temporary brain swelling and small bleeds in or on the brain. Three patients who took donanemab had serious ARIA and died. Lecanemab side effects include headache, infusion-related reactions, ARIA, and potentially fatal intracerebral hemorrhages. These risks are concerning, Dr. Wolk says, but “the vast majority of these cases are asymptomatic and reversible when symptomatic.” People with the APOE4 gene—a strong risk factor for Alzheimer's—are more likely to have ARIA accompanied by swelling, small or large brain hemorrhages, or long-term, chronic slow bleeding in the brain. People on blood thinners are eligible for these drugs, Dr. Musiek says, but they should know the risk.